Chronic high Epstein–Barr viral load carriage in pediatric small bowel transplant recipients

Lau AH, Soltys K, Sindhi RK, Bond G, Mazariegos GV, Green M. Chronic high Epstein–Barr viral load carriage in pediatric small bowel transplant recipients.
Pediatr Transplantation 2010: 14:549–553. © 2010 John Wiley & Sons A/S. Abstract: The development of EBV infection and PTLD is normally associated with a high EBV load in peripheral blood. Often, children undergoing primary or reactivation of EBV infection subsequent to ITx will have chronically elevated EBV loads. To better understand this phenomenon and its consequences, we retrospectively reviewed the records of children who underwent ITx (either isolated or part of multivisceral transplantation) at our center from 1992 to 2007, to identify chronic high EBV load carriers in this population. CHL state was defined as the presence of high load for >50% of samples for greater than or equal to six months following either asymptomatic infection or complete clinical resolution of EBV disease/PTLD. Thirty‐five CHL carriers were identified from our patient population. Pretransplant serologies were available on 34 of these patients: 17 were EBV negative and 17 seropositive; one had unknown EBV serostatus prior to transplant. Seven of the 17 seronegative patients developed their CHL carrier state at the time of their primary EBV infection. Thirteen of the 35 (37%) HLC patients developed EBV disease after meeting the definition of high‐load carrier states. EBV‐related diseases developing in CHL carriers included EBV adenitis (n = 1), EBV enteritis (n = 7), PTLD (n = 4), and EBV+ spindle cell tumor (n = 1). Disease was seen in 7/17 of the seronegative (one PTLD) and 6/17 of the seropositive patients (three PTLD). Thirteen of 35 patients (37%) resolved their CHL state without apparent sequelae while nine remain asymptomatic CHL carriers. Three children have had more than one episode of CHL. These data provide important information about the outcome of chronic EBV high‐load carriage in pediatric intestinal transplant recipients.     

Post‐transplant lymphoproliferative disorder: No relationship to recombinant human growth hormone use in Australian and New Zealand pediatric kidney transplant recipients

PTLD is a potentially life‐limiting complication of pediatric transplantation. Previous registry‐based studies in renal transplantation have suggested a link between rhGH use and PTLD. In this study, demographic and transplant data on those aged <18 yr and transplanted between 1991 and 2008 were collected from the ANZDATA Registry. Associations between gender, age at time of transplant, recipient CMV and EBV status, use of monoclonal antibody therapy, and use of rhGH were studied as potential predictors of PTLD. Among 650 transplants, there were 20 cases (3.1%) of PTLD, with half presenting within two yr post‐transplant. Eight patients exposed to rhGH at any time developed PTLD, and this association was not statistically significant (RR = 1.5[0.6–3.4], p = 0.36). On multivariate analysis, there were no significant predictors for PTLD. In this study, previously identified potential risk factors were not identified as significant predictors for the development of PTLD. Although limited sample size may affect our ability to infer safety, this large retrospective cohort study does not suggest an increased risk of PTLD in pediatric kidney transplant recipients who received rhGH treatment.     

Risk factors for post-transplant lymphoproliferative disorder in pediatric patients: a case-control study

Post-transplant Lymphoproliferative Disorder (PTLD) because of the Epstein-Barr Virus (EBV) is a major concern after pediatric transplantation. The group at greatest risk is EBV-seronegative recipients who receive EBV-seropositive organs. Additional risk factors remain to be determined, including those among EBV-seropositive recipients. In this case-control study, PTLD cases were biopsy-proven over a period of 4 yr (1997-2000, inclusive). Each case was matched with 2 controls, based on the type of organ transplanted and the period of transplantation (+/-1 yr). Variables compared between cases and controls included those relating to the clinical and virologic profiles and immunosuppressive therapy. Twenty-two cases of PTLD were diagnosed during the study period. PTLD cases occurred at a median of 22.8 months post-transplantation (range 1-131). The median age of cases was 26.2 months (range 6.1-194) compared with 47.4 months (range 0.8-202.2) for controls (p = 0.93). Cases had a higher mean baseline EBV load compared with controls (3.1 log(10) (s.d. +/- 1.0) vs. 1.6 log(10)/10(6) PBMCs (s.d. +/- 1.4), with every 1 log increase in viral load resulting in a three times increase in the likelihood of PTLD (p < 0.007). Close to one in four cases of PTLD were EBV-seropositive pretransplantation. These seropositive recipients tended to be older patients with a trend to a worse outcome compared with their seronegative counterparts. The occurrence of PTLD was not associated with the use of any specific immunosuppressants. A significant proportion of PTLD cases occurred among EBV-seropositive transplant recipients, with a tendency towards an unfavorable outcome. Besides EBV-seronegative recipients who receive seropositive organs, some EBV-seropositive pediatric patients are at risk of PTLD. Additional studies are warranted to further define the factors associated with PTLD in EBV-seropositive transplant recipients.     

