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The International Pediatric Transplant Association convened an expert consensus conference to assess current evidence and develop recommendations for various aspects of care relating to post‐transplant lymphoproliferative disorders (PTLD) after pediatric solid organ transplantation. This report addresses the outcomes of deliberations by the PTLD Management Working Group. A strong recommendation was made for reduction in immunosuppression as the first step in management. Similarly, strong recommendations were made for the use of the anti‐CD20 monoclonal antibody (rituximab) as was the case for chemotherapy in selected scenarios. In some scenarios, there is uncoupling of the strength of the recommendations from the available evidence in situations where such evidence is lacking but collective clinical experiences drive decision‐making. Of note, there are no large, randomized phase III trials of any treatment for PTLD in the pediatric age group. Current gaps and future research priorities are highlighted. [ABSTRACT FROM AUTHOR]

Background: Epstein–Barr virus (EBV)‐associated post‐transplant lymphoproliferative disorders (PTLD) is the most common malignancy in children after transplant; however, difficulties for early detection may worsen the prognosis. Methods: The prospective, multicenter, study enrolled 944 children (≤21 years of age). Of these, 872 received liver, heart, kidney, intestinal, or multivisceral transplants in seven US centers between 2014 and 2019 (NCT02182986). In total, 34 pediatric EBV+ PTLD (3.9%) were identified by biopsy. Variables included sex, age, race, ethnicity, transplanted organ, EBV viral load, pre‐transplant EBV serology, immunosuppression, response to chemotherapy and rituximab, and histopathological diagnosis. Results: The uni−/multivariable competing risk analyses revealed the combination of EBV‐seropositive donor and EBV‐naïve recipient (D+R−) was a significant risk factor for PTLD development (sub‐hazard ratio: 2.79 [1.34–5.78], p =.006) and EBV DNAemia (2.65 [1.72–4.09], p <.001). Patients with D+R− were significantly more associated with monomorphic/polymorphic PTLD than those with the other combinations (p =.02). Patients with monomorphic/polymorphic PTLD (n = 21) had significantly more EBV DNAemia than non‐PTLD patients (p <.001) and an earlier clinical presentation of PTLD than patients with hyperplasias (p <.001), within 6‐month post‐transplant. Among non‐liver transplant recipients, monomorphic/polymorphic PTLD were significantly more frequent than hyperplasias in patients ≥5 years of age at transplant (p =.01). Conclusions: D+R− is a risk factor for PTLD and EBV DNAemia and associated with the incidence of monomorphic/polymorphic PTLD. Intensive follow‐up of EBV viral load within 6‐month post‐transplant, especially for patients with D+R− and/or non‐liver transplant recipients ≥5 years of age at transplant, may help detect monomorphic/polymorphic PTLD early in pediatric transplant. [ABSTRACT FROM AUTHOR]

Background: There are scant data on the effect of rituximab on EBV DNA levels and prevention of post‐transplant lymphoproliferative disorder (PTLD) in pediatric kidney transplant recipients with EBV DNAemia. Methods: Kidney transplant recipients with EBV DNAemia treated with rituximab to prevent PTLD between 7/1999 and 7/2019 at five pediatric centers were included. Those with confirmed PTLD at the onset of rituximab were excluded. Primary outcomes included percentage change in EBV DNAemia and occurrence of PTLD post rituximab. Results: Twenty‐six pediatric kidney transplant recipients were included. Median age at transplant was 4 years (IQR 2.1–10.3). EBV DNA load monitoring by qPCR was performed at 1–3 month intervals. EBV DNAemia onset occurred at a median of 73 days post‐transplant (IQR 52–307), followed by DNAemia peak at a median of 268 days (IQR 112–536). Rituximab was administered at a median of 9 days post peak (IQR 0–118). Rituximab regimens varied; median dose 375 mg/m2 (IQR 375–439) weekly for 1–4 doses per course. Following rituximab, EBV DNA load decreased to <10% of baseline at 120 days in 20/26 patients; however, only 30% achieved complete resolution at last follow‐up (median 2094 days post‐transplant [IQR 1538–3463]). Two (7%) developed PTLD at 915 and 1713 days post rituximab. All recipients had functioning grafts. One death occurred in a child with PTLD following remission due to unrelated reasons. Conclusions: In the largest pediatric kidney transplant recipient case series with EBV DNAemia given rituximab to prevent PTLD, rituximab achieved a short‐term reduction in DNA load; however, recurrent DNAemia is common. [ABSTRACT FROM AUTHOR]

The International Pediatric Transplant Association (IPTA) convened an expert consensus conference to assess current evidence and develop recommendations for various aspects of care relating to post‐transplant lymphoproliferative disorder after solid organ transplantation in children. In this report from the Prevention Working Group, we reviewed the existing literature regarding immunoprophylaxis and chemoprophylaxis, and pre‐emptive strategies. While the group made a strong recommendation for pre‐emptive reduction of immunosuppression at the time of EBV DNAemia (low to moderate evidence), no recommendations for use could be made for any prophylactic strategy or alternate pre‐emptive strategy, largely due to insufficient or conflicting evidence. Current gaps and future research priorities are highlighted. [ABSTRACT FROM AUTHOR]

