Presentation and early detection of post-transplant lymphoproliferative disorder after solid organ transplantation

Post-transplant lymphoproliferative disorder (PTLD) is a serious and still frequently observed complication of solid organ transplantation. Despite the recent introduction of anti B-cell monoclonal antibody therapy (rituximab) for treatment of PTLD, mortality rates remain high. Because PTLD often presents in a nonspecific way in clinically unsuspected patients, it is a major challenge to diagnose PTLD at an early stage. Epstein-Barr virus (EBV)-DNA load monitoring is a promising tool for the identification of patients at risk for PTLD development. However, there are some limitations of this method, and not all patients at risk for PTLD can be identified by EBV-DNA measurements alone. Therefore, it is of major importance to recognize early clinical signs and symptoms of PTLD. In this review, risk factors for PTLD development, disease presentation, and methods for early detection will be discussed. Special attention is given to allograft and digestive tract localization and the relation with time of onset of PTLD. The value and pitfalls of EBV-DNA load monitoring are discussed. In addition, because fluorodeoxyglucose (FDG)-positron emission tomography (PET) has shown to be a powerful tool for staging and response evaluation of malignant lymphoma, the role of FDG-PET for early diagnosis and staging of PTLD is addressed.     

Review of Epstein-Barr virus and post-transplant lymphoproliferative disorder post-solid organ transplantation

Post-transplant lymphoproliferative disorder (PTLD) following solid organ transplantation is an important form of post-transplant malignancy. PTLD is typically associated with Epstein-Barr virus (EBV) and occurs in the setting of profound immunosuppression resulting in a deficiency of EBV-specific cytotoxic T lymphocytes (CTL). Predisposing factors include EBV mismatch between donor and recipient, use of immunosuppression especially T-cell depletive therapies and genetic predisposition of recipients. The standard approach has been to reduce immunosuppression but is often insufficient to induce tumour regression. Further understanding of the immunobiology of PTLD has resulted in improved monitoring techniques (including EBV viral load determined by polymerase chain reaction) and newer treatment options. Recent work has highlighted a potential role for dendritic cells in both the pathogenesis and treatment of PTLD. Current treatment modalities include adoptive immunotherapy using ex vivo generated autologous EBV-specific CTL or allogeneic CTL, cytokine therapies, antiviral agents, and more recently, rituximab and dendritic-cell based therapies. This review focuses on the developments and progress in the pathogenesis, diagnosis and treatment of PTLD.     

Post-transplant lymphoproliferative disorders in kidney transplantation: histological and molecular genetic assessment

Abstract:  We performed histopathological and immunohistochemical studies, in situ hybridization (ISH) for Epstein–Barr virus (EBV) and molecular genetic analysis using the PCR method for the immunoglobulin heavy chain gene in six patients with post-transplant lymphoproliferative disorders (PTLD) to clarify these problems. In two patients, PTLD developed in the graft, and in the remaining four it developed in systemic lymphoid tissues or organs. In terms of morphological classification, lesions in the graft of two patients were polymorphic with features of rejection in the background. In the other four patients, three of them presented monomorphic lesions and the remaining one presented features of reactive lymphoid hyperplasia. All the patients were positive for EBV as determined by ISH. The molecular genetic study could be performed for four patients, the cells in lesions of two patients were found to be monoclonal and those of the remaining two were polyclonal in IgH as determined by PCR. We conclude that PTLD are of two types, namely, intragraft PTLD and extra-graft PTLD. In the cases of intragraft PTLD their diagnosis is relatively difficult, because lesions are mixed with features of rejection. Molecular genetic analysis and detection of EBV by ISH are useful for diagnosis. In contrast, the diagnosis of extra-graft PTLD is easier than that of intragraft PTLD, by basing of the latest classification of malignant lymphoma. Grading of severity of PTLD should be carried out according to the newest system and protocols for treatment based on the grade of the lesion should be established as soon as possible.     