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.     

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.     

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.     

Gene expression using microarrays in transplant recipients at risk of EBV lymphoproliferation after organ transplantation: Preliminary proof‐of‐concept

Abstract: We hypothesized that aspects of the virus–host interaction could be measured to help predict progression to EBV–PTLD. We examined the spectrum of host genes differentially expressed and any relevant clustering in children at risk of EBV lymphoproliferation after organ transplantation. We compared the genes expressed among patients with different levels of viral loads. Gene expression was measured by microarray analysis of RNA from CD19+ B lymphocytes using the Human Genome U133 Plus 2.0 GeneChip. Among 27 samples from 26 transplant recipients, the viral load categories were: low or undetectable loads (LU), n = 14; high or intermediate loads (HI), n = 13. There were seven healthy EBV‐seropositive (P) and ‐seronegative controls (N). Median time of post‐transplantation was 0.5 yr (range 0.1–3.8). We identified 24–54 differentially expressed genes in each of four comparisons of HI vs. P, LU vs. P, HI vs. LU, and P vs. N. We identified patterns of 563 gene expressions, creating five clusters aligned with levels of viral load. PTLD occurred in four of five clusters. In summary, we demonstrated varying degrees of alignment between levels of VL and gene clusters. Analyses for differential expression of genes showed genes that could be implicated in the pathogenesis of EBV–PTLD.     

Post-transplant lymphoproliferative disease in pediatric lung transplant recipients: Recent advances in monitoring

Abstract: To investigate the clinical validity of newer diagnostic tests such as monitoring of EBVqPCR and lymphocyte function assay ImmuKnow in helping to diagnose PTLD in pediatric lung transplant recipients. Single‐center, retrospective case–control study. CsA trough levels, EBVqPCR and ImmuKnow (Cyclex Inc., Columbia, MD, USA) levels were measured serially as part of routine care. Re‐transplant patients and patients who did not reach 12 months post‐transplant at the time of analysis were excluded. Twenty‐seven patients met the inclusion criteria. The study group consisted of seven patients who developed PTLD, five of which were EBV? recipients who received EBV+ lungs. The rest of the eligible patients served as controls. Median time to develop PTLD was 273 days (range: 166–343). One, two, three, six, and nine months after transplant, mean (±s.d.) CsA trough whole blood levels (ng/mL) were not different between the two groups: 378 ± 38, 390 ± 52, 402 ± 89, 359 ± 42, and 342 ± 115, vs. 416 ± 105, 347 ± 64, 337 ± 78, 333 ± 86, and 281 ± 54 [PTLD vs. no‐PTLD, respectively (p > 0.05 for all time points)]. Mean (±s.d.) EBVqPCR levels (copies/mL) measured at three, six, and nine months post‐transplant were significantly elevated in PTLD group compared to no‐PTLD group: 84 ± 99, 3384 ± 7428 and 839 ± 1444 vs. 9 ± 26, 8 ± 36 and 32 ± 136, respectively (p < 0.05 for all time points). Mean (±s.d.) ImmuKnow levels (ATP ng/mL) at three, six, and nine months post‐transplant were significantly lower in the PTLD group when compared with no‐PTLD group: 144 ± 67, 137 ± 110, and 120 ± 153 vs. 290 ± 161, 300 ± 162, and 293 ± 190, respectively (p < 0.05 for all time points). Close monitoring of EBV viral load by qPCR and the degree of immunosuppression via ImmuKnow may guide physicians to reach the diagnosis of PTLD early.     