The International Pediatric Transplant Association convened an expert consensus conference to assess current evidence and develop recommendations for various aspects of care relating to post‐transplant lymphoproliferative disorders after solid organ transplantation in children. In this report from the Viral Load and Biomarker Monitoring Working Group, we reviewed the existing literature regarding the role of Epstein‐Barr viral load and other biomarkers in peripheral blood for predicting the development of PTLD, for PTLD diagnosis, and for monitoring of response to treatment. Key recommendations from the group highlighted the strong recommendation for use of the term EBV DNAemia instead of "viremia" to describe EBV DNA levels in peripheral blood as well as concerns with comparison of EBV DNAemia measurement results performed at different institutions even when tests are calibrated using the WHO international standard. The working group concluded that either whole blood or plasma could be used as matrices for EBV DNA measurement; optimal specimen type may be clinical context dependent. Whole blood testing has some advantages for surveillance to inform pre‐emptive interventions while plasma testing may be preferred in the setting of clinical symptoms and treatment monitoring. However, EBV DNAemia testing alone was not recommended for PTLD diagnosis. Quantitative EBV DNAemia surveillance to identify patients at risk for PTLD and to inform pre‐emptive interventions in patients who are EBV seronegative pre‐transplant was recommended. In contrast, with the exception of intestinal transplant recipients or those with recent primary EBV infection prior to SOT, surveillance was not recommended in pediatric SOT recipients EBV seropositive pre‐transplant. Implications of viral load kinetic parameters including peak load and viral set point on pre‐emptive PTLD prevention monitoring algorithms were discussed. Use of additional markers, including measurements of EBV specific cell mediated immunity was discussed but not recommended though the importance of obtaining additional data from prospective multicenter studies was highlighted as a key research priority. [ABSTRACT FROM AUTHOR]

The International Pediatric Transplant Association (IPTA) Consensus Conference on Practice Guidelines for the Diagnosis, Prevention, and Management of Post‐Transplant Lymphoproliferative Disorders after Solid Organ Transplantation in Children took place on March 12–13, 2019, and the work of conference members continued until the end of December 2021. The goal was to produce evidence‐based consensus guidelines on the definitions, diagnosis, prevention, and management of PTLD and related disorders based on the critical review of the literature and consensus of experts. This report describes the goals, organization, and methodology of the consensus conference and follow‐up activities. The results of each working group (Definitions, Prevention, Management, and Epstein–Barr viral [EBV] load/Biomarker Monitoring) are presented in separate manuscripts within this volume of Pediatric Transplantation. [ABSTRACT FROM AUTHOR]

Background: After solid organ transplantation, children are at risk for Epstein–Barr virus‐associated post‐transplant lymphoproliferative disorder and smooth muscle tumors. Little is known about the clinical course, Epstein–Barr viral load variations, and optimal treatment for such patients. We set forth to understand the course of repeated episodes of post‐transplant lymphoproliferative disorder and smooth muscle tumors. Methods: We performed a retrospective chart review of patients up to 21 years old with solid organ transplantation and post‐transplant lymphoproliferative disorder at the Children's Hospital of Philadelphia from January 2003 through June 30, 2020. Results: Six patients had multiple episodes of Epstein–Barr virus‐associated post‐transplant lymphoproliferative disorder and smooth muscle tumors. When the second episode was discovered, only one patient was symptomatic. Histology differed from diagnosis in four patients. Treatment included viral‐specific T‐lymphocytes (2), rituximab (3), reduction in immunosuppression alone (1). Five patients had complete response, and one had stable disease, but three patients developed a subsequent tumor. Two patients developed Epstein–Barr virus‐associated smooth muscle tumors. Of these six patients, four are alive. The deaths were not related to their tumors. Conclusions: Despite a complete response to initial therapy, children are at risk for repeated episodes of Epstein–Barr virus‐associated post‐transplant lymphoproliferative disorder and smooth muscle tumors. Histology and location were not typically consistent with initial diagnosis, suggesting these are second primaries rather than recurrences. Disease may be managed with individualized treatment plans but EBV‐specific T cells need further study in such tumors. [ABSTRACT FROM AUTHOR]

Background: Posttransplant lymphoproliferative disease (PTLD) is a serious complication after pediatric liver transplantation (pLT), which may lead to death. 18F‐FDG PET/CT is rarely considered in PTLD after pLT and lacks clear diagnostic guidelines, especially in the differential diagnosis of nondestructive PTLD. The aim of this study was to find a quantifiable 18F‐FDG PET/CT index to identify nondestructive PTLD after pLT. Methods: This retrospective study collected the data of patients who underwent pLT, postoperative lymph node biopsy, and 18F‐FDG PET/CT at Tianjin First Central Hospital from January 2014 to December 2021. Quantitative indexes were established using lymph node morphology and the maximum standardized uptake value (SUVmax). Results: A total of 83 patients met the inclusion criteria and were included in this retrospective study. To distinguish between PTLD‐negative cases and nondestructive PTLD cases, according to the receiver operating characteristic curve, (the shortest diameter of the lymph node at the biopsy site [SDL]/the longest diameter of the lymph node at the biopsy site [LDL])*(SUVmax at the biopsy site [SUVmaxBio]/SUVmax of the tonsils [SUVmaxTon]) had the maximum area under the curve (0.923; 95% confidence interval: 0.834–1.000), and the cutoff value was 0.264 according to the maximum value of Youden's index. The sensitivity, specificity, positive predictive value, negative predictive value, and accuracy were 93.6%, 94.7%, 97.8%, 85.7%, and 93.9%, respectively. Conclusions: (SDL/LDL)*(SUVmaxBio/SUVmaxTon) has good sensitivity, specificity, positive predictive and negative predictive values, and accuracy, and can be used as a good quantitative index for the diagnosis of nondestructive PTLD. [ABSTRACT FROM AUTHOR]