Use of cytokine polymorphisms and Epstein-Barr virus viral load to predict development of post-transplant lymphoproliferative disorder in paediatric liver transplant recipients

OBJECTIVE: Currently there are no tests to accurately identify paediatric liver transplant patients at risk for post-transplant lymphoproliferative disorder (PTLD). Herein we describe the use of cytokine polymorphisms and real-time quantitative polymerase chain reaction (qPCR) Epstein-Barr virus (EBV) viral load to identify patients at risk for PTLD development. METHODS: Between 2001 and 2004, approximately 1047 patient samples were collected for qPCR for EBV in 59 patients. EBV viral load was reported in three groups: low EBV (<4,000 copies/microg DNA), high EBV/no PTLD (>4000 copies/microg DNA) and biopsy-proven PTLD. All 59 patients also had cytokine polymorphism genotyping performed for six cytokine polymorphisms (transforming growth factor (TGF)-beta, tumor necrosis factor (TNF)-alpha, interleukins (IL)-6, IL-10, IL-2, and interferon (IFN)-gamma) from DNA isolated from peripheral blood mononuclear cells. Positive predictive value (PPV) and negative predictive value (NPV) were calculated using qPCR and cytokine polymorphism results. Data are reported as a mean +/- standard error of the mean. RESULTS: There were 35 males and 24 females with a mean follow-up of 34.9 months. EBV viral load had a PPV and NPV of 29 and 95%, respectively. The low IFN-gamma (A/A) polymorphism was found to be present in 4/6 PTLD patients (67%) and only 17/53 (33%) non-PTLD patients. When the low A/A IFN-gamma polymorphism was combined with EBV viral load for prediction of PTLD, PPV and NPV were 57 and 93%, respectively. DISCUSSION: Use of cytokine genotyping in conjunction with qPCR for EBV viral load can significantly improve the predictive value of diagnostic tests for identification of patients at high risk for PTLD.     

Polyomavirus interstitial nephritis and concurrent post‐transplant lymphoma in a renal allograft: coincidence or more?

We describe a case of an Epstein-Barr virus (EBV)-negative post-transplant large B-cell non-Hodgkin lymphoma located in the renal allograft, spleen, liver and left inguinal lymph node of a renal recipient and accompanied by a simultaneous polyomavirus-associated nephropathy. To our knowledge, this is the first report of a simultaneous polyomavirus infection and post-transplant lymphoproliferative disorder.     

Associations of serum EBV DNA and gammopathy with post-transplant lymphoproliferative disease

Abstract: Background: Post‐transplant lymphoproliferative disease (PTLD) is a life‐threatening complication of immunosuppression following transplantation. Epstein–Barr virus (EBV) and gammopathy in serum are associated with PTLD, but these two parameters have not been evaluated in parallel for their association with PTLD. Methods: We evaluated the incidence of EBV load positivity, gammopathy, and protein expression in sera from all PTLD patients diagnosed at our hospital during the past seven yr. Results were compared with those of a control group including matched transplanted patients who did not develop PTLD. Results: Seven of 10 PTLD patients presented EBV⁺ PTLD, for which five patients had detectable serum EBV DNA levels compared with none of 38 controls (RR between two groups =121, p < 0.0001). Five out of 10 patients had gammopathy at PTLD diagnosis compared with 5/38 controls (RR between two groups = 6.6, p = 0.022). Additionally, protein serum analysis by high‐resolution two‐dimensional gel electrophoresis and image examination failed to evidence specific abnormality in patients with PTLD compared with controls. Conclusions: Our results confirm an association between EBV in sera and gammopathy with PTLD, and highlight the high specificity of the former analysis. Whether a combination of both analyses will improve the clinical detection of PTLD remains to be evaluated in a larger prospective cohort study.     

Treatment of EBV-Related Post-Renal Transplant Lymphoproliferative Disease with a Tailored Regimen Including EBV-Specific T Cells

The treatment of EBV-associated post-transplant lymphoproliferative disease (PTLD) poses a considerable challenge. Efforts have been made to define regimens based on combination of the available therapeutic agents, chosen and tailored on a patient-by-patient basis, with the aim of augmenting event-free patient and graft survival. Recently, autologous EBV-specific cytotoxic T-lymphocytes (CTL) have proved effective in enhancing EBV-specific immune responses and reducing viral load in organ transplant recipients with active infection. We investigated the use of a tailored combined approach including autologous EBV-specific CTL for the treatment of EBV-related PTLD developing after pediatric kidney transplantation. Five patients with disseminated monoclonal (n = 3) or localized polyclonal (n = 2) PTLD unresponsive to reduction of immunosuppression were enrolled. The patients with disseminated PTLD received 4-5 courses of reduced-dosage polychemotherapy, accompanied by rituximab on the first day of each course, while localized disease was removed surgically. At treatment completion, autologous EBV-specific CTL were infused. All patients showed a complete response to treatment, without therapy-related toxicity or rejection, and persist in remission with good renal function at a median follow-up of 31 months. These preliminary results suggest that a combined chemoimmunotherapy regimen including virus-specific T-cells is well tolerated and potentially effective as first-line treatment of EBV-related PTLD.     

