Long-term follow-up of kidney transplant patients with posttransplant lymphoproliferative disorder: duration of posttransplant lymphoproliferative disorder-induced operational graft tolerance,interleukin-18 course,and results of retransplantation

BACKGROUND: Posttransplant lymphoproliferative disorder (PTLD) can be resolved in many transplant patients by the reduction or cessation of immunosuppression, after which many grafts continue to function as the result of a form of operational tolerance. When graft function deteriorates, retransplantation may be an option. Cytokines such as interleukin (IL)-10 and IL-18 may play a role in PTLD tolerance induction and tumor regression. We report long-term follow-up on the duration of graft tolerance and the course of retransplantation in a series of patients who underwent kidney transplantation and demonstrated PTLD, and in whom we were able to perform IL-18 analyses. RESULTS: Patients were followed for up to 7 years after PTLD diagnosis. Treatment consisted of immunosuppression cessation with radiation therapy in cases with overt monomorphic lymphomas. All patients' PTLDs were resolved, and all patients but one (whose graft was removed) demonstrated a period of operational graft tolerance of up to 5 years. Five patients underwent retransplantation without sign of recurrence of the PTLD up to 3 years after transplantation. In the eight patients analyzed, IL-18 increased significantly during PTLD regression and follow-up in those with long-term operational tolerance. CONCLUSION: We report on a series of patients with resolved PTLDs demonstrating long-term recurrence-free survival, of whom most experienced a long period of operational graft tolerance. IL-18 seems to play a role in the resolution of the PTLDs. Five patients underwent retransplantation with standard immunosuppression without recurrence. A previous diagnosis of PTLD should not be regarded as a contraindication for later retransplantation.     

Ratio between Epstein-Barr viral load and anti-Epstein-Barr virus specific T-cell response as a predictive marker of posttransplant lymphoproliferative disease

BACKGROUND: Posttransplant lymphoproliferative disease (PTLD) is closely linked to primary Epstein-Barr virus (EBV) infection and a defect of EBV specific cellular immunity is supposed to be the basis of PTLD. However, EBV load is so far the only marker proposed to evaluate PTLD risk, and no study has investigated the role of specific anti-EBV T lymphocytes (EBV-TL). METHODS: We therefore prospectively measured the EBV-TL by enzyme-linked immunospot (elispot) assay, in correlation to EBV load by real-time quantitative PCR and lymphoproliferation occurrence in 45 liver transplanted children. RESULTS: EBV load at the time of primary infection was high in all patients irrespective to subsequent emergence of PTLD. Seven patients developed PTLD, all of them following primary EBV infection. All seven had low EBV-TL (<2/mm3) associated with high viral load (>25,000 copies/microg DNA). Both parameters can be combined in a 100% positive predictive index. Healing from lymphoma was characterized by rapid EBV-TL increase concomitant to decreasing viral load. EBV-TL follow-up helped to adapt immunomodulation. No patient had PTLD whenever EBV-TL were above 2/mm3. CONCLUSIONS: We conclude that high viral load is systematic in patients who underwent primary EBV infection and is indicative of the PTLD risk only if there is low concomitant cellular immune response. Healing from PTLD requires modulation of immunosuppression, and appearance of EBV-TL.     

Surveillance of Epstein-Barr virus infection as a risk factor for post-transplant lymphoproliferative disorder in pediatric renal transplant recipients

Post-transplant lymphoproliferative disorder (PTLD) represents a heterogeneous group of abnormal lymphoid proliferations, generally of B-cells, that occur in the setting of ineffective T-cell function because of pharmacological immunosuppression after organ transplantation. The vast majority of PTLDs are associated with Epstein-Barr virus (EBV) infection, as manifested by the presence of EBV within the malignant tissue. Surveillance for the presence of primary or reactivated EBV infection may have the potential to prevent the development of PTLD by early intervention. However, there are, at present, no means of discriminating between innocent infectious mononucleosis syndromes and PTLD. Furthermore, standardization of measurement of EBV copies between centers is urgently required for the definition of high EBV viral load. Because of a lack of a close relationship between viral load and the occurrence of PTLD, other strategies such as the combined analysis of EBV viral load and EBV-specific T-lymphocytes may be better to assess the risk for the development of PTLD. Whereas the mainstay of therapy for overt PTLD is reduction of immunosuppression, such reduction based solely on a high EBV viral load without clinical evidence for PTLD is not based on scientific evidence. This strategy could result in the under-immunosuppression of many transplant recipients in the absence of a real risk for PTLD, with potentially harmful consequences such as an increased rate of acute rejection episodes.     