Background: Late airway complications, as consequence of immunosuppression following pediatric liver transplantation are uncommonly reported. Methods: In this retrospective case series, we describe two young children presenting with symptoms of airway obstruction, secondary to differing pathologies in the supraglottic airway, as a result of immunosuppression following liver transplantation. Results: Case 1, a 2‐year‐old girl who presented with stridor 12‐months following liver transplantation, was found to have a proliferative soft tissue mass involving the supraglottic larynx. Biopsies were consistent with infiltrative eosinophilic laryngitis and associated eosinophilic esophagitis. Case 2, a 12‐month‐old female who presented with stridor 5‐months following liver transplantation, was found to have an exophytic soft tissue mass involving the supraglottis and hypopharynx. Biopsies revealed polymorphic Epstein–Barr virus (EBV) driven post‐transplant lymphoproliferative disease (PTLD). Case 1 was managed with local resection and high dose oral corticosteroids. Case 2 responded to debulking of the necrotic supraglottic mass, reduction of immunosuppression and rituximab. Conclusion: A high index of suspicion needs to be maintained for complications of immunosuppression for appropriate diagnosis of airway presentations following pediatric liver transplantation. Further research is necessary to improve early detection and consolidate management strategies for these airway lesions. [ABSTRACT FROM AUTHOR]

Background: The anti‐CD20 rituximab is often used in the treatment of children with steroid‐resistant nephrotic syndrome or EBV‐induced post‐transplant lymphoproliferative disorder. This single‐center series reports the use of rituximab as induction therapy in pediatric kidney transplantation. Methods: Four children who received rituximab as induction therapy for kidney transplantation since 2016 were retrospectively analyzed. Clinical and laboratory data were extracted from medical records. Results: The patients (2 boys and 2 girls) were aged from 6.1 to 11.9 years and were treated with rituximab on the day of the transplantation procedure; all the transplants came from deceased donors. In all patients, rituximab was used because of positive EBV viral loads before kidney transplantation. Viral loads remained undetectable for the first 6 months after the transplantation procedure and remained below the 4.5 log threshold thereafter. After a median follow‐up of 2.3 years, none of the patients displayed rejection or de novo donor‐specific antibodies; the glomerular filtration rate remained above 70 ml/min/1.73 m2. No post‐transplant lymphoproliferative disorder was observed. Conclusion: The results suggest that rituximab can be used as induction therapy to prevent EBV replication and its complications in case of positive viral load prior to kidney transplantation. [ABSTRACT FROM AUTHOR]

Background: Post‐transplant lymphoproliferative disorder (PTLD) are the most common de novo malignancies after liver transplantation (LT) in children. The aim of our study was to assess the role of pre‐LT EBV status and post‐LT EBV viral load as risk factors for developing PTLD in a cohort of pediatric LT recipients. Methods: Data of all children who underwent LT between January 2002 and December 2019 were collected. Two cohorts were built EBV pre‐LT primary infected cohort and EBV post‐LT primary infected cohort. Moreover, using the maximal EBV viral load, a ROC curve was constructed to find a cutoff point for the diagnosis of PTLD. Results: Among the 251 patients included in the study, fifteen PTLD episodes in 14 LT recipients were detected (2 plasmacytic hyperplasia, 10 polymorphic PTLD, 2 monomorphic PTLD, and 1 Classical‐Hodgkin's lymphoma). Patients of the EBV post‐LT primary infected cohort were 17.1 times more likely to develop a PTLD than patients of the EBV pre‐LT primary infected cohort (2.2–133.5). The EBV viral load value to predict PTLD was set at 211 000 UI/mL (93.3% sensitivity and 77.1% specificity; AUC 93.8%; IC 0.89–0.98). In EBV post‐LT primary infected cohort, patients with a viral load above 211 000 were 30 times more likely to develop PTLD than patients with a viral load below this value (OR 29.8; 3.7–241.1; p < 0.001). Conclusions: The combination of pretransplant EBV serological status with EBV post‐transplant viral load could be a powerful tool to stratify the risk of PTLD in pediatric LT patients. [ABSTRACT FROM AUTHOR]

