Case-control study of risk factors for the development of post-transplant lymphoproliferative disease in a pediatric heart transplant cohort

PTLD is an important complication following heart transplantation. To better define the risk factors of PTLD in children, we performed a case-control study. All pediatric cardiac transplant recipients who developed their first episode of PTLD were matched by age (+/-1 yr) and time since transplant (+/-1 yr) with those who did not. PTLD occurred in nine of 95 cardiac transplant recipients (9%), 0.3-7.8 yr following cardiac transplantation (median = 2.5 yr). Patients were 0.1-16.4 yr (median = 3.7) at transplantation. Biopsies revealed polymorphic B cell hyperplasia (three), polymorphic B cell lymphoma (one), monomorphic diffuse large cell B cell lymphoma (three) and monomorphic Burkitt's-like lymphoma (two). Patients who developed PTLD were at no greater risk of death (p = 0.31). Recipient EBV seronegativity at time of transplant (p = 0.08), EBV seroconversion (p = 0.013) and recipient CMV seronegativity (p = 0.015) were associated with the development of PTLD by conditional logistic regression; sex, race, donor age, recipient diagnosis, donor CMV seropositivity, recipient treatment for CMV infection, EBV seropositivity at the time of PTLD diagnosis, and number of rejection episodes, treated rejection episodes, and lympholytics used were not. There was no significant association between PTLD and death in our recipients. EBV seroconversion and recipient CMV seronegativity were associated with the development of PTLD.     

Post-transplant lymphoproliferative disorder following pediatric heart transplantation

Immunosuppression after heart transplantation is implicated in development of post-transplant lymphoproliferative disorder (PTLD). Despite a higher prevalence of PTLD in children, there is scarce knowledge about incidence, pathophysiologic mechanisms and risk factors for PTLD in pediatric recipients of cardiac allografts. We examined retrospectively the medical records of all 143 pediatric patients (mean age 9.2 +/- 6.1 yr) who received donor allografts between 1984 and 2002 and survived over 30 days. Five children (3.5%) developed PTLD over a mean follow-up period of 41.1 +/- 46.0 months. Time from transplant to diagnosis of PTLD ranged from 3.9 to 112 months (mean 48.0 +/- 41.9 months). Excluding PTLD, no other malignancies were found in this population. Actuarial freedom from PTLD was 99.2%, 99.2% and 96.2% at 1, 2, and 5 yr, respectively. Children who developed PTLD were more likely (by univariate analysis) to have been Rh negative (p = 0.01), Rh mismatched (p = 0.003), Epstein-Barr virus (EBV) seronegative (p = 0.001) and transplanted for congenital heart disease (p < 0.02). PTLD was associated with significant morbidity and mortality with a mean survival following diagnosis of 21.2 months. PTLD is a serious complicating outcome of cardiac transplantation that occurs in approximately 3.5% of children. Aside of immunosuppression, risk factors in this series for developing PTLD include EBV seronegativity and Rh negative status and mismatch. Non-hematogenous malignancies are rare in light of short allograft half-life.     

Epstein-Barr Virus–Associated Lymphoproliferative Disorder Presenting as Apparently Isolated Gastrointestinal Lesions in Childhood

We present an unusual case of post-transplant lymphoproliferative disorder (PTLD) presenting as apparently isolated gastrointestinal lesions in a pediatric renal transplant recipient. The multiple bowel lesions were related to Epstein-Barr virus and demonstrated the appearance of a monomorphic PTLD that was morphologically indistinguishable from diffuse large B-cell lymphoma. The patient responded to therapy with targeted anti-CD20 immunotherapy. PTLD may manifest as apparently isolated gastrointestinal tract lesions in childhood.     

Serial detection of Epstein-Barr virus DNA in sera and peripheral blood leukocyte samples of pediatric renal allograft recipients with persistent mononucleosis-like symptoms defines patients at risk to develop post-transplant lymphoproliferative disease

We tested blood samples of 25 pediatric renal transplant recipients for Epstein-Barr virus (EBV) DNA load by quantitative polymerase chain reaction (PCR). Eleven of these transplant recipients showed clinical persistent mononucleosis-like symptoms years after transplantation (Tx). A quantitation of EBV DNA by PCR in peripheral blood lymphocyte (PBL) and serum samples revealed variable EBV DNA titers. The majority of EBV PCR results in samples of the 14 asymptomatic transplant recipients was repeatedly below detection limit. In contrast, patients with mononucleosis-like symptoms showed persistent EBV genome titers over a period of 6 months, ranging from 75 to 18 750 copies/10 000 PBL and from 680 to 335 000 copies/mL serum, respectively. One child suffering from this mononucleosis-like condition developed an EBV-associated Burkitt-like lymphoma 29 months after Tx. Whereas clinical and histological investigations did not indicate a post-transplant lymphoproliferative disorder (PTLD) until tumor detection, EBV titers in PBL and serum had been high for at least 8 months. We propose that pediatric transplant recipients who show both, recurrent mononucleosis-like symptoms and a sustained high EBV genome load, are at increased risk for severe EBV-related post-transplant complications.     

Treatment of monomorphic B-cell lymphoma with rituximab after liver transplantation in a child

Rituximab, a monoclonal antibody directed against the B-cell specific CD20 antigen has been used with success in post-transplant lymphoproliferative disorder (PTLD) of B-cell phenotype. However, the use of such drug in children with liver transplantation and PTLD is very limited. We report a 2-yr-old liver transplant recipient with monomorphic non-Hodgkin lymphoma of B-cell origin. The lymphoma did not respond to immunosuppression withdrawal, with a subsequent allograft rejection. Despite resumption of immunosuppression and rejection treatment, the lymphoma was successfully treated with rituximab.     

Primary tacrolimus (FK506) therapy and the long-term risk of post-transplant lymphoproliferative disease in pediatric liver transplant recipients

While the overall incidence of post-transplant lymphoproliferative disease (PTLD) in pediatric liver transplant recipients has been reported to be 4-11%, the long-term risk of PTLD associated with primary tacrolimus therapy is unknown. Therefore, in order to determine the incidence and long-term risk of PTLD, the present study examined 131 pediatric recipients who underwent liver transplantation (LTx) between October 1989 and December 1991 and received primary tacrolimus therapy. This cohort of children was evaluated over an extended time-period (until December 31 1996) with a mean follow-up of 6.3 yr. Actuarial Kaplan-Meier analysis was utilized to determine the risk of PTLD over time. The overall incidence of PTLD was 13% (17/131) with an average age of 4.3 +/- 0.75 yr at diagnosis. Pretransplant Epstein-Barr virus (EBV) serologies were negative in 82%, positive in 12%, and not available in 6% of the patients. The median time to diagnosis of PTLD post-Tx was 11.9 months (mean 16.4 +/- 3.9, range 1.7-63.0 months). Mean tacrolimus dose and plasma trough level (as evaluated by enzyme-linked immunosorbent assay [ELISA]) at the time of diagnosis was 0.32 +/- 0.06 mg/kg/day and 1.3 +/- 0.3 ng/mL, respectively. The cumulative long-term risk of PTLD was found to increase over time: 3% at 6 months, 8% at 1 yr, 12% at 2 yr, 14% at 3 yr, and 15% at 4 and 5 yr. Mortality from PTLD was 12% (two of 17 patients). Primary tacrolimus use in pediatric LTx has a long-term risk of PTLD approaching 15%, with the majority of episodes (78%) occurring in the first 2 yr, suggesting that intense EBV surveillance should occur early post-transplantation.     

Epstein-Barr virus-associated post-transplant lymphoproliferative disease after bone marrow transplantation mimicking graft-versus-host disease

In contrast to solid organ transplantation (Tx), the incidence of post-transplant lymphoproliferative disease (PTLD) after hematopoietic stem cell Tx (HSCT) is generally low. This risk, however, is significantly elevated in patients receiving human leukocyte antigen (HLA) mis-matched or T-cell-depleted grafts, or after treatment for severe graft-versus-host disease (GvHD). An 18-yr-old patient with positive Epstein-Barr virus (EBV) serology received a fully matched, unmanipulated bone marrow graft from an unrelated EBV-positive donor for treatment of acute myeloid leukemia (AML) in second complete remission. GvHD prophylaxis was performed with cyclosporin A (CsA) and a short course of methotrexate. Four months after Tx, the patient developed ulcerative tonsillitis that was unresponsive to antibiotic treatment. Diarrhea appearing simultaneously was interpreted as gastrointestinal GvHD and steroids were added to CsA. A few days later the patient was admitted to hospital because of generalized seizure and pneumonia. Despite reduction of immunosuppression, intensification of anti-viral treatment, and subsequent mechanical ventilation, the patient died of acute respiratory distress 6 days later. Autopsy demonstrated disseminated EBV-induced, multi-nodular lymphoma infiltration of the entire colon but no signs of GvHD. Moreover, both lungs, paratracheal lymph nodes, kidneys, thyroid gland, and liver were infiltrated with large B-cell non-Hodgkin's lymphomas. This case underlines the rapid and aggressive course of EBV-induced disseminated PTLD after HSCT, initially mimicking intestinal GvHD because of massive colonic lymphoma infiltration. Tissue biopsies should be performed early for establishing correct diagnosis, thus enabling specific therapy, e.g. infusion of donor leukocytes with cytotoxic T-lymphocytes.     

Successful treatment of a classic Hodgkin lymphoma‐type post‐transplant lymphoproliferative disorder with tailored chemotherapy and Epstein–Barr virus‐specific cytotoxic T lymphocytes in a pediatric heart transplant recipient

CHL type is the least common major form of EBV‐related PTLD but rarely occurs in pediatric recipients; development of CHL subsequent to other PTLD subtypes in the same transplant recipient is even more unusual. Because of its rarity, indications on the best treatment strategy are limited. Patients have been mostly treated with standard HL chemotherapy/radiotherapy, and prognosis seems more favorable than other monomorphic PTLDs. Herein, we describe a pediatric case of EBV‐associated, stage IV‐B, CHL arising in a heart allograft recipient eight yr after diagnosis of B‐cell polymorphic PTLD. The patient was successfully treated with adjusted‐dose HL chemotherapy and autologous EBV‐specific CTL, without discontinuation of maintenance immunosuppression. At two yr from therapy completion, the patient is in CR with stable organ function. With this strategy, it may be possible to reproduce the good prognostic data reported for CHL‐type PTLD, with decreased risk of organ toxicity or rejection.     

Post-transplantation lymphoproliferative disorder in pediatric kidney-transplant recipients - A national study

Cleper R, Ben Shalom E, Landau D, Weissman I, Krause I, Konen O, Rahamimov R, Mor E, Bar‐Nathan N, Frishberg Y, Davidovits M. Post‐transplantation lymphoproliferative disorder in pediatric kidney‐transplant recipients – A national study. Abstract: PTLD is the most common malignancy in pediatric kidney‐transplant recipients. We examined the prevalence, clinical features, and outcome of PTLD in Israel. Twelve (4.4%) of 272 pediatric (<19 yr) kidney‐transplant recipients retrieved from a search of the NIKTR for 1991–2008 had acquired PTLD at a median of 3.2 yr post‐transplantation. PTLD‐affected patients were younger at transplantation (4.2 vs. 12.5 yr, p = 0.02), had a higher rate of OKT3 therapy for acute rejection (25% vs. 4%, p = 0.015), and 5/12 were EBV‐seropositive at transplantation. Graft dysfunction was the presenting sign in six (50%). PTLD was predominantly abdominal (83%) and B‐cell type (67%); T‐cell PTLD occurred exclusively in EBV‐seropositive patients. Treatment consisted of immunosuppression cessation (6/12, 50%), antiviral agents (7/12, 58%), anti‐CD20 monoclonal antibodies (4/12, 33%), and chemotherapy (6/12, 50%). Survival was 100% in the EBV‐naïve patients and 40% in the EBV‐seropositive patients. Graft loss occurred in three of eight survivors (37.5%). PTLD‐associated mortality risk was older age: 11.2 vs. 3.4 yr, longer dialysis: 15 vs. 6.5 months, T‐cell type disease (75%), later PTLD onset: 6.35 vs. 1.9 yr post‐transplantation and era of transplantation (43% mortality before vs. 20% after 2001). Pretransplantation EBV‐seronegative status might confer a survival benefit with early detected PTLD. EBV‐seropositive patients are at risk for aggressive late‐onset lethal PTLD.     