Preventing acute rejection, Epstein-Barr virus infection, and posttransplant lymphoproliferative disorders after kidney transplantation: use of aciclovir and mycophenolate mofetil in a steroid-free immunosuppressive protocol.

BACKGROUND: A widely held view is that any increase in the potency of an immunosuppressive agent will lead to an increase in infection and malignancy, such as life-threatening Epstein-Barr virus (EBV) induced posttransplant lymphoproliferative disorders (PTLD). We tested this paradigm by studying the effect of adding mofetil to a steroid-free protocol under cover of high-dose aciclovir prophylaxis on the number of acute rejections, EBV infections and PTLDs after kidney transplantation. METHODS: EBV serology was performed in 267 consecutive renal transplantations (1990-1997). All were treated with cyclosporine with an initial 10-day antilymphocyte globulin course, supplemented from September 1995 with MMF. In 208 consecutive transplantations after June 1992 aciclovir 3200 mg/day was given for 3 months posttransplantation. RESULTS: After an observation period of up to 7 years we found that: (1) primary or reactivated EBV infection (PREBV) was correlated to acute rejection (treated with OKT3; P<0.00005) and to the incidence of PTLD (P=0.03; P=0.01, if Hodgkin's disease is included); (2) aciclovir protected against PREBV (P<0.00005) and (3) adding mofetil to the immunosuppressive protocol reduced PREBV further (P=0.0001), (4) in 78 transplantations treated with cyclosporine/antilymphocyte globulin/mofetil we observed only 10 acute rejections (P=0.0001), 10 PREBVs (P<0.00005), and no PTLDs compared with the cyclosporine/antilymphocyte globulin group (P=0.04). CONCLUSIONS: Supplemental immunosuppression with mofetil protects against acute rejection. In combination with aciclovir, there is also a reduction in the number of PREBVs, apparently as a result of both direct viral prophylaxis and better rejection control, and in the incidence of EBV-induced PTLD.     

Plasmacytoma-like posttransplant lymphoproliferative disorder following orthotopic liver transplantation: a case report

Posttransplant lymphoproliferative disorders (PTLDs) are among the most serious and potentially fatal complications of both stem-cell and solid-organ transplantation. Most monomorphic PTLDs are of B-cell origin and frequently associated with Epstein-Barr virus (EBV) infection in the setting of pharmacological immunosuppression posttransplantation. The majority of monomorphic PTLDs commonly resemble diffuse large B-cell or Burkitt's lymphoma; plasmacytoma-like PTLDs are very rare. We report a case of plasmacytoma-like PTLD arising in the allograft in a 66-year-old male diagnosed 2 months following an orthotopic liver transplant for alcohol-related end-stage liver disease. The liver biopsy revealed marked infiltration of atypical plasma cells with lambda light chain restriction and positivity for EBV by in situ hybridization confirming the diagnosis. Also noted was a remarkable increase of tissue eosinophils. Reduction of immunosuppression led to improvement in his clinical condition, and also resolution of the hepatic lesions and abdominal lymphadenopathy noted on imaging studies. While a few cases of plasmacytoma-like PTLDs have been described in literature, to our knowledge, this is the first reported case of early onset plasmacytoma-like PTLD in a liver transplant recipient occurring in the allograft with associated lymphadenopathy having distinct histopathologic features including tissue eosinophilia. Timely recognition of such an entity is critical in order to initiate early and appropriate intervention.     