Background: Protein‐losing enteropathy (PLE) is a devastating complication of the Fontan circulation. Although orthotopic heart transplantation (HTx) typically results in resolution of PLE symptoms, isolated cases of PLE relapse have been described after HTx. Methods: Patients with Fontan‐related PLE who had undergone HTx at participating centers and experienced relapse of PLE during follow‐up were retrospectively identified. Available data related to pre‐ and post‐HTx characteristics and PLE events were collected. Results: Eight patients from four different centers were identified. Median time from Fontan procedure to the development of PLE was 8 years, and median age at HTx was 17 years (range 7.7–21). In all patients, PLE resolved at a median time of 1 month after HTx (0.3–5). PLE recurrences occurred at a median time of 7.5 months after HTx (2–132). Each occurrence was associated with one or more significant clinical events; most commonly cellular‐ or antibody‐mediated rejection; and less commonly graft dysfunction, infection, thrombosis, and posttransplant lymphoproliferative disease. PLE recurrences resolved after the successful treatment of the concomitant event, after a median time of 2 months in seven cases, while persisted and recurred in one patient in association with atypical mycobacterium infection and subsequent PTLD onset and relapses. Six patients were alive during follow‐up at a median time of 4 years (1.3–22.5) after HTx. Conclusions: This is the largest series of PLE recurrence after HTx. All cases were associated with one or more concomitant and significant clinical events. PLE typically resolved after resolution of the inciting clinical event. [ABSTRACT FROM AUTHOR]

Background: This study aimed to characterize features present at the time of diagnosis and describe outcomes in patients with post‐transplant lymphoproliferative disorder (PTLD) following pediatric solid organ transplantation. Methods: We performed a retrospective review of solid organ transplant patients who developed pathologically confirmed PTLD at our center from 2006 to 2016. Results: Of 594 patients included in this study, 41(6.9%) were diagnosed with PTLD. Median age at transplant was 5.6(IQR 1.7–16.1) years. Proportion of PTLD cases by organ transplanted and median time (IQR) to disease onset were: heart 11/144(7.6%) at 13.6(8.5–55.6) months, lung 7/52(13.5%) at 9.1(4.9–35) months, kidney 8/255(3.1%) at 39.5(13.9–57.1) months, liver 12/125(9.6%) at 7.7(5.5–22) months, intestine 0/4(0%), and multi‐visceral 3/14(21.4%) at 5.4(5.4–5.6) months. No significant correlation was seen between recipient EBV status at transplant and timing of development of PTLD. There were six early lesions, 15 polymorphic, 19 monomorphic, and one uncharacterizable PTLD. Following immunosuppression reduction, 30 patients received rituximab, and 14 required chemotherapy. At median 25(IQR 12–53) months follow‐up from the onset of PTLD, eight patients died secondary to transplant related complications, three are alive with active disease, and 30 have no evidence of disease. Conclusion: PTLD is a significant complication following pediatric solid organ transplantation. EBV levels in conjunction with symptomatic presentation following transplant may assist in detection of PTLD. Most patients can achieve long‐term disease‐free survival through immunosuppression reduction, anti‐CD20 treatment, and chemotherapy in refractory cases. [ABSTRACT FROM AUTHOR]

Background: Pediatric kidney transplant recipients are at risk for the development of post‐transplant lymphoproliferative disorders (PTLD), a group of potentially devastating diseases that present on a spectrum of severity ranging from nondestructive PTLD to more histologically destructive lesions. Currently, there is inadequate evidence to guide evaluation and management of nondestructive PTLD. Methods: This is a single‐center case series of pediatric kidney transplant recipients between January 1, 2008 and December 31, 2019, who were diagnosed with PTLD. The aim was to describe clinical characteristics, presentation, and management of nondestructive versus advanced PTLD. Results: Eighteen patients were diagnosed with nondestructive PTLD and seven with more advanced PTLD histopathology. The majority (66.7%) of nondestructive PTLD patients (n = 16) presented with tonsillar hypertrophy and/or snoring and were managed conservatively, with minimal reduction in tacrolimus dose and no further evaluation. No patient progressed to more advanced PTLD. Advanced PTLD patients (n = 7) were more likely to present with fever, elevated creatinine, a new mass of gastrointestinal symptoms. They received workup with imaging and oncology consultation, and were managed with chemotherapy. Conclusions: Patients with nondestructive PTLD often present with symptoms of sleep‐disordered breathing and can be managed conservatively with excellent clinical outcomes. More study is needed to guide care of this under‐researched population. [ABSTRACT FROM AUTHOR]

Background: PTLD is a clinical condition with high mortality. Monitoring EBV replication can be a useful tool to avoid the development of PTLD. Materials and Methods: This was a retrospective analysis of 428 pediatric patients who underwent liver transplantation between 1989 and 2016. The patients were divided into 2 groups (transplanted before 2006, when PCR‐EBV was not monitored, and after 2006, when PCR‐EBV monitoring was started). Patients with continuous PCR measurements for EBV were evaluated for the impact of a reduction in immunosuppression or a change in immunosuppressants on the number of viral copies. A logistic regression model was applied to evaluate factors related to PTLD. Results: The prevalence of PTLD was 4.2%. After monitoring patients with PCR for EBV levels, a predominance of the most severe, monomorphic form of lymphoproliferative disorder was observed (p =.009). The PTLD mortality was 5%. There was a change in the PCR level after tacrolimus reduction (p =.002) and after tacrolimus exchange for mTOR (p =.008). The number of EBV copies was significantly higher (p =.029) in patients who developed PTLD. In the multiple regression model, seropositivity for CMV was an independent protective factor for lymphoproliferative disorder (OR=0.09; 95% CI 0.02–0.42), reducing the chance of having PTLD adjusted by serology for EBV by 91%. Conclusions: Monitoring the EBV viral load by PCR seems to prevent the emergence of milder forms of lymphoproliferative disorder. Pretransplant seropositivity for CMV is a protective factor for PTLD. [ABSTRACT FROM AUTHOR]