The changing face of post‐transplant lymphoproliferative disease in the era of molecular EBV monitoring

Kerkar N, Morotti RA, Madan RP, Shneider B, Herold BC, Dugan C, Miloh T, Karabicak I, Strauchen JA, Emre S. The changing face of post‐transplant lymphoproliferative disease in the era of molecular EBV monitoring.
Pediatr Transplantation 2010: 14:504–511. © 2010 John Wiley & Sons A/S. Abstract: Pediatric PTLD is often associated with primary EBV infection and immunosuppression. The aim was to retrospectively review the spectrum of histologically documented PTLD for two time intervals differentiated by changes in use of molecular EBV monitoring. Eleven of 146 patients (7.5%) in 2001–2005 (Era A) and 10 of 92 (10.9%) in 1993–1997 (Era B) were diagnosed with PTLD. The median age at liver transplantation (0.8 and 0.9 yr, respectively) and the median duration between liver transplant and diagnosis of PTLD (0.6 and 0.7 yr, respectively) were similar in both eras. However, patients in Era A presented with significantly less advanced histological disease compared to patients in Era B (p = 0.03). Specifically, nine patients (82%) in Era A had Pl hyperplasia/polymorphic PTLD, whereas in Era B, six had advanced histological disease (five monomorphic and one unclassified). Three transplant recipients in Era B died secondary to PTLD, whereas there were no PTLD‐related deaths in Era A (p = 0.03). Heightened awareness of risk for PTLD, alterations in baseline immunosuppression regimens, implementation of molecular EBV monitoring, pre‐emptive reduction in immunosuppression and improved therapeutic options may have all contributed to a milder PTLD phenotype and improved clinical outcomes.     

Mortality after pediatric kidney transplantation in England – a population‐based cohort study

The aim of this study was to explore mortality after pediatric kidney transplantation in England over the last decade. We used data from HES to select all kidney transplant procedures performed in England between April 2001 and March 2012. Data linkage analysis was performed with the ONS to identify all deaths occurring among this study cohort. Data for 1189 pediatric recipients were compared to 17 914 adult recipients (number of deaths, 33 vs. 2052, respectively, p < 0.001), with median follow‐up 4.4 yr (interquartile range 2.2–7.3 yr). There was no difference in mortality within the pediatric cohort; age 0–1 (n = 25, patient survival 100.0%), age 2–5 (n = 198, patient survival 96.0%), age 6–12 (n = 359, patient survival 97.5%), and age 13–18 (n = 607, patient survival 97.4%), respectively (p = 0.567). The most common causes of death were renal (n = 8, 24.2%), infection (n = 6, 18.2%), and malignancy (n = 5, 15.2%). All deaths from malignancy were secondary to PTLD. In a fully adjusted Cox regression model, only white ethnicity was significantly associated with risk of pediatric mortality post‐kidney transplantation (hazard ratio 2.7, 95% confidence interval [1.0–7.3], p = 0.047). To conclude, this population‐based cohort study confirms low mortality after pediatric kidney transplantation with short follow‐up.     

Outcomes in pediatric hepatitis C transplant recipients: Analysis of the UNOS database

HCV may lead to the development of ESLD in late childhood and, consequently, contributes to the need for liver transplantation. The aim of this study was to examine post‐transplant outcomes in HCV‐positive pediatric patients with ESLD from any cause and to determine the impact of the PELD scoring system, introduced in February 2002, on post‐transplant patient and graft survival. A retrospective analysis of the UNOS database from 1994 to 2010 was performed to assess graft and patient survival in pediatric HCV‐seropositive liver transplant recipients. Graft survival and patient survival comparing subjects in the pre‐PELD era and post‐PELD era were analyzed using Kaplan–Meier statistics. Factors associated with survival were identified using Cox regression analysis. Of 120 pediatric HCV transplant recipients, 80 were transplanted in the pre‐PELD era and 40 were transplanted post‐PELD. Median serum total bilirubin, INR, and creatinine were 4.8 mg/dL, 1.6, and 0.7 mg/dL in the pre‐PELD era vs. 5.5 mg/dL, 1.7, and 0.6 mg/mL, respectively, in the post‐PELD era (p NS). One‐yr graft survival in the pre‐PELD vs. post‐PELD era was 65.0% and 89.7%, respectively (p < 0.01); corresponding three‐yr graft survival was 57.3% vs. 76.2% (p = 0.04). One‐yr patient survival in the pre‐PELD vs. post‐PELD era was 79.0% and 97.5%, respectively (p < 0.01); corresponding three‐yr survival was 79.0% vs. 89.4% (p = 0.17). Twenty‐eight patients (23.3%) were retransplanted: 24 (30%) in the pre‐PELD era (median time to retransplant 272 days) and four (10%) in the post‐PELD era (median time to retransplant 586 days). Early follow‐up demonstrates a trend toward improved pediatric HCV liver transplant graft and patient survival in the post‐PELD era. Superior outcomes may be attributed to pretransplant factors, improved surgical technique and better treatment options for HCV infection.     