Indications and results of chemotherapy in children with posttransplant lymphoproliferative disease after liver transplantation

Among 39 posttransplant lymphoproliferative diseases (PTLD) in a cohort of 450 pediatric liver transplant recipients, 3 had a malignant lymphoma, unresponsive to arrest of immunosuppression and to gancyclovir, interferon, and anti-interleukin 6 antibodies. Lymphoma appeared 20, 46, and 96 months posttransplantation and 16, 43, and 90 months after primary Epstein-Barr virus infection. In one case, the patient had histological progression from plasmacytic hyperplasia PTLD, concomitant with symptomatic primary infection, to Burkitt-like lymphoma 43 months later. These three patients received five courses of chemotherapy, after a cyclophosphamide, doxorubicin, vincristine, and prednisone regimen for Burkitt-like or LH 89 scheme for Hodgkin-like PTLDs. Chemotherapy was well tolerated, and all three were free of disease and without immunosuppression 19, 14, and 4 months after chemotherapy. In Burkitt-like or Hodgkin-like PTLDs, immunomodulatory or antiviral drugs were inefficient. Chemotherapy is indicated and can be safely and successfully used. Long-term arrest of immunosuppression seems feasible without graft rejection.     

T-cell posttransplant lymphoproliferative disorder occurring in a pediatric solid-organ transplant patient

Posttransplantation lymphoproliferative disorder (PTLD) is a serious complication seen in transplant patients as a consequence of immunosuppressant therapy. Most cases are of B-cell origin and are commonly associated with Epstein-Barr virus (EBV) infection. T-cell PTLDs are rare and only 13 pediatric T-cell PTLDs with clinicopathologic correlation have been reported previously. We present the histologic, immunophenotypic, and molecular features of a monomorphic PTLD (T-cell lymphoma) identified in a pediatric patient following orthotopic liver transplantation. The lymphoma was identified in the ileum, rectum, and mesenteric lymph nodes. In situ hybridization revealed numerous EBER-1-positive tumor cells. A current review of the literature is also discussed. Of the 14 cases of pediatric T-cell PTLD reported in the literature, only 3 (21.4%) are described as being EBV positive. Most of the reported PTLDs are monoclonal, with 9 of 11 cases (82%) showing a clonal T-cell population by gene rearrangement studies. T-cell PTLD cases appear to have a poor prognosis (11 of 14 patients died of the disease), although patients with involvement of specific anatomic sites may have a better outcome.     

Spleen-Restricted Posttransplant Lymphoproliferative Disorder in the First Year After Kidney Transplant – A Case Report

Posttransplant lymphoproliferative disorders (PTLDs) are a feared complication after transplant. They are mostly of B cell origin and are frequently Epstein-Barr virus (EBV)–positive, particularly in early onset PTLD. Later on, non-B and EBV-negative PTLD are increasingly reported. EBV seronegative receptors (particularly when paired with an EBV seropositive donor) together with the net degree of immunosuppression—a concept often difficult to quantify—are the most consistently described risk factors for the development of PTLD. Conversely, its association with a particular immunosuppressive agent or other virus, namely cytomegalovirus (CMV) infection or disease, has been inconsistently reported. We present a challenging case where an EBV negative monomorphic peripheric T-cell lymphoma was diagnosed in the first year after kidney transplant in a patient with a recent history of CMV disease from a resistant strain.     

Posttransplant lymphoproliferative disorder of the lung in a renal transplant recipient treated successfully with surgery

Posttransplant lymphoproliferative disorders (PTLDs) are a heterogeneous group of lymphoid diseases that occur after solid organ and bone marrow transplantation. Lung-located PTLD has been reported in recipients of the heart, cord blood stem cells, lungs, and bone marrow transplants, but only four cases were reported previously after kidney transplantation. Thoracic location of PTLD must be regarded as an especially dangerous complication. The pathogenesis, and clinical and histological features of PTLD remain poorly defined but predisposing risk factors are becoming better understood. Namely, Epstein-Barr virus (EBV) and immunosuppressive agents appear to be such risk factors. There has been marginal success in treating PTLD using a number of treatment modalities, including combination chemotherapy with anti-CD20 or high-dose chemotherapy with stem cell rescue. We report a renal allograft recipient transplanted in March 2000, diagnosed with EBV-associated and lung-located PTLD. His initial immunosuppression consisted of tacrolimus, azathioprine, and steroids. Azathioprine was withdrawn in September 2001. In November 2001 a high-resolution computed tomography scan revealed two round masses in the right lung. The patient underwent right thoracotomy and resection of the lower and middle lobe. The diagnosis of PTLD was settled by intraoperative histopathological evaluation. The postoperative histological assessment confirmed the diagnosis and revealed positive staining for EBV. The patient remained in complete remission for 3 years with a well-functioning renal allograft, with current serum creatinine of 1.2 mg%. This case illustrates that the treatment of lung-located PTLD may be successful, but it depends on a combination of prompt diagnosis, reduction of immunosuppression, and of course surgery.     