Background: Epstein‐Barr virus (EBV) can cause severe disease following hematopoietic stem cell transplant (HSCT), including post‐transplant lymphoproliferative disorder (PTLD). The objective was to analyze risk factors associated with post‐transplant EBV outcomes among pediatric allogeneic HSCT recipients. Methods: We used data from 156 pediatric allogeneic HSCT recipients enrolled in the Canadian multicenter TREASuRE study. Cox and Prentice‐Williams‐Petersen models were used to analyze risk factors for post‐transplant EBV events including occurrence and recurrence of EBV DNAemia, increase in EBV viral load (EBV‐VL), and preemptive use of rituximab, an effective therapy against PTLD. Results: Females were at higher risk for increasing EBV‐VL (adjusted hazard ratio (HR) = 2.83 [95% confidence intervals (CI): 1.33–6.03]) and rituximab use (HR = 3.08 [1.14–8.30]), but had the same EBV DNAemia occurrence (HR = 1.21 [0.74–1.99]) and recurrence risks (HR=1.05 [0.70–1.58]) compared to males. EBV DNAemia was associated with recipient pre‐transplant EBV seropositivity (HR = 2.47 [1.17–5.21]) and with graft from an EBV‐positive donor (HR = 3.53 [1.95–6.38]). Anti‐thymocyte globulin (ATG) was strongly associated with all EBV outcomes, including the use of rituximab (HR = 5.33 [1.47–19.40]). Mycophenolate mofetil (MMF) significantly decreased the risk of all EBV events including the rituximab use (HR = 0.13 [0.03–0.63]). Conclusion: This study in pediatric allogeneic HSCT patients reveals a reduced risk of all EBV outcomes with the use of MMF. Risk factors for EBV events such as EBV‐VL occurrence and recurrence include EBV positivity in the donor and recipient, and use of ATG, whereas risk factors for the most severe forms of EBV outcome (EBV‐VL and the use of rituximab) include female sex and ATG use. [ABSTRACT FROM AUTHOR]

Background: Post‐transplant lymphoproliferative disease (PTLD) is a life‐threatening complication in renal transplant recipients. Immunomodulatory and chemotherapeutic treatment potentially affect allograft function. The aim of this study was to evaluate graft function of pediatric kidney transplant recipients following diagnosis and standardized treatment of PTLD. Methods: Patients were identified from the German Ped‐PTLD registry, and data on renal function were retrospectively retrieved from patient charts. For PTLD treatment, immunosuppressive therapy was reduced and all children received rituximab (375 mg/m2) for up to six doses. Two patients required additional low‐dose chemotherapy. Renal allograft function was monitored by consecutive measurements of estimated glomerular filtration rate (eGFR) at defined time points. Follow‐up was up to 60 months after PTLD. Results: Twenty patients were included in this cohort analysis. Median time from transplantation to PTLD was 2.4 years. Histopathology showed monomorphic lesions in 16 and polymorphic in 4 patients. Two patients experienced PTLD relapse after 2 and 14 months. Range‐based analysis of variance showed stable allograft function in 17 of 20 patients (85%). Mean eGFR increased during early treatment phase. One patient experienced graft rejection 5.3 years after diagnosis of PTLD. Another patient developed recurrence of primary renal disease (focal‐segmental glomerulosclerosis) and lost his renal allograft 3.8 years post‐transplant (2.0 years after PTLD diagnosis). Conclusion: Treatment of PTLD with rituximab with or without low‐dose chemotherapy in combination with reduced immunosuppression, mostly comprising of an mTOR inhibitor‐based, calcineurin inhibitor‐free regimen, is associated with stable graft function and favorable graft survival in pediatric renal transplant patients. [ABSTRACT FROM AUTHOR]

Background: PNP is a malignancy‐associated autoimmune mucocutaneous syndrome due to autoantibodies against plakins, desmogleins, and other components of the epidermis and basement membrane of epithelial tissues. PNP‐causing malignancies comprise mainly lymphoproliferative and hematologic neoplasms. PNP is extremely rare, especially in children. Methods: Here, we present the first case of a child who developed PNP on a PTLD after small bowel transplantation because of a severe genetic protein‐losing enteropathy. Results: The patient in this case report had a severe stomatitis, striate palmoplantar keratoderma, and lichenoid skin lesions. In addition, she had marked esophageal involvement. She had lung pathology due to recurrent pulmonary infections and ventilator injury. Although we found no evidence of BO, she died from severe pneumonia and respiratory failure at the age of 12 years. Conclusion: It is exceptional that, despite effective treatment of the PTLD, the girl survived 5 years after her diagnosis of PNP. We hypothesize that the girl survived relatively long after the PNP diagnosis due to strong T‐cell suppressive treatments for her small bowel transplantation. [ABSTRACT FROM AUTHOR]

