Persistent Epstein-Barr virus infection: unrestricted latent and lytic viral gene expression in healthy immunosuppressed transplant recipients.

BACKGROUND: Posttransplant lymphoproliferative disease (PTLD) is a common Epstein-Barr virus (EBV)-associated complication of transplantation which, despite treatment, is often fatal. This study was undertaken to monitor persistent EBV infection in transplant recipients, to compare EBV load and gene expression in healthy individuals and EBV-associated diseases, and to highlight differences in PTLD that could be used to define those at risk of the disease. METHODS: A cohort of 96 cardiothoracic transplant recipients was monitored posttransplant for up to 1110 days (median 268 days). Levels of EBV DNA and viral mRNA transcripts in peripheral blood mononuclear cells (PBMs) were measured at regular intervals and compared with those found in healthy individuals, infectious mononucleosis (IM) patients, and 12 PTLD patients bled at the time of diagnosis. Overall posttransplant levels were significantly higher than pretransplant and healthy subjects, and correlate with dose of immunosuppression. EBV DNA levels in both IM and PTLD were significantly higher than in healthy recipients, with the highest levels in PTLD patients. Individual measurements in 12 healthy transplant recipients reached levels seen in PTLD, and thus single estimations are not of predictive significance for PTLD development. RESULTS: Analysis of viral gene expression in peripheral blood mononuclear cells showed a restricted (LMP 2 only) pattern in healthy subjects, and an unrestricted (latency 3) pattern with lytic replication in 14% of IM blood and 45% of cases of PTLD. A total of 55% of healthy transplant recipients had additional transcripts in one or more blood samples, and this finding correlated with high viral load. Analysis of the 12 samples from healthy recipients with viral loads equivalent to those seen in PTLD showed additional transcripts in all cases and latency 3 with lytic replication in 33%. Thus, an isolated finding of high viral load and/or unrestricted latent and lytic gene expression is not indicative of PTLD.

Immunodeficiency-related lymphoproliferative disorders: prospective data from the United Kingdom Children's Cancer Study Group Registry.

Clinical data and biological samples were prospectively collected in 42 children with lymphoproliferative disease (LPD) secondary to organ/bone marrow transplant-related immunosuppression (30: 11 liver, 10 heart/lung, 8 kidney and 1 bone marrow), other drug-induced immunosuppression (2), congenital immunodeficiency (8) or human immunodeficiency virus (HIV)-related immune dysfunction (2). Ages ranged from 10 months to 17 years and there were 15 girls. Pathology was centrally reviewed and showed polymorphic features in 5 cases, monomorphic in 23, mixed pattern in 5 patients and 9 other types. Using the Revised European-American Classification of Lymphoid Neoplasms, 5 were B lymphoblastoid, 24 were high-grade B and 14 were other subtypes. Using the Pittsburgh classification, 9 were lymphadenopathic, 10 were systemic, 25 were lymphomatous and, with the Murphy grouping for non-Hodgkin's lymphoma (NHL), 10 were localized and 32 non-localized. Twenty-four out of 38 evaluable cases were Epstein-Barr virus positive. Thirty-five patients were evaluable for clonality; 24 were monoclonal and 11 were polyclonal. Reduced immunosuppression in solid organ transplant patients resulted in resolution of disease in 14/24, which was sustained in 11. Nineteen patients received chemotherapy, 14/18 evaluable responded, which was sustained in 8 cases. Seven out of 29 solid organ transplant and 10/13 other immune-deficient patients died. In the largest group of patients, solid organ transplants, no significant clinical or biological characteristics that predicted outcome were identified. In the transplant group close monitoring of response during reduction in immunosuppression is essential and the early use of B NHL chemotherapy may be effective.