Posttransplant lymphoproliferative disorder after umbilical cord blood transplantation in children

Reported are 7 cases of posttransplant lymphoproliferative disorder (PTLD) arising in children who received umbilical cord blood transplantation (UCBT). There were 4 females and 3 males with a median age of 3 years (range, 1-16 years). All 7 patients received UCBT, including 1 patient who received multiple units and 1 transplanted under nonmyeloablative condition. The time interval from UCBT to PTLD averaged 4 months (range, 2 weeks to 9 months). Patients typically presented with high-stage disease with visceral organ involvement. Histology of the PTLDs showed monomorphic morphology in 5 cases and polymorphic morphology in the remaining 2 cases. Bone marrow biopsies were performed in 3 cases and were negative for PTLD. Epstein-Barr virus (EBV) was detected in the PTLD in all 7 patients by in situ hybridization. Evidence of past EBV infection was found in the recipients, but the EBV genome was not detected in the donor cord blood samples, suggesting that donor cord blood was not the source of EBV infection. The origin of the PTLD was investigated in 5 cases. PTLD was of host origin in 2 patients who failed engraftment and of donor origin in the remaining 3 patients who had complete engraftment. Four of 5 patients with monomorphic PTLD failed to demonstrate significant responses to rituximab and/or reduction of immunosuppression and died within 1 month after diagnosis. The remaining 2 patients with polymorphic PTLD showed complete response to therapy. One patient was alive 35 months after transplant, and the other patient died of infection 6 months after transplant. It is concluded that PTLD arising after UCBT in children occurs early after transplant and represents a serious EBV-related complication. PTLD may be of donor or recipient origin depending on engraftment status. Both monomorphic and polymorphic histology may be seen, and monomorphic histology appears to predict an unfavorable prognosis.     

Early posttransplant lymphoproliferative disease in pediatric liver transplant recipients

Among 23 pediatric patients who underwent orthotopic liver transplant (OLT), we report two (11 and 26 months old) with posttransplant lymphoproliferative disease (PTLD) that occurred in the early posttransplantation period. They were Epstein-Barr Virus (EBV)-negative and received graft from EBV-positive donors. The surveillance for EBV viremia using serial EBV polymerase chain reaction determinations in the peripheral blood was positive at 10 and 90 days after OLT concomitant with symptoms of primary infection, both patients were treated with gancyclovir. The patients should progression to a Burkitt's and a non-Hodgkin's lymphoma that appeared 3 months posttransplantation. They were treated by withdrawal of immunosuppression and six courses of cyclophosphamide as well as anti-CD20 monoclonal antibody (Rituximab) every 21 days. One patient experienced acute graft rejection, which resolved with steroids and low doses of tacrolimus, she is free of disease at 24 months after the end of treatment. The other patient relapsed with a cerebral lymphoma, receiving aggressive chemotherapy, but died due to sepsis. In conclusion, PTLD occurred among in 2/23 patients who underwent OLT and appeared in the first quarter post OLT. The risk factors associated with early PTLD were primary EBV infection after OLT, young age, and EBV-negative recipient receiving a transplant from an EBV-positive donor. Antiviral treatment alone was inefficient; withdrawal of immunosuppression and courses of Rituximab and cyclophosphamide were well tolerated and controlled PTLD. The risk of graft rejection was increased by withdrawal of immunosuppression. One patient died.     

Epstein-Barr virus-negative post-transplant lymphoproliferative disorders: a distinct entity?

Post-transplant lymphoproliferative disorders (PTLDs) are usually but not invariably associated with Epstein-Barr virus (EBV). The reported incidence, however, of EBV-negative PTLDs varies widely, and it is uncertain whether they should be considered analogous to EBV-positive PTLDs and whether they have any distinctive features. Therefore, the EBV status of 133 PTLDs from 80 patients was determined using EBV-encoded small ribonucleic acid (EBER) in situ hybridization stains with or without Southern blot EBV terminal repeat analysis. The morphologic, immunophenotypic, genotypic, and clinical features of the EBV-negative PTLDs were reviewed, and selected features were compared with EBV-positive cases. Twenty-one percent of patients had at least one EBV-negative PTLD (14% of biopsies). The initial EBV-negative PTLDs occurred a median of 50 months post-transplantation compared with 10 months for EBV-positive cases. Although only 2% of PTLDs from before 1991 were EBV negative, 23% of subsequent PTLDs were EBV negative (p <0.001). Of the EBV-negative PTLDs, 67% were of monomorphic type (M-PTLD) compared with 42% of EBV-positive cases (p <0.05). The other EBV-negative PTLDs were of infectious mononucleosis-like, plasma cell-rich (n = 2), small B-cell lymphoid neoplasm, large granular lymphocyte disorder (n = 4) and polymorphic (P) types. B-cell clonality was established in 14 specimens and T-cell clonality was established in three (two patients). None of the remaining specimens were studied with Southern blot analysis and some had no ancillary studies. Rearrangement of c-MYC was identified in two M-PTLDs with small noncleaved-like features, and rearrangement of BCL-2 was found in one large noncleaved-like M-PTLD. Ten patients were alive at 3 to 63 months (only three patients received chemotherapy). Seven patients, all with M-PTLDs, are dead at 0.3 to 6 months. Therefore, EBV-negative PTLDs have distinct features, but some do respond to decreased immunosuppression, similar to EBV-positive cases, suggesting that EBV positivity should not be an absolute criterion for the diagnosis of a PTLD.     

Evidence for genetic susceptibility towards development of posttransplant lymphoproliferative disorder in solid organ recipients

BACKGROUND: Posttransplant lymphoproliferative disorder (PTLD) is a life-threatening complication after organ transplantation. The identification of risk factors for PTLD development is important for disease management. It has been shown that cytokine gene polymorphisms are associated with lymphoma and Epstein-Barr virus (EBV)-associated diseases in nonimmunosuppressed patients. In the present case-control study, we analyzed the impact of -1082 interleukin (IL)-10, -308 tumor necrosis factor (TNF)-alpha, transforming growth factor (TGF)-beta1 (codon 10, 25), and +874 interferon (IFN)-gamma gene single-nucleotide polymorphisms on the late onset EBV-associated PTLD. METHODS: Out of 1,765 solid organ recipients, 38 patients with late-onset EBV-associated PTLD and 408 matched solid organ recipients were selected and enrolled in the study. Single nucleotide polymorphisms (SNPs) for -1082IL-10, -308TNF-alpha, TGF-beta1 (codon 10, 25), and +874IFN-gamma genes were analyzed by a sequence specific primer polymerase chain reaction and were related to the PTLD development, and the disease course and outcome. RESULTS: The TGF-beta1 (codon 25) GG genotype was detected more frequently in controls than in PTLD patients (odds ratio=0.34, 95% confidence interval: 0.17-0.69, P=0.0022). The frequency of -1082 IL-10 GG genotype was also significantly higher in controls than in PTLD patients (odds ratio=0.5, 95% confidence interval: 0.25-1.0, P=0.044). There were no associations between -308TNF-alpha, TGF-beta1 codon 10, and +874IFN-gamma SNPs and PTLD. Disease course and outcome were not associated with any cytokine SNPs. CONCLUSIONS: Polymorphisms in two key anti-inflammatory cytokines, IL-10 and TGF-beta, are associated with susceptibility to EBV-associated PTLD, suggesting that a shift in pro-/anti-inflammatory response is involved in the pathogenesis of PTLD.     