Post‐transplant lymphoproliferative disorders (PTLD) are a group of lesions that can complicate solid organ or hematopoietic stem cell transplantation and are often associated with Epstein‐Barr virus (EBV). The treatment of PTLD is dependent on the type of lesion and includes a wide range of therapies, but chimeric antigen receptor (CAR) T‐cell therapy has not previously been reported as a treatment option for PTLD. We present a patient who developed refractory PTLD in her right retroperitoneum, right inguinal and iliac chains, and right axillary region shortly after heart transplantation and was treated with CAR T‐cell therapy. She could not tolerate complete discontinuation of immunosuppression due to the risk of rejection of a life‐supporting graft. The patient's PTLD responded to CAR T‐cell therapy, and her heart was monitored throughout the treatment course without any signs of rejection or ventricular dysfunction. CAR T‐cell therapy may be a viable treatment option in patients who develop PTLD after a solid organ transplant. [ABSTRACT FROM AUTHOR]

Some centers prefer CMV-IVIG over IVIG for the prophylaxis of EBV-related PTLD in solid organ transplant patients. Our objective was to compare the relative dose-related EBV ELISA antibody concentrations and cost of standard IVIG and CMV-IVIG. The concentration of EBV IgG to VCA was analyzed via ELISA in four lots of IVIG and four lots of CMV-IVIG. Relative EBV ELISA antibody concentrations and cost were compared assuming an IVIG dose of 0.5 gm/kg and CMV-IVIG dose of 0.15 gm/kg in a 50-kg patient. The price of IVIG was $70/gm and CMV-IVIG $430/gm. IVIG contains the same EBV antibody concentrations (20 790 ELISA antibody units/mL) than CMV-IVIG (17 430 ELISA antibody units/mL, p > 0.2) in the four lots of each product sampled. When factoring in the dosing scheme for a 50-kg patient, IVIG contains two times more EBV antibody than CMV-IVIG. Yet, CMV-IVIG is 1.8 times more expensive than IVIG ($3225 vs. $1750). In the four lots of each product sampled, IVIG contains more EBV antibodies and costs less than CMV-IVIG when factoring in the dosing scheme. Studies are needed to determine whether there is clinical efficacy of immunoglobulin products for EBV-related PTLD prophylaxis.

The majority of cancer diagnoses in pediatric solid organ transplant recipients (SOTRs) are post‐transplantation lymphoproliferative disorders (PTLD) or skin cancers. However, pediatric SOTRs are also at significantly elevated risk for multiple other solid and hematological cancers. The risks of specific cancers vary by transplanted organ, underlying disease, and immunosuppression factors. More than one‐quarter of pediatric SOTRs develop cancer within 30 years of transplantation and their risk of solid cancer is 14 times greater than the general population. Pediatric SOTRs are at significantly higher risk of cancer‐associated death. Improving patient survival among pediatric SOTRs puts them at risk of adult epithelial cancers associated with environmental carcinogenic exposures. Vaccination against oncogenic viruses and avoidance of excessive immunosuppression may reduce the risk of solid cancers following transplantation. Patient and family education regarding photoprotection is an essential component of skin cancer prevention. There is significant variability in cancer screening recommendations for SOTRs and general population approaches are typically not validated for transplant populations. An individualized approach to cancer screening should be developed based on estimated cancer risk, patient life expectancy, and screening test performance. [ABSTRACT FROM AUTHOR]

Post‐transplant lymphoproliferative disorders (PTLD) are the main malignancy seen after pediatric heart transplant and are a significant cause of morbidity and mortality. Prior to the development of detailed guidelines, we sought to identify trends in screening, diagnosis, and treatment of pediatric PTLD. All Pediatric Heart Transplant Society (PHTS) institutions were surveyed. No identifiable patient information was shared. From 56 PHTS centers, 22 responses were received (39.3%). 100% agree PTLD cannot be diagnosed solely based on elevated Epstein‐Barr virus (EBV) load. All respondents routinely screen for EBV by blood PCR, but frequency of screening varies. There was intermediate consensus regarding the use of computed tomography (CT) and/or positron emission tomography (PET) in surveillance management for PTLD. Most centers require a diagnostic biopsy before initiating new treatment for PTLD (14 of 18, 77.8%), but many reduce immune suppression based on elevated EBV without pathologic PTLD (16 of 22, 72.7%). Beyond immune modulation, rituximab is most commonly used (9 of 13, 69.2%). Consultation with oncology is common (17 of 17, 100%), but timing varies widely. Our survey highlights significant elements of agreement and significant practice variation among PHTS institutions regarding pediatric PTLD. Reduction of immune suppression prior to pathologic diagnosis of PTLD is a common management strategy. When this fails, rituximab is used, but is most often reserved until after confirmation of the diagnosis. Oncology subspecialists are commonly involved in these cases. Our findings highlight the need to develop improved guidelines for evaluation and treatment of pediatric PTLD. [ABSTRACT FROM AUTHOR]

