Regional Variations and Risk Factors for Post-Transplant Lymphoproliferative Disorder in Pediatric Solid Organ Transplant Recipients: A Nationwide Study

Post-transplant lymphoproliferative disorder (PTLD) is a severe complication of organ transplantation and is most often associated with the Epstein-Barr virus (EBV). The prevalence of PTLD varies widely depending on several factors, including transplant type, intensity of the immunosuppressive therapy (IST), and EBV status before transplantation. Children are especially at risk, given frequent EBV seronegativity at the time of transplant, due to their relatively young age and lack of prior EBV exposure. Studies examining the regional differences in pediatric PTLD rates are lacking, as most studies and reviews focus on overall incidence rates and risk factors. However, it is well understood that PTLD rates are variable across transplant populations due to different IST maintenance requirements, with more aggressive regimens at the highest risk for the development of PTLD. In addition, the number and combinations of immunosuppressive medications used are vast and often personalized to individual patient needs. Whether these practices are region-specific and driving PTLD prevalence has yet to be documented.

This study was conducted in solid organ transplant recipients ages 0-21 diagnosed with PTLD using a nationwide administrative database of free-standing children’s hospitals in the United States – the Pediatric Health Information System (PHIS), from 10/1/2015-12/31/2023. PTLD diagnosis was captured up to 5 years from the first solid organ transplant date. This study aimed to describe the prevalence of PTLD across the US in various transplant populations, regions, and age groups and describe the use of Rituximab, a monoclonal antibody with excellent efficacy against B cell-driven EBV viremia and PTLD, in the first two years following transplant. Diagnostic and pharmaceutical billing codes were used to identify patients with PTLD, and potential clinical and demographic characteristics were collected. Chi-square tests were used to test for associations between PTLD and clinical and demographic characteristics.

We identified 6,788 unique patients who received a solid organ transplant within our study period. Our cohort was 57% male, 49% non-Hispanic White, and 24% Hispanic, and the median age at transplant was 11.6 years. Transplant types comprised 52% kidney, 42% heart, 3% lung, and 3% multiple organ transplants. A PTLD diagnosis within five years post-transplant was observed in 4.4% of patients (n=297). The highest prevalence of PTLD occurred among those aged <1 year (6.5%) and 1-5 years (6.2%), consistent with known data that children <5 years of age are at the highest risk for developing PTLD. In this PHIS cohort, PTLD was associated with the region (p<.001) and transplant type (p<.001), with PTLD observed most frequently in the Midwest (6.4%). The heart transplant population was observed to have the highest prevalence (6.3%), followed by lung (5.0%) and kidney transplants (2.9%). For those without a PTLD diagnosis, Rituximab use within the two years following transplantation was significantly associated with transplant type (p=.003); it was noted most frequently in the lung transplant population (17.1%), followed by heart (13.5%) and kidney (11.3%).

Despite requiring more aggressive IST regimens in lung transplantation, the highest PTLD prevalence rates did not occur in this population in our cohort. It was also noted that Rituximab use without a PTLD diagnosis occurred most frequently in this population when compared to other transplant types. This finding suggests a trend for prophylactic use of Rituximab for presumed EBV viremia in lung transplant recipients. Unfortunately, laboratory values are not a data element captured in the PHIS database, and therefore, the presence and quantification of EBV viremia that triggered Rituximab use cannot be elucidated. Confirmatory steps utilizing other clinical databases are needed to tease out this association further and determine if this lower PTLD prevalence rate is connected to this practice trend.