De novo gastrointestinal tumours after renal transplantation: role of CMV and EBV viruses

The development of new and more effective immunosuppressive agents has provided long-term survival for transplant recipients, thereby increasing the risk of de novo malignancy in chronic immunocompromised hosts. While de novo post-transplant lymphoproliferative diseases and skin cancer has been shown to have an increased incidence in long-term surviving solid organ transplant recipients, the association with gastrointestinal (GI) cancer is controversial. Over 12 yr, 20 patients (5%) out of 395 renal transplant recipients developed 23 de novo tumours; 11 skin cancer and 12 non-skin cancer. Four patients (1%) developed de novo tumours of the GI tract (three colon, and one gastric cancer). Immediately after tumour's diagnosis, immunosuppressive therapy was reduced; all patients were shifted from cyclosporine to Rapamicine within 30 d. The tumour was surgically resected with curative intent in three cases, while one patient had only palliative surgery because of metastatic disease. The post-operative courses was uneventful. All patients maintained normal graft function. However, three out of four patients (75%) died of progression of the neoplasm, within a median time from the diagnosis of 12 months. Further, we investigated a possible correlations between de novo GI cancer and HCV, HBV status, infections, cytomegalovirus (CMV) and Epstein-Barr virus (EBV) reactivation, episodes of rejection, and blood transfusions. All cases with GI de novo cancers reported in this paper developed CMV and EBV reactivation within three months after transplantation. Thereafter we suggest a closer follow-up for de novo GI cancer in renal transplants with early CMV and EBV reactivation in order to avoid delayed diagnosis.     

Management of Epstein–Barr Virus-induced Post-transplant Lymphoproliferative Disease in Recipients of Solid Organ Transplantation

The optimal management of Epstein-Barr virus (EBV)-induced post-transplant lymphoproliferative diseases (PTLD) remains controversial. While withdrawal or reduction of immunosuppression is widely accepted as the strategy for the treatment of EBV/PTLD, the role of additional therapeutic interventions remains less clear. Newer strategies, including anti-B-cell monoclonal antibodies and adoptive immunotherapy offer the promise of impaired efficacy and outcome against EBV disease, but lack data demonstrating how and when to use these approaches. The current review provides an overview of potential strategies and presents guidelines for the management of EBV/PTLD in solid-organ transplant recipients.     

肾移植术后淋巴增殖性疾病的诊治体会

目的探讨肾移植术后淋巴细胞增殖性疾病(PTLD)的发病原因、临床特点、诊治方法及预后。方法回顾性分析2000年1月至2019年1月海军军医大学长征医院2844例肾移植受者中术后并发PTLD的13例受者的临床资料,收集受者性别、年龄、血肌酐、药物浓度、糖尿病、肾移植术后有无移植肾功能延迟恢复、急性排斥反应和免疫抑制剂方案的使用等相关资料。13例PTLD受者中,男11例,女2例,确诊时年龄为55岁(31~78岁)。结果PTLD病变位置分布在肺部1例,胃肠道8例,区域淋巴结2例,皮肤1例,颅内1例,均病理诊断为弥漫性大B淋巴细胞淋巴瘤,距肾移植手术中位时间为86个月(12~204个月)。76.9%受者病理组织EB病毒检测呈阳性。确诊后给予免疫抑制剂减量为主的综合治疗,无法耐受利妥昔单抗+CHOP(R-CHOP)方案化学药物治疗的受者切换为利妥昔单抗+来那度胺(R2)方案,2例受者肺部感染死亡,完全缓解10例,部分缓解1例,病情进展1例,总有效率91.6%。结论肾移植术后淋巴细胞增殖性疾病进展迅速,病死率高,与EB病毒感染密切相关,减少免疫抑制剂用量是综合治疗的核心,根据受者耐受性选择合理的化学药物治疗方案,R2方案为无法耐受一线R-CHOP方案的受者更多选择。     

An autopsy case of late-onset Epstein–Barr virus associated post-transplant lymphoproliferative disorders 11 yr after kidney transplantation