Introduction: PTLD is the most frequent malignancy following SOT in children and the second most common SOT complication in adults. However, factors determining outcomes in children are poorly understood due to its relative rarity. Methods: This study was performed at the University of Florida. Univariate and multivariate analyses were used to identify prognostic factors in pediatric patients diagnosed with PTLD. Results: We reviewed records of 54 pediatric (younger than 18 years old at diagnosis) patients diagnosed with PTLD from 1994 to 2017. The median follow‐up was 28.8 months. The estimated 5‐year survival rate was 87.6% (95% CI 74.3‐94.2%). Univariate analysis showed that organ transplanted (specifically heart transplant), poor response to initial treatment, allograft rejection, and low Karnofsky score were statistically significant for negative prognostic factors in determining survival. Multivariate analysis determined progression in response to initial treatment and presence of allograft rejection as statistically significant prognostic factors affecting overall survival. We found no statistically significant impact of EBV serological status on PTLD prognosis. Conclusions: Disease progression and allograft rejection were strong negative prognostic indicators in our study cohort. Close attention to graft status and development of therapies that protect the graft from rejection while bolstering anti‐EBV immunity will be essential to further improving PTLD outcomes in children. [ABSTRACT FROM AUTHOR]

Pediatric recipients of intestinal transplants have a high incidence of PTLD, but the impact of specific induction immunosuppression agents is unclear. In this single‐center retrospective review from 2000 to 2017, we describe the incidence, characteristics, and outcomes of PTLD after primary intestinal transplantation in 173 children with or without liver, after induction with rATG, alemtuzumab, or anti‐IL‐2R agents. Thirty cases of PTLD occurred among 28 children, 28 EBV+ and 2 EBV−. Although not statistically significant, the PTLD incidence was higher after isolated intestinal transplant compared with liver‐inclusive allograft (19.3% vs 13.3%, P =.393) and after induction with anti‐IL‐2R antibody and alemtuzumab compared with rATG (28.6% and 27.3% vs 13.3%, P =.076). The 30 PTLD cases included 13 monomorphic PTLD, 13 polymorphic PTLD, one spindle cell, one Burkitt lymphoma, and two cases too necrotic to classify. After reduction of immunosuppression, management was based on disease histology and extent. Resection with or without rituximab was used for polymorphic tumors and limited disease extent, whereas chemotherapy was used for diffuse disease. Of the 28 patients, 11 recovered with functioning allografts (39.3%), 10 recovered after enterectomy (35.7%), and seven patients died (25%), three due to PTLD and four due to other causes. All who died of progressive PTLD had received chemotherapy, highlighting the mortality of PTLD, toxicity of treatment and need for novel agents. Alemtuzumab is no longer used for induction at our center. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

PTLD is a rare but potentially life‐threatening condition, which shows a higher prevalence in children than in adults. From 129 children who underwent LT, we reported 5 cases with biopsy‐proven PTLD at a single teaching hospital. Four patients had shared clinical presentations including fever, lymphadenopathy, and splenomegaly. They were noted to be given a prolonged course of IS due to the management of comorbid complications such as acute cellular rejection or severe food allergy or eosinophilic gastrointestinal disease. The other one patient presented with upper gastrointestinal bleeding from gastric mass during an early post‐transplantation period. Notably, hypoalbuminemia was noted in all reported patients. Similar to previous studies, both EBV serology mismatch between the donor and recipient with high EBV viral load were noted in all except one case, whose EBV serology was unknown before LT. At least one episode of CMV reactivation was also observed in 3 of 5 patients prior to the PTLD diagnosis. The histopathology revealed 1 of 5 early PTLD, 1 of 5 polymorphic PTLD, and 3 of 5 monomorphic PTLD. The treatment included IS withdrawal, chemotherapy, and/or rituximab. One patient died of multiorgan dysfunction, one remains in complete remission, and three patients are either still on treatment or await response evaluation. Even though most of our reported PTLD cases had shared manifestations with fever, lymphadenopathy, splenomegaly, EBV serology mismatch, and high EBV viral load, various initial presentations such as respiratory symptoms, hypoalbuminemia, and prolonged use of IS from other causes such as significant food allergy were noted. [ABSTRACT FROM AUTHOR]

Intestinal transplantation is a successful treatment for children with intestinal failure, but has many potential complications. PTLD, a clinically and histologically diverse malignancy, occurs frequently after intestinal transplantation and can be fatal. The management of this disease is particularly challenging. The rejection‐prone intestinal allograft requires high levels of immunosuppression, a precondition for PTLD. While EBV infection clearly plays a role in disease pathogenesis, the relatively naïve immune system of children is another likely contributor. As a result, pediatric intestine recipients have a higher risk of developing PTLD than other solid organ recipients. Other risk factors for disease development such as molecular and genomic changes that precipitate malignant transformation are not fully understood, especially among children. Studies on adults have started to describe the molecular pathogenesis of PTLD, but the genomic landscape of the malignancy remains largely undefined in pediatric intestinal transplant patients. In this review, we describe what is known about PTLD in pediatric patients after intestinal transplant and highlight current knowledge gaps to better direct future investigations in the pediatric population. [ABSTRACT FROM AUTHOR]