Epstein‐Barr virus DNA monitoring in serum and whole blood in pediatric liver transplant recipients who do or do not discontinue immunosuppressive therapy

The rate of PTLD can be reduced by weaned IS guided by monitoring of EBV DNA. In this single‐center retrospective case series study, we analyzed how reduction in IS influenced EBV DNA levels in whole blood and serum in 30 children during the first year after liver transplantation, and how these levels were related to symptoms putatively due to EBV. Primary and reactivated EBV infection was seen in 18 (60%) and eight patients (27%), respectively. Thirteen patients (42%) developed chronic high load the first year post‐transplant. IS was successfully discontinued in six patients the first year post‐transplant and in another two patients within 3 years. EBV DNA levels were reduced, but persisted long term in all the eight patients who had IS completely withdrawn. There was no case of PTLD. In summary, EBV DNAemia and chronic high load were very common after pediatric liver transplantation. Liver graft tolerance facilitates radical reduction in IS treatment, which may prevent PTLD, but EBV DNAemia may persist long term after discontinued IS.     

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 viremia levels after pediatric liver transplantation as measured by real-time polymerase chain reaction

Abstract: Effective immunosuppression has improved the results following liver transplantation, but also increased the risk for opportunistic infections. Epstein–Barr virus (EBV) infection in transplant patients can cause various symptoms including the life‐threatening premalignant condition, post‐transplantation lymphoproliferative disorder (PTLD). Serum specimens from 24 consecutive children (mean 7.6 specimens/patient), who had undergone liver transplantation in Göteborg from January 1995 to May 2002, were analyzed retrospectively for EBV DNA by real‐time TaqMan^® polymerase chain reaction (PCR). The results were related to clinical picture, immunosuppression, graft rejection and infections with other agents. Eleven patients (46%) developed primary EBV infection at a mean time of 4.8 months after transplantation, and six (25%) reactivated EBV infection at a mean of 4.0 months after transplantation. Four of the 11 patients with primary infection had symptomatic EBV infection: two had PTLD and two hepatitis. One patient in the group with reactivated infection developed PTLD. EBV DNA levels were significantly higher in the group with primary symptomatic infection compared with the patients with primary asymptomatic infection (mean 65 500 copies/mL; range 14 200–194 300 vs. 3700 copies/mL; range 100–9780). In patients with symptomatic infection EBV DNA levels did not differ between PTLD and hepatitis patients. The data suggest that quantitative analysis of EBV DNA in serum by real‐time PCR is useful for identification of EBV‐related disease.     

Epstein‐Barr viral load monitoring for diagnosing post‐transplant lymphoproliferative disorder in pediatric liver transplant recipients

This study aimed to investigate the incidence of PTLD in pediatric liver transplant recipients and the risk factors for the development of PTLD. We also determined clinically useful quantitative EBV PCR parameters for aiding in the diagnosis of EBV‐associated PTLD in the pediatric liver transplant recipients at our institute. We reviewed children < 18 years old who had undergone liver transplantations and quantitative analysis of whole blood EBV load at our institute from January 2006 to March 2015. A total of 142 liver transplant recipients were included, and their median age was 1.5 years. Clinically significant high‐level EBV DNAemia ≥ 10 000 copies/mL at least twice was observed in 53.5% and PTLD occurred in 9.9%. Among PTLD group, graft failure and mortality rate were as high as 21.4% and 14.3%, respectively. Deceased donor, presence of high‐level EBV DNAemia, and primary CMV infection following transplant were associated with an increased risk for PTLD in the multivariate analysis. The peak titer at 10 875 copies/mL could be used as a cutoff value with a sensitivity of 92.9% and a specificity of 37.9%; the rate of increase in EBV load suggested a sensitivity of 64.3% and a specificity of 70.9% at the cutoff value of 44 000 copies/mL/week. In conclusion, the incidence of PTLD following liver transplant in children was as high as 10%. PTLD is associated with significant morbidity and mortality. Close monitoring of EBV DNAemia is crucial for the early diagnosis and proper treatment of PTLD in pediatric liver transplant recipients.     

Kidney transplant in pediatric patients with severe bladder pathology

The aim of the current study was to compare results in pediatric renal transplantation of patients with and without SBP. Between 2001 and 2013, a total of 168 kidney transplants were performed at our center. A retrospective analysis was performed and recipients were divided into two groups: NB and SBP. Incidence of surgical complications after procedure, and graft and patient survival were evaluated. A total of 155 recipients (92%) with complete data were analyzed, and 13 recipients that had had previous bladder surgeries were excluded (11 with VUR surgery and two with previous kidney transplants), of the 155 recipients: 123 (79%) patients had NB, and 32 (21%) patients had SBP, with a median follow‐up of 60 (1–137) and 52 (1–144) months, respectively. Among post‐transplant complications, UTI (68.8% vs. 23%, p < 0.0001) and symptomatic VUR to the graft (40.6% vs. 7.3%, p < 0.0001) were significantly higher in the SBP group. There was no significant difference in overall graft and patient survival between groups. Renal transplantation is safe in pediatric recipients with SBP; however, urologic complications such as UTI and VUR were significantly higher in this group. Graft and patient survival was similar in SBP and NB groups.     