Abstract:  A 42-yr-old Japanese female presented with right cervical lymphadenopathy. She had been diagnosed with IgA glomerulonephritis at the age of 19 and had a one-yr history of hemodialysis after giving birth to her first child. At the age of 31, she had a living-related renal transplantation from her mother. On admission, she was diagnosed with diffuse large B-cell lymphoma (DLBL) by lymph node biopsy and was treated with Rituxymab plus CHOP (Rituximab/Cyclophosphamide/Doxorubicin/Vincristine/Prednisone). However, the therapy was not successful, and the patient had a rapidly deteriorating clinical course with elevated Epstein–Barr virus (EBV) loads in her peripheral blood. She died four months after the onset of lymphoma, because of disseminated intravascular coagulation and multiple organ failure. In kidney transplantation, the incidence of post-transplant lymphoproliferative disorders (PTLD) is between 0.4% and 2% and mostly occurs within a year after transplantation, in strong association with EBV infection. Late-onset PTLD, however, is more like standard lymphomas and is rarely induced by EBV. The present case was quite atypical of late-onset PTLD because the patient's high viral load was first detected 11 yr after transplantation and presented as a monomorphic B-cell lymphoma.     

Clinical characteristics and outcomes of PTLD following intestinal transplantation

Post‐transplant lymphoproliferative disease (PTLD) has the highest incidence following intestinal transplantation (ITx). Our center has seen a recent increase in PTLD. Our aim was to review a single‐center PTLD experience with a focus on clinical characteristics and outcomes. We completed a retrospective review of biopsy‐proven PTLD cases using a prospectively maintained database of 115 ITx recipients transplanted between 1991 and 2014. Nineteen (17%) ITx recipients developed 25 PTLD cases during a median follow‐up time of 6.4 (1.6‐14.6) years. The incidence of early PTLD was 6% (n = 7). There was a trend toward increased risk of PTLD in children compared with adults (P = .11) and a significantly increased risk of PTLD in re‐ITx compared with primary ITx recipients (P = .03). Most PTLD cases were diagnosed between 2010 and 2014 (n = 14). All early PTLD cases were EBV+ on in situ hybridization. Overall graft and patient survival are 68% and 74%, respectively. Second episodes of PTLD were diagnosed in 43% of surviving pediatric patients. Our program has a low incidence of early PTLD with overall excellent graft and patient survival following diagnosis. However, we have also seen a rising incidence of late PTLD. The cause of the increase is unknown as no major changes in immunosuppression protocols have occurred since 1999.     

Post-transplant lymphoproliferative disorders after live donor renal transplantation

The development of post-transplant lymphoproliferative disorders (PTLD) is a well-recognized complication of solid organ transplantation in patients receiving immunosuppressive therapy. The literature on PTLD in live renal allograft recipients is scarce and most of the data pertains to PTLD in cadaveric transplants. As live donor grafts form the mainstay of transplantation programme in India, this study was carried out to define the profile of PTLD in live donor renal allograft recipients. On retrospective evaluation, nine cases of PTLD amongst 1700 live donor allograft recipients from January 1989 to August 2004, were detected at a tertiary care hospital in north India. The clinicopathological features of these cases were evaluated. Mean age at diagnosis of PTLD was 38 yr with median post-transplant latency period of 7 yr. All cases were from extra-renal sites, five being in ileum/jejunum, three in retroperitoneal lymph nodes and one in epididymus. All cases received cyclosporin, azathioprine and prednisolone in varying combinations as immunosuppressive therapy. One case was treated for rejection by anti-thymocyte globulin. Seven patients were seronegative for Epstein-Barr virus at the time of diagnosis. All were B-cell monomorphic PTLD, classifiable as B-cell diffuse large cell lymphomas, with five extranodal and three nodal lymphomas. Management included reduction in immunosuppression, acyclovir therapy, surgical excision and chemotherapy. On follow-up, four patients died, two presented with recurrence, two were in remission and one was lost to follow-up. This study comprising of live related/unrelated renal allograft recipients observed late onset high grade monomorphic PTLD with paucity of early onset polymorphic lesions. Long post-transplant latency period, aggressive behaviour and poor response to treatment necessitate long-term cancer surveillance to facilitate early detection and newer therapeutic strategies to improve the outcome in these patients.     