Abstract: 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. [ABSTRACT FROM AUTHOR]

Abstract: The development of EBV infection and PTLD is normally associated with a high EBV viral load in peripheral blood. Observations have previously identified existence of a CHL carrier state that demonstrated variable outcomes based upon the organ which was transplanted. Data defining the incidence and outcome of CHL in pediatric KTx are not well described. The charts of children undergoing isolated KTx at Children's Hospital of Pittsburgh between January 2000 and December 2014 were retrospectively reviewed. EBV loads in the peripheral blood were routinely measured as part of surveillance protocols at our center. CHL was defined as the presence of high load for >50% of samples for ≥6 months. PTLD was defined histologically using WHO definitions. Of 188 isolated KTx recipients, we identified a total of 16 (8%) children who developed CHL carrier state. No patient developed EBV‐driven late‐onset PTLD. Age at the time of KTx was significantly lower in the CHL group (median 3.9 years, interquartile range: IQR 2.9‐6.6, P = .0004). Children in the CHL group were more likely to be EBV‐seronegative prior to KTx (94%, 15/16), compared to the UVL and LVL groups (55% and 50%, respectively, P < .002). The median duration of CHL carrier state was 20 months (IQR 10.7‐35.8). Fifteen of the 16 CHL carriers experienced spontaneous resolution of CHL carrier state. Children in the CHL group were younger at the time of primary EBV infection (P = .023). Finally, antiviral medication was not effective in either preventing or decreasing the EBV viral load in blood (P = .84). Overall incidence of late‐onset PTLD is very low compared to heart and intestinal transplant, even though KTx recipients can develop CHL carrier state. The CHL carriers in KTx recipients were EBV‐seronegative prior to transplant and were younger both at the time of KTx and at the time of primary EBV infection compared to those in the UVL and HVL groups. Antivirals did not prevent EBV infection or decrease EBV viral loads. [ABSTRACT FROM AUTHOR]

Abstract: 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. [ABSTRACT FROM AUTHOR]

De novo hepatocellular carcinoma ( HCC) post-transplantation in patients without viral hepatitis is extremely rare, with only three reported adult cases in the English literature. Here, we present a case of de novo HCC that developed in a 7-year-old female, who at 8 months of age received a liver, small bowel, spleen, and pancreas transplantation 6.5 years ago for gastroschisis and total parenteral nutrition ( TPN)-related cirrhosis. The post-transplant course was complicated by Epstein-Barr virus ( EBV) infection, post-transplant lymphoproliferative disease, and subsequent development of multifocal EBV-associated post-transplant smooth muscle tumors ( EBV- PTSMT) in the small bowel 1 year and 10 months after transplantation, respectively. This was managed by reducing immunosuppression with rituximab and EBV-specific cytotoxic T-cell therapy. She was noted to have a new lesion in her transplanted liver graft 6.5 years post-transplantation that was diagnosed as HCC. The HCC was resected, and the patient remained clinically stable for 7 months. At that time, recurrence of the HCC was discovered on MRI. She passed away 6 months after. To the best of our knowledge, this is the first reported occurrence of de novo HCC post-transplantation in the pediatric population that is unrelated to viral hepatitis in either recipient or donor. [ABSTRACT FROM AUTHOR]

PTLD is a serious complication of both solid organ and BMT. This study assessed whether 18F-FDG PET, when added to CT scan, had additional value in the initial evaluation of PTLD in pediatric patients and whether PET/CT at baseline can reliably guide biopsy. This retrospective study evaluated 34 consecutive pediatric patients (14 female), aged 3.5-17.0 yr (mean age: 9.9 yr, s.d.: 4.9 yr), who had undergone 18F-FDG PET/CT from May 2007 to December 2014 at initial diagnosis of PTLD following heart (n = 13), lung (n = 8), kidney (n = 4), liver (n = 3), liver and bowel (n = 3), and bone marrow (n = 3) transplantation. PTLD was diagnosed histopathologically in 33 patients and was based on clinical findings, elevated EBV, and imaging and follow-up results in one patient. On lesion-based analysis, 18F-FDG PET showed more lesions than conventional CT scan (168 vs. 134), but CT revealed 22 lesions negative on PET. On per patient analysis, PET detected more lesions in 13 patients, CT identified more abnormalities in seven, and both showed the same number of lesions in 14. Adding 18F-FDG PET to CT scans upstaged the disease in seven patients (20.5%). A combination of 18F-FDG PET and CT was also useful in guiding biopsy, being positive in 36 of 39 samples (92.3%). These findings indicated that 18F-FDG PET and CT are complementary at initial staging of pediatric PTLD and that 18F-FDG PET/CT scanning can guide biopsies. [ABSTRACT FROM AUTHOR]

EBV-associated PTLD is increasingly recognized as an important cause of morbidity and mortality in both solid organ and hematopoietic stem cell transplant recipients. Mortality rates due to PTLD and virus-induced HLH are reported to be quite high. We report a case of EBV-associated PTLD and HLH in a child after liver transplantation who was successfully managed due to timely intervention. This case highlights that measurement of EBV load by quