The diagnostic value of soluble Epstein-Barr Virus BZLF1 protein (sZEBRA) in the Detection of Post-transplant lymphoproliferative Disease (PTLD) among Solid Organ (SOT) and Haematopoietic Cell (HSCT) Transplant Recipients

Background Post-transplant lymphoproliferative disorder (PTLD) is a serious complication of solid organ transplant (SOT) and hematopoietic stem cell transplant (HSCT) recipients and is often associated with Epstein-Barr virus (EBV) reactivation. The sZEBRA protein, a soluble form of the EBV nuclear Immediate-early antigen BZLF1 (also called Zta), plays a crucial role in EBV reactivation and immune evasion. This study aimed to externally validate an association between sZEBRA and the diagnosis of PTLD. Methods In this retrospective case-control study, the relative odds of having PTLD according to sZEBRA plasma levels at diagnosis of PTLD and comparable follow-up for controls was analyzed using logistic regression adjusting for demographics, transplant information and sample timing. The model was further also adjusted for corresponding EBV PCR plasma levels. Levels of sZEBRA was fitted in the model either as present/absent or in quartiles. Results 33 (17%) PTLD cases and 161 (83%) controls were included. The adjusted odds ratio (aOR) of a positive versus negative sZEBRA test for PTLD diagnosis was 2.82 (95% CI 1.37-7.68); after additional adjustment for EBV PCR levels, the aOR was 4.15 (95% CI 1.31-13.14). Separating sZEBRA levels into quartiles, aOR of sZEBRA in the 4th quartile was 12.43 (95% CI 1.99–77.55) compared to a negative result in the fully adjusted model. Conclusion Elevated sZEBRA levels, especially those in the highest quartile and when combined with EBV PCR, were associated with PTLD and may serve as a complementary biomarker to EBV PCR to identify patients with PTLD.