Antiphospholipid antibodies after renal transplantation and cardiovascular disease

Abstract: Background: The aim was to assess the presence of pre‐ or post‐transplant serum antiphospholipid antibodies (APA) and its association with the development of cardiovascular disease (CVD) in renal transplantation. Methods: We studied 138 patients transplanted with a cadaver kidney graft between 1990 and 1998 and with a graft functioning for longer than one yr. One pre‐transplant sample and another obtained after transplantation from our serum bank were analyzed. The ELISA used were set up in our laboratory, following established international guidelines, and results were confirmed in three different runs. Results: 23.9% and 31.2% of patients had pre‐ and post‐transplant positive titers of APA, respectively. 16% developed those antibodies de novo after transplantation. Post‐transplant CVD was observed in 20.3% of patients but they were not associated with the production of APA in the whole population studied. However, multivariate analysis demonstrated an increased risk (RR 2.27; p = 0.02) for CVD when APA were produced after acute rejection. Conclusions: The presence of serum APA alone was not an independent risk factor for CVD after kidney transplantation. Nonetheless, in kidney recipients who produced APA de novo after acute rejection, the control of cardiovascular risk factors must be intensified.     

Characteristics,risks, and outcomes of post‐transplant lymphoproliferative disease >3 years after pediatric heart transplant: A multicenter analysis

Post‐transplant lymphoproliferative disorder (PTLD) is a significant complication after pediatric heart transplantation (HT), occurring in 5%‐15% of patients within 3 years. Data >3 years from HT are limited. We sought to describe the prevalence, risk factors, and outcomes of PTLD occurring late (>3 years) after pediatric HT in the Pediatric Heart Transplant Study from 1993 to 2010. Among 3844 primary HT patients, 110 (3%) developed late, nonrecurrent PTLD. The hazard rate for late PTLD was constant at 0.01 events/year out to 20 years after HT. Risk factors for late PTLD were younger age at HT (HR 1.06, P = 0.003) and Epstein‐Barr virus (EBV) naivety (HR 1.65, P = 0.02). Survival after late PTLD was 86% and 68% at 1 and 5 years, with nonwhite race (HR 2.27, P = 0.03) and earlier year of HT (HR 1.03, P = 0.04) independently associated with mortality. Acute rejection and infection were both common after late PTLD, occurring in 26% and 34% of patients. The constant late hazard and contribution of EBV to late PTLD suggest that vigilance for development of PTLD, including for EBV conversion, should persist indefinitely after pediatric HT. The reasons for elevated risk of death for nonwhites after late PTLD are unclear and warrant further investigation.     

(Val-)Ganciclovir prophylaxis reduces Epstein-Barr virus primary infection in pediatric renal transplantation

Epstein‐Barr virus (EBV) primary infection constitutes a serious risk for pediatric transplant recipients, particularly as regards the development of EBV‐related post‐transplant lymphoproliferative disease (PTLD). Currently, there is no established prophylactic regimen. We investigated the association between chemoprophylaxis with valganciclovir (VGCV) or ganciclovir (GCV) and the incidence of EBV viremia in EBV‐naïve pediatric renal transplant recipients (R?) who had received a graft from an EBV‐positive donor (D+) and are therefore at high risk of EBV primary infection. In a prospective, multicenter trial (n = 114), we compared a cohort on chemoprophylaxis (n = 20) with a similar control cohort without chemoprophylaxis (n = 8). Over the 1‐year study period, antiviral prophylaxis with VGCV/GCV was associated with a significantly decreased incidence of EBV primary infection: 9/20 patients (45%) in the prophylaxis group experienced an EBV primary infection compared to 8/8 controls (100%) (P < 0.0001). Chemoprophylaxis was associated with a significantly lower EBV viral load (P < 0.001). Type or intensity of immunosuppressive therapy did not influence the occurrence of EBV primary infection or the level/persistence of EBV viral load. Chemoprophylaxis with VGCV/GCV is associated with a reduced incidence of EBV viremia in high‐risk pediatric kidney allograft recipients in the first year post‐transplant. (ClinicalTrials.gov number: NCT00963248).     

Recurrent dense deposit disease after renal transplantation: an emerging role for complementary therapies

Dense deposit disease is a rare glomerulonephritis caused by uncontrolled stimulation of the alternative complement pathway. Allograft survival after kidney transplantation is significantly reduced by the high rate of disease recurrence. No therapeutic interventions have consistently improved outcomes for patients with primary or recurrent disease. This is the first reported case of recurrent dense deposit disease being managed with eculizumab. Within 4 weeks of renal transplantation, deteriorating graft function and increasing proteinuria were evident. A transplant biopsy confirmed the diagnosis of recurrent dense deposit disease. Eculizumab was considered after the failure of corticosteroid, rituximab and plasmapheresis to attenuate the rate of decline in allograft function. There was a marked clinical and biochemical response following the administration of eculizumab. This case provides the first evidence that eculizumab may have a place in the management of crescentic dense deposit disease. More information is necessary to clarify the effectiveness and role of eculizumab in dense deposit disease but the response in this patient was encouraging. The results of clinical trials of eculizumab in this condition are eagerly awaited.     

