The IPTA Nashville Consensus Conference on Post‐Transplant lymphoproliferative disorders after solid organ transplantation in children: III – Consensus guidelines for Epstein‐Barr virus load and other biomarker monitoring

Abstract

The International Pediatric Transplant Association convened an expert consensus conference to assess current evidence and develop recommendations for various aspects of care relating to post‐transplant lymphoproliferative disorders after solid organ transplantation in children. In this report from the Viral Load and Biomarker Monitoring Working Group, we reviewed the existing literature regarding the role of Epstein‐Barr viral load and other biomarkers in peripheral blood for predicting the development of PTLD, for PTLD diagnosis, and for monitoring of response to treatment. Key recommendations from the group highlighted the strong recommendation for use of the term EBV DNAemia instead of “viremia” to describe EBV DNA levels in peripheral blood as well as concerns with comparison of EBV DNAemia measurement results performed at different institutions even when tests are calibrated using the WHO international standard. The working group concluded that either whole blood or plasma could be used as matrices for EBV DNA measurement; optimal specimen type may be clinical context dependent. Whole blood testing has some advantages for surveillance to inform pre‐emptive interventions while plasma testing may be preferred in the setting of clinical symptoms and treatment monitoring. However, EBV DNAemia testing alone was not recommended for PTLD diagnosis. Quantitative EBV DNAemia surveillance to identify patients at risk for PTLD and to inform pre‐emptive interventions in patients who are EBV seronegative pre‐transplant was recommended. In contrast, with the exception of intestinal transplant recipients or those with recent primary EBV infection prior to SOT, surveillance was not recommended in pediatric SOT recipients EBV seropositive pre‐transplant. Implications of viral load kinetic parameters including peak load and viral set point on pre‐emptive PTLD prevention monitoring algorithms were discussed. Use of additional markers, including measurements of EBV specific cell mediated immunity was discussed but not recommended though the importance of obtaining additional data from prospective multicenter studies was highlighted as a key research priority.

Post‐transplant lymphoproliferative disorder in pediatric liver transplant recipients: Experience from a South African transplant center

“…The precise pathophysiology of the relationship between CMV and PTLD PLT recipients is unknown and needs to be further interrogated. 25 Most patients (82%) in our cohort had gastrointestinal (extranodal) involvement. This may explain why low albumin levels, at a cut-off threshold of 21 g/dL implying protein-losing enteropathy secondary to gastrointestinal involvement, were significantly associated with developing PTLD.…”

Chronic Epstein-Barr viral load carriage after pediatric organ transplantation

“…Observations from HIV-infected patients and otherwise healthy individuals with EBV infection suggest the presence of viral set-points (some low and some high) for each EBV-infected patient. The set-point for a given patient is thought to reflect the physiologic host-virus equilibrium state in that individual, and once established it appears to be stable for years, at least in the HIV population ( 2 ). A wide range of set points occur, from very low load levels that are below the detection limit with available NAAT assays to very high as seen in some patients with HIV ( 2 ) and other immunosuppressed patients including SOT recipients and the presence of the CHL carrier state is associated with a high viral load set point compared to low or no load.…”

“…Measurement of EBV loads in the peripheral blood was introduced into clinical care of SOT recipients in the 1990s. Longitudinal observations in these patients have shown that a high EBV load in the peripheral blood is sensitive but not specific for the presence of EBV disease including PTLD (EBV/PTLD) ( 2 ). While a high level of EBV DNAemia is typically present in SOT recipients with EBV/PTLD, not all patients with high EBV loads develop disease.…”

“…While a high level of EBV DNAemia is typically present in SOT recipients with EBV/PTLD, not all patients with high EBV loads develop disease. The meaning of a given EBV load must be interpreted based on local experience with individual assays given variations in NAAT performance between centers as well as differences attributable to which blood compartment is being measured (e.g., whole blood, plasma) ( 2 ). Despite these limitations, the use of sequential surveillance measurement of EBV loads in pediatric SOT recipients has been associated with declining rates of EBV/PTLD, and EBV monitoring is now recommended for SOT recipients at risk for EBV/PTLD ( 3 ).…”

Epstein–Barr virus‐associated post‐transplant lymphoproliferative disorders in pediatric transplantation: A prospective multicenter study in the United States

“…1 EBV+ PTLD is more common in children and tends to develop earlier post-transplant than in adults. 9,13 Although the consensus guidelines for EBV viral load and other biomarker monitoring for PTLD after solid organ transplantation have recently been published, 24 it remains essential to continue to accumulate evidence, especially for early detection of aggressive PTLD in pediatric recipients, who are frequently EBV-naïve at the time of transplant.…”