Identification of early antigen BZLF1/ZEBRA protein of Epstein–Barr virus can predict the effectiveness of antiviral treatment in patients with post‐transplant lymphoproliferative disease

Abstract

Summary. Epstein–Barr virus (EBV)‐associated B‐cell lymphoproliferations may arise in solid organ transplant recipients. In these patients, an insufficient control of EBV‐infected B cells commonly occurs. Antiviral treatment against EBV may represent a causal, relatively low‐toxic treatment option. Treatment with foscarnet, an inhibitor of viral‐DNA polymerase, in three patients with EBV‐associated post‐transplant lymphoproliferative disease (PTLD) after heart (n = 2) and heart/kidney transplantation (n = 1), who did not respond to, or were not eligible for reduction of immunosuppression, resulted in complete remission (48+, 27 and 15 months respectively). Response of PTLD to antiviral treatment correlated with the expression of lytic phase antigen BZLF1/ZEBRA protein, an early antigen of lytic EBV‐activity, in the biopsied PTLD specimens.

Efficiency of antiviral therapy plus IVIG in a case of primary EBV infection associated PTLD refractory to rituximab, chemotherapy, and antiviral therapy alone

“…2). On the basis of previous experience of antiviral therapy in ZEBRA-positive PTLD [2], antiviral therapy with cidofovir was commenced.…”

“…For patients that do not respond to a reduction of immunosuppression, many will go on with rituximab monotherapy [3][4][5] and/or CHOP-like chemotherapy [1]. However, early treatment algorithms for PTLD also included antiviral therapy in an attempt to control EBV infection [6][7][8] and polymorphic and monomorphic PTLD with expression of ZEBRA-an early marker of EBV's lytic replication-do respond to foscarnet [2]. Thus, immunologic and antiviral therapy may be moderately successful for treating EBV-associated PTLD especially PTLDs with a significant lytic replication of EBV, which may have been a critical point to success in the patient described.…”

In vivo intratumoral Epstein–Barr virus replication is associated with XBP1 activation and early-onset post-transplant lymphoproliferative disorders with prognostic implications

“…Thus, the effect of antiviral therapies is very controversial probably due to not considering the amount of intratumoral viral load and the EBV replication stage in the decision to treat a patient. 18 In this study, we analyzed for the first time the role of both latent and lytic intratumoral EBV infection programs in a series of primary samples of post-transplant lymphoproliferative disorders, as well as the importance of plasma cell differentiation through the study of XBP1 in this group of patients.…”

“…4,9,[18][19][20] However, the decision to treat and the type of therapy a patient receives largely rely only on clinical features such as: current dosing, type of allograft, history of rejection, or infections. Thus, the effect of antiviral therapies is very controversial probably due to not considering the amount of intratumoral viral load and the EBV replication stage in the decision to treat a patient.…”

“…14,18 Both the growth-transforming and the replication programs are highly immunogenic stages of EBV infection that may be only tolerated in deeply immunosuppressed individuals. A systematic study of these different EBV latent and lytic programs in tumor cells has not been performed yet in patients with post-transplant lymphomas.…”