Pediatric renal transplantation: A retrospective single‐center study on epidemiology and morbidity due to EBV

Pediatric R‐Tx patients are at high risk of developing EBV primary infection. Although high DNA replication is a risk factor for PTLD, some patients develop PTLD with low viral load. In this retrospective single‐center study including all pediatric patients having received R‐Tx (2003‐2012 period), we aimed to identify risk factors for uncontrolled reactions to EBV (defined as the presence of a viral load >10 000 copies/mL or PTLD). A Cox proportional hazard model was performed. A total of 117 patients underwent R‐Tx at a mean age of 9.7 ± 5.3 years, 46 of them being seronegative for EBV at the time of R‐Tx. During follow‐up, 54 patients displayed positive EBV viral load, 22 of whom presenting with primary infection. An uncontrolled reaction to EBV was observed in 24 patients, whilst 4 patients developed PTLD. Univariate and multivariate analyses suggested the following risk factors for an uncontrolled reaction: age below 5 years, graft from a deceased donor, ≥5 HLA mismatches, EBV‐seronegative status at the time of R‐Tx, and a secondary post‐Tx loss of anti‐EBNA. Monitoring anti‐EBNA after R‐Tx may contribute to the early identification of patients at risk for uncontrolled reaction.     

Monitoring and modulation of Epstein-Barr virus loads in pediatric transplant patients

A major risk faced by bone-marrow and solid organ transplant patients is the development of post-transplant lymphoproliferative disease or post-transplant lymphoma (PTLD). In pediatric transplantation, PTLD onset is often associated with a rapid rise in Epstein-Barr virus (EBV) load in peripheral blood mononuclear cells (PBMC). We have analyzed EBV viral loads in PBMC over time using real-time quantitative PCR in 56 patients, 19 of which have been followed for more than 1 year. In nine patients; eight bone marrow (BMT) and one kidney transplant, PTLD was associated with a rapid rise in viral load, exceeding 1 x 10(5) EBV genomes/microg of PBMC-derived DNA. Four of these patients exceeded 1 x 10(6) EBV genomes/microg PBMC DNA. All patients with viral loads exceeding 1 x 10(5) EBV genomes/microg PBMC DNA were clearly at high risk for transplant-associated mortality, with only six of nine surviving. Importantly, only one of these deaths was directly attributable to EBV. A second elevated state of EBV load, defined as exceeding 2 x 10(4) EBV genomes/microg PBMC, was seen in a total of 12 BMT, kidney, heart, and liver transplant patients. These patients did not appear to be at immediate lethal risk for PTLD and one EBV-attributable death was found in this group as well. Thirty-four transplant patients whose EBV viral load oscillated from undetectable to 10 000 EBV genomes/microg PBMC DNA are reported as well. The threshold for normal EBV viral load based on our combined experience with viral load analysis is defined as 1 x 10(4) EBV genomes/microg PBMC DNA. The ability to rapidly analyze EBV load allows rapid changes in viral load, such as those that occur with PTLD onset, and the impact of anti-CD20 antibody therapy to be rapidly detected.     

Intraventricular rituximab and systemic chemotherapy for treatment of central nervous system post-transplant lymphoproliferative disorder after kidney transplantation

Twombley K, Pokala H, Ardura MI, Harker-Murray P, Johnson-Welch SF, Weinberg A, Seikaly M. Intraventricular rituximab and systemic chemotherapy for treatment of central nervous system post-transplant lymphoproliferative disorder after kidney transplantation. Abstract: PTLD of the CNS is a rare complication of solid organ transplantation, and there are only case reports/series available in the literature. Current literature suggests that CNS PTLD carries a worse prognosis than PTLD outside the CNS, and most are of B-cell lineage, predominately monomorphic, and are associated with EBV infection. Because this disorder is so rare, there is no standard chemotherapy for pediatric patients with CNS PTLD and reported therapies for EBV-associated CNS PTLD are heterogeneous with mixed results. Since outcomes of CNS PTLD are historically poor, we attempted to develop a novel therapeutic treatment regimen. Based on a review of the literature and with the help of a multidisciplinary team, we created a regimen of chemotherapy that included dexamethasone and high-dose methotrexate in addition to intravenous and intraventricular Rituximab in two pediatric patients. The intraventricular chemotherapy succeeded in shrinking the tumor in both of our patients; however, as shown in the second case, the clinical outcome depends on the location of the tumor. Systemic and intraventricular therapies hold promise in the management of EBV-associated CNS PTLD; however the rarity of this entity prevents the development of well-designed studies necessary for the establishment of an evidence-based treatment standard.     

Pulmonary re-occurrence of post-transplant lymphoproliferative disease with hypogammaglobulinaemia

We report the case of a 12-year-old boy, who developed Epstein-Barr virus (EBV) associated post-transplant lymphoproliferative disease (PTLD) 7 years after renal transplantation. He responded well to the reduced immunosuppressive therapy and treatment with ganciclovir. Two years later he developed severe pneumonia and hypogammaglobulinaemia related to EBV infection exacerbation. An X-ray film revealed persistent pneumonia in the right lung. Lung biopsy showed a large, diffuse EBV-associated B-cell lymphoma. This constellation suggested re-occurrence of the primary PTLD. CONCLUSION: We present a case of recurring Epstein-Barr virus-associated post-transplant lymphoproliferative disease with a remarkably late onset in addition to hypogammaglobulinaemia.     

Low-dose immunosuppression reduces the incidence of post-transplant lymphoproliferative disease in pediatric liver graft recipients

OBJECTIVES: In pediatric solid organ transplantation, the Epstein-Barr virus (EBV)-related lymphoproliferative disorders (PTLD) still play a major role in post-transplant morbidity and mortality. The aim of the study was to determine the incidence of PTLD in pediatric patients with liver transplant who receive low-dose immunosuppression protocols. METHODS: All pediatric patients (n = 269) received a dual immunosuppression therapy consisting of cyclosporine A (initial trough levels, 170-200 microg/L; trough levels for maintenance immunosuppression after 1 year, 80-100 microg/L) and prednisolone (starting dose, 60 mg/m2). Steroids were reduced to 30 mg/m2 after 1 week, followed by a weekly tapering to 5 mg/m2. Seventy-seven of 269 patients were switched to tacrolimus therapy. The authors evaluated the significance of EBV-DNA monitoring by quantitative polymerase chain reaction in identifying patients at risk for PTLD. RESULTS: Patient survival was 90.3%; graft survival was 85.9%. Eight patients lost their grafts because of chronic rejection. The incidence of PTLD was low (0.7%), although a significant EBV viral load was found in 42.4% of the patients. One third of the patients with a viral load of 3,000 genomes/10(5) cells or greater had clinical signs of EBV infection. CONCLUSIONS: The authors conclude that low-dose immunosuppressive protocols significantly reduce the incidence of PTLD. In patients treated with that regimen, the monitoring of EBV viral load seems not to be helpful. It can be assumed that low-dose immunosuppression does not suppress EBV-specific cytotoxic CD8+ T cells, thus allowing the host to control EBV infection without the risk of PTLD. Our low-dose immunosuppression protocol did not increase the risk of chronic rejection.     

Can pediatric steroid‐free renal transplantation improve growth and metabolic complications?

We analyzed the effects of a steroid avoidance protocol in pediatric renal transplant recipients on calculated CrCl (Schwartz), CMV infection, cholesterol, height Z scores, weight Z scores, and BMI Z scores in a case control trial with contemporaneous controls. From 1999 to 2004, 19 pediatric patients (age 1-20 yr) received transplants without steroids using immunosuppression with tacrolimus, mycophenolate mofetil, and daclizumab. Control patients (n = 30) were matched for length of follow-up (minimum one yr), donor type age, type of immunosuppression, sex, date of transplant, and original disease, and CMV status. Graft survival at one year was 100% in both groups. Mean CrCl of steroid-free vs. control patients were not different at 1 year post-transplant. CMV disease was more prevalent in steroid-treated control group (seven of 30 patients) vs. the steroid free control group (zero of 19). Height delta Z scores at one year were NOT different between groups. Weight and BMI delta Z scores were significantly higher in the control group. Cholesterol levels at one year post-transplant were different in the two groups but NOT ABNORMALLY elevated in either group. At one yr post-transplant, steroid-free immunosuppression with tacrolimus, mycophenolate mofetil and daclizumab provides outcomes that are equivalent or superior to those in contemporaneous control patients receiving steroids.     

Cytotoxic T‐lymphocyte therapy for post‐transplant lymphoproliferative disorder after solid organ transplantation in children

EBV‐CTL immunotherapy targets EBV antigens expressed by tumor cells in PTLD. Data on outcome of EBV‐CTL in pSOT patients are limited. The aim of the study is to describe our experience with allogeneic, third‐party EBV‐CTL for the treatment of PTLD in pSOT patients in a single tertiary center. Retrospective review was performed of all pSOT patients who received EBV‐CTL for PTLD. PTLD was diagnosed using World Health Organization histologic criteria. EBV‐CTLs were derived from human leukocyte antigen‐typed, EBV‐seropositive third‐party donors, and cryopreserved and maintained by an accredited national blood transfusion service. Ten patients received EBV‐CTL for histologically proven PTLD from 1999 to 2016 following liver (n=5), combined intestinal/liver (n=4), and liver/kidney (n=1) transplantation. PTLD occurred at median age of 40 months (range: 12‐144) and median post‐transplant interval of 8 months (range: 2‐107). Seven had monomorphic, two had polymorphic, and one had Hodgkin‐type PTLD. All were of B‐cell origin and EBV‐positive on histology. EBV‐CTL achieved an overall remission rate of 80% (8 of 10). Transient adverse effects included fever, tachycardia, and vomiting. None developed graft‐versus‐host disease or opportunistic infections. EBV‐CTL is an effective treatment for PTLD in pSOT patients, with good remission rate and minimal toxicity.     

Subclinical cytomegalovirus and Epstein-Barr virus viremia are associated with adverse outcomes in pediatric renal transplantation

Post-transplant clinical disease with cytomegalovirus (CMV) and Epstein-Barr virus (EBV) is a known risk factor for graft dysfunction and lymphoproliferation. We postulate that subclinical, asymptomatic viremia also adversely impacts outcomes, and may warrant re-assessment of current monitoring and antiviral prophylaxis protocols. A single-center study was conducted on 102 pediatric (51 steroid-free and 51 matched steroid-based historical controls). Quantitative viral loads were serially monitored and correlated with outcome measures. Overall, the incidence of CMV and EBV clinical disease was 5% (1% CMV and 4% EBV); however, the incidence of subclinical viremia was 44% (12.7% CMV, 38.2% EBV, 6.9% CMV + EBV). Risk factors for subclinical viremia were EBV naivety (p = 0.07), age less than five yr (p = 0.04), lack of prophylaxis (p = 0.01), and steroid usage (p = 0.0007). Subclinical viremia was associated with lower three-yr graft function (p = 0.03), increased risk of acute rejection (odds ratio 2.07; p = 0.025), hypertension (p = 0.04), and graft loss (p = 0.03). Subclinical asymptomatic CMV and EBV viremia is a risk factor for graft injury and loss. These findings support the need for aggressive, serial viral monitoring to better determine the appropriate length of post-transplant antiviral prophylaxis, and to determine the effect of immunosuppression protocols on the development of viremia.     

Significance of Epstein–Barr virus status and post‐transplant lymphoproliferative disease in pediatric thoracic transplantation

Epstein-Barr virus (EBV)-associated post-transplant lymphoproliferative disease (PTLD) is a serious complication of organ and bone marrow transplantation. The importance of EBV matching between recipient and donor remains unclear. Between October 1987 and December 1997, 64 pediatric cardio-pulmonary transplants were performed at this center (58 hearts, two heart/lungs, four sequential single lungs). The EBV viral capsid antigen (VCA) immunoglobulin G (IgG) status of both donor and recipient was determined at the time of transplant. Of 56 patients from whom paired sera was available for analysis, 27 (50%) were recipient and donor EBV IgG positive, four (7%) were recipient EBV IgG positive and donor EBV IgG negative, and 12 (20%) were recipient EBV IgG negative and donor EBV IgG negative. The remaining 13 (23%) patients were EBV IgG negative but received organs from EBV IgG-positive donors. The EBV immunoglobulin M (IgM) status was determined from 6 weeks post-transplant in the 11 mismatches who survived for longer than 28 d. Seven became EBV IgM positive, two remained EBV IgM negative; the status of the remaining two remains unknown. The EBV IgM status was also determined retrospectively in patients who were EBV IgG negative pretransplant and received organs from EBV IgG-negative donors. Nine became EBV IgM positive; the rest remained negative. PTLD was diagnosed in two of 56 patients from whom paired sera was available; one was donor and recipient EBV IgG negative; the other was donor and recipient EBV IgG positive. No cases of PTLD were diagnosed in the remaining eight patients from whom paired sera was not available. Our experience suggests that PTLD does not occur with any greater frequency in the 'mismatch' group, and does not justify EBV matching in pediatric thoracic transplantation where there is a higher proportion of EBV-negative recipients than in adults.     

Complete immunosuppressive withdrawal as a uniform approach to post-transplant lymphoproliferative disease in pediatric liver transplantation

Epstein–Barr virus (EBV)‐associated post‐transplant lymphoproliferative disease (PTLD) in pediatric liver transplant recipients is associated with a high mortality (up to 60%) and the younger age groups, who are predominantly EBV‐naïve, are at highest risk for development of this disease. The aim of this study is to assess, in this high‐risk group, patient outcome and graft loss to rejection when complete withdrawal of immunosuppressive agents (IMS) is instituted as the mainstay of treatment in addition to the use of standard therapy. A retrospective analysis of 335 pediatric patients whose liver transplants were performed by our team between September 1988 and September 2002, was carried out through review of computer records, database and patient charts. Fifty patients developed either EBV or PTLD; 80% were ≤2 yr of age. Of these 50 patients, 19 had a positive tissue diagnosis for PTLD and 31 were diagnosed with EBV infection, 14 of whom had positive tissue for EBV. Fifty‐eight percent of patients who developed PTLD and 51.6% of patients with EBV received antibody for induction or treatment of rejection prior to onset of disease. Forty‐six patients (92%) received post‐transplant antiviral prophylaxis with ganciclovir or acyclovir. Antiviral treatment included ganciclovir in 76%, acyclovir in 20% and Cytogam (in addition to one of the former agents) in 44%. In those with PTLD, treatment included chemotherapy (n = 1), Rituximab (n = 2), and ocular radiation (n = 1). IMS was stopped in all patients with PTLD and in 19 with EBV infection and was held as long as there was no allograft rejection. Eight patients have remained off IMS for a mean of 1535.5 ± 623 days. Of the 21 patients who were restarted on IMS for acute rejection, 18 responded to steroids and/or reinstitution of low‐dose calcineurin inhibitors. The mean time to rejection while off IMS in this group was 107.43 ± 140 days (range: 7–476). Two patients were re‐transplanted for chronic rejection; one had chronic rejection that existed prior to discontinuing IMS. The mortality rate in our series was 31.6% in those with PTLD and 6% in those with EBV disease. The cause of death was related to PTLD or sepsis in all cases; no deaths were due to graft loss from acute or chronic rejection. PTLD is associated with high mortality in the pediatric population. Based on this report, we advocate aggressive management of PTLD that is composed of early cessation of IMS, the use of antiviral therapy, and chemotherapy when indicated. Episodes of rejection that occur after stopping IMS can be successfully treated with standard therapy without graft loss to acute rejection.