The role of quantitative Epstein-Barr virus polymerase chain reaction and preemptive immunosuppression reduction in pediatric liver transplantation: a preliminary experience.

BACKGROUND: Risk factors for the development of posttransplant lymphoproliferative disease (PTLD), a major cause of morbidity and mortality after pediatric liver transplantation, are primary Epstein-Barr virus (EBV) infection and intensity of immunosuppression. The authors assessed monitoring of EBV replication and preemptive immunosuppression reduction in pediatric liver transplant recipients. METHODS: The authors prospectively followed monthly EBV-quantitative competitive polymerase chain reaction to measure EBV replication in 23 patients who underwent liver transplant between July 1997 and November 1998. Preemptive immunosuppression reduction was instituted for significant EBV replication. Patients were followed up for at least 1 year and divided in two groups for analysis (group 1, pretransplant seronegative for EBV [13 patients]; group 2, seropositive for EBV [10 patients]). RESULTS: In group 1, 9 of 13 patients had positive polymerase chain reaction results at a mean time of 22.4 weeks after transplantation. All but one of these patients were asymptomatic. In seven of nine patients, preemptive immunosuppression reduction was undertaken without development of PTLD or rejection. In two of nine patients, immunosuppression could not be continuously reduced, and both patients experienced low-grade and medically responsive PTLD. In no patient in group 2 did an EBV-positive viral load or PTLD develop. CONCLUSIONS: Prospective longitudinal measurement of EBV by quantitative competitive polymerase chain reaction permits early detection of asymptomatic viral replication. Subsequent preemptive reduction of immunosuppression may prevent the progression to PTLD.     

Diagnosis and treatment of post-transplantation lymphoproliferative disorder in pediatric heart transplant patients

PTLD is a severe complication in transplant recipients. Detection of increased EBV load in the peripheral blood acts as a surrogate marker for increased risk of PTLD development. We analyzed the time course of the disease, its severity, the organs involved, and mortality rates in our institutional experience of pediatric heart transplantation. This paper identifies risk factors for PTLD and describes the different ways of diagnosing and treating the disease. PTLD was screened for in 146 pediatric heart transplant patients using a retrospective analysis in patients who received transplantation before 1998. Prospective determination was performed in 72/146 patients transplanted after 1998 within the post-transplant follow-up. The occurrence of PTLD with all interventions, including tapering of immunosuppression, surgery, viral monitoring, and antiviral interventions, was recorded. PTLD was diagnosed in 12/147 (8.2%) children at a mean age of 7.2 +/- 3.3 yr after a mean post-transplant period of 3.2 +/- 2.2 yr. PTLD manifested in: lymph nodes (n = 4), intestine (n = 3), tonsils and adenoids (n = 2), eye (n = 2), and lung (n = 1). It was diagnosed in 7/12 as a monomorphic B-cell lymphoma and in four patients as a monomorphic Burkitt lymphoma, a polymorphic B-cell lymphoma, a T-cell rich or angiocentric lymphoma (Liebow) and as reactive plasmacytic hyperplasia (early lesion), respectively. Histology was not possible in one patient with ocular manifestation. EBV association was 83%. Risk factors in the comparison with patients without PTLD were age at time of Tx, primary EBV infection after Tx, use of Azathioprine and >or=3 doses of ATG. CMV mismatch and CMV infection, rejection episodes and steroids were not risk factors. Despite reduction of immunosuppression, treatment consisted of surgical procedures to remove tumor masses (n = 6), Rituximab (n = 5), polychemotherapy (n = 3), antiviral (n = 1) and autologous T-cell therapy (n = 1). All patients demonstrated full remission without death related to PTLD or treatment at 3.9 (1.3-6.2) yr median follow-up time. The manifestation of PTLD in pediatric heart transplant recipients is associated with EBV infection and is predominantly in the form of a B-cell lymphoma. A tight and specific follow-up including early assessment of immunity status and specific therapeutic intervention to improve cellular immunity is warranted and may contribute to a significant reduction of PTLD-related morbidity and mortality.