Human herpesvirus 8 and Epstein-Barr virus-related monotypic large B-cell lymphoproliferative disorder coexisting with mixed variant of Castleman's disease in a lymph node of a renal transplant recipient

Human herpesvirus 8 (HHV8) has been related to some malignant lymphoproliferations, including post-transplant lymphoproliferative disorders (PTLD). We describe a case of a HHV8 and Epstein-Barr virus (EBV) positive large B-cell lymphoproliferation coexisting with Castleman's disease in the same lymph node of a long-term renal transplant recipient. Biopsy revealed mixed type of Castleman's disease and anaplastic cells showing IgA restriction, although molecular analysis failed to detect monoclonality. Only large cells were co-infected by both EBV and HHV8. After reduction of immunosuppression, the lesion partially regressed. After 1 yr, local evolution required surgery followed by irradiation. The present case represents a unique form of localized monotypic but polyclonal large cell PTLD associated with Castleman's disease. It can be added to PTLD with HHV8 and EBV co-infection.     

Post‐transplant lymphoproliferative disorder after pancreas transplantation: a United Network for Organ Sharing database analysis

There are not a great deal of data on post‐transplant lymphoproliferative disorder (PTLD) following pancreas transplantation. We analyzed the United Network for Organ Sharing national database of pancreas transplants to identify predictors of PTLD development. A univariate Cox model was generated for each potential predictor, and those at least marginally associated (p < 0.15) with PTLD were entered into a multivariable Cox model. PTLD developed in 43 patients (1.0%) of 4205 pancreas transplants. Mean follow‐up time was 4.9 ± 2.2 yr. In the multivariable Cox model, recipient EBV seronegativity (HR 5.52, 95% CI: 2.99–10.19, p < 0.001), not having tacrolimus in the immunosuppressive regimen (HR 6.02, 95% CI: 2.74–13.19, p < 0.001), recipient age (HR 0.96, 95% CI: 0.92–0.99, p = 0.02), non‐white ethnicity (HR 0.11, 95% CI: 0.02–0.84, p = 0.03), and HLA mismatching (HR 0.80, 95% CI: 0.67–0.97, p = 0.02) were significantly associated with the development of PTLD. Patient survival was significantly decreased in patients with PTLD, with a one‐, three‐, and five‐yr survival of 91%, 76%, and 70%, compared with 97%, 93%, and 88% in patients without PTLD (p < 0.001). PTLD is an uncommon but potentially lethal complication following pancreas transplantation. Patients with the risk factors identified should be monitored closely for the development of PTLD.     

Quantitative EBV Viral Loads and Immunosuppression Alterations can Decrease PTLD Incidence in Pediatric Liver Transplant Recipients

Epstein-Barr virus (EBV) is a common viral infection in pediatric liver transplant patients and can lead to development of post-transplant lymphoproliferative disorder (PTLD). Differing studies have used immunosuppression reduction, antiviral medications or i.v. CMV-immunogloublin for EBV prevention and treatment. The purpose of this study was to determine whether implementation of a protocol for frequent EBV monitoring and EBV viral load-driven immunosuppression reduction could decrease the incidence of PTLD in our patient population. All data were prospectively collected between 2001 and 2004 at a single institution. Seventy-three patients were entered into the study. Patients were divided into a historical control group (pre-2001, 30 patients) and a treatment group (post-2001, 43 patients). Approximately 1271 blood samples of 73 patients were collected between 2001 and 2004. Eleven out of 43 patients received immunosuppression tapering due to high EBV viral loads (>4000 copies/microg DNA). One patient developed allograft rejection after immunosuppression modulation. Prior to 2001, the incidence of PTLD at our institution was 16%. After instituting a protocol for EBV monitoring, the incidence of PTLD decreased to 2% (p-value<0.05). These findings illustrate that frequent EBV viral load monitoring and preemptive immunosuppression modulation have an integral role in preventing PTLD in the pediatric liver transplant population.