Posttransplant lymphoproliferative disorder following nonmyeloablative allogeneic stem cell transplantation

Posttransplantation lymphoproliferative disorder (PTLD) is a well-recognized complication of conventional bone marrow/stem cell and solid organ transplantation. However, not much is known about PTLD following the more recently introduced nonmyeloablative allogeneic stem cell transplantation (NMST). This study reports the findings from two cases of PTLD following NMST and compares them to the one previously reported case. The donor origin of the PTLD was determined using short tandem repeat analysis, and B- and T-cell clonalities were evaluated by polymerase chain reaction. Two cases of PTLD evolved in a total of 70 patients who have undergone NMST at our institution from 1999 to 2003. Both patients received conditioning with Fludarabine/Cytoxan/Campath 1H (alemtuzumab, anti-CD52 antibody) and T-cell-depleted donor cells with Campath-1H. Both PTLDs were EBV positive (by immunohistochemistry and in situ hybridization) with diffuse large B-cell lymphoma morphology. Our findings indicate the incidence of PTLD following NMST is 3% (2 of 70 patients from our institution and 1 of 30 from the previously reported case). All three PTLDs arose 6 to 7 months after NMST and were rapidly fatal. The pathology of the PTLD in all cases was donor origin, EBV positive, diffuse large B-cell lymphoma.     

Posttransplant lymphoproliferative disorders after liver transplantation: analysis of early and late cases in a 255 patient series

We reviewed the incidence and the impact of posttransplant lymphoproliferative disorders (PTLDs) on patient survival among a consecutive series of 255 patients. Five cases of PTLD were observed in adults: two cases were early (less than 1 year) and three cases, late lymphomas. The EBV positivity and the degree of immunosuppression were the main risk factors. We labeled cases as early or late according to whether the time elapsed from the transplant to the first clinical evidence of PTLD was less than 12 months. The median time from transplant to diagnosis of PTLD was 8 (early) and 108 (late) months. All cases were treated by reduction in immunosuppressive therapy with conventional chemotherapy and rituximab. The early cases with lymphoma located at the hepatic hilum died due to local complications (biliary sepsis and hemobilia), after an initial partial response to chemotherapy. The three patients with late cases are in remission after a mean follow-up of 23 months.     

A quantitative assay for Epstein-Barr Virus-specific immunity shows interferon-gamma producing CD8+ T cells increase during immunosuppression reduction to treat posttransplant lymphoproliferative disease

Reduction of immunosuppression (RIS) to allow development or recovery of Epstein-Barr virus (EBV) immunity can be used to treat EBV-associated posttransplant lymphoproliferative disease (PTLD). Quantification of EBV-specific immunity would help assessment of the efficacy of RIS therapy. Use of intracellular cytokine staining and analysis by flow cytometry to monitor functional EBV-specific T-cell immunity was evaluated in healthy volunteers. The technique was then used to monitor EBV immunity in nine renal transplant patients with PTLD during RIS. The number of interferon (IFN)-gamma producing CD8+ T cells specific for EBV increased distinctly before regression of EBV+ PTLD tumors occurred. The findings confirm the importance of IFN-gamma producing CD8+ T cells in controlling the malignant EBV-transformed B cells of PTLD. The assay effectively quantified EBV immunity during RIS in transplant patients with PTLD.     

Metachronous EBV-associated B-cell and T-cell posttransplant lymphoproliferative disorders in a heart transplant recipient

Posttransplant lymphoproliferative disorders (PTLDs) may occur as a complication of immunosuppression in patients who have received solid organ or bone marrow allografts. Most PTLDs are of B-cell lineage, whereas T-cell proliferations are rare. The majority of B-cell lesions are associated with Epstein-Barr virus infection. The occurrence of both B-cell and T-cell PTLDs in the same patient is extremely rare and only 6 cases have been previously published. We report a case of a 63-year-old man who developed 2 metachronous Epstein-Barr virus-related PTLDs beginning 10 years after heart transplantation. A polymorphic B-cell PTLD developed first that completely regressed after immunosuppressive therapy was partially withdrawn. Then, a monomorphic T-cell PTLD developed 31 months later. The patient died 17 months later owing to disease progression. We highlight the diagnostic challenge of this case that required numerous ancillary studies for lineage assessment and classification. Such studies are often needed in patients with a history of immunosuppression.     

Posttransplant lymphoproliferative disorders in liver transplanted patients: a report of four cases

BACKGROUND: Posttransplant lymphoproliferative disorders (PTLDs) are an uncommon but important cause of morbidity and mortality in solid organ transplant recipients. They are often the result of Epstein-Barr virus (EBV)-induced proliferation of B-lymphocytes in the setting of immunosuppression. PATIENTS AND METHODS: We retrospectively analyzed four cases of PTLD after liver transplantation. In all patients immunosuppression was reduced and anti-CD20 monoclonal antibody (rituximab) was administered. In two of four patients, EBV viral load was positive in the peripheral blood, and gancyclovir was therefore also prescribed. Chemotherapy (CHOP) was used as a rescue in the event of treatment failure. RESULTS: Even if no severe adverse events were observed during the treatment period, our treatment approach to PTLD was not effective, and only one patient out of four is still alive. CONCLUSIONS: Well-designed clinical trials are necessary to evaluate the role of this combined approach in the treatment of PTLD in liver transplant recipients.     

Epstein-Barr virus DNA in serum after liver transplantation — surveillance of viral activity during treatment with different immunosuppressive agents

In immunocompromised HIV-infected and transplanted patients, there is a risk of developing Epstein-Barr virus (EBV)-associated lymphoproliferative disorders (LPD) and lymphomas. EBV has previously been detected by the polymerase chain reaction (PCR) in cerebrospinal fluid from all AIDS patients with EBV-associated cerebral lymphomas. We therefore thought it would be of interest to determine whether transplant patients with extracerebral EBV-associated LPD have detectable EBV genomes in serum. Nested PCR (nPCR) showed that 58% (18/31) of liver transplant (LTX) patients had EBV DNA in 17% (21/125) of serum samples obtained within the first 3 months after LTX. In 39% (7/18) of the patients, the first EBV nPCR-positive sample was found within 2 weeks post-LTX. Basic immunosuppression with cyclosporin A or FK506 did not seem to influence the frequency of detectable EBV genomes in serum. In contrast, positive EBV nPCR correlated to secondary OKT3 treatment for severe acute rejection (P=0.009). EBV-associated malignant lymphoma developed in three patients 2–6 months post-LTX. In all of them, EBV DNA was amplifiable within 12–14 days after LTX. The EBV antibody titers were not directly related to detectable EBV DNA in serum. We conclude that monitoring of LTX patients receiving increased immunosuppression by nPCR for EBV DNA in serum may help in the early identification of those at risk of developing EBV-associated LPD.     

Circulating Epstein‐Barr virus DNA to monitor lymphoproliferative disease following pediatric liver transplantation

Abstract Epstein‐Barr virus (EBV) infection can induce uncontrolled lymphocyte B proliferation in immunosuppressed transplant patients. Monitoring circulating EBV‐infected lymphocytes can help in identifying patients at risk of post‐transplant lymphoproliferative disease (PTLD). Circulating EBV genome levels were determined in 54 liver transplant pediatric recipients. Ten patients had more than 500 EBV genome/10⁵ peripheral blood lymphocytes (PBL) and exhibited clinical manifestations of EBV infection; three developed PTLD. To treat EBV infection, the level of immunosuppression was reduced and acute rejection developed in 4 patients. Three were treated with steroid and one had to be switched from cyclosporine to tacrolimus. Treatment of acute rejection was associated with increases in circulating EBV genome. None of the patients with less than 500 EBV genome/10⁵ PBL developed PTLD or EBV infection. Monitoring of EBV DNA is useful in the management of EBV infection and PTLD following pediatric liver transplantation. EBV infection should be treated in ways which do not expose patients to the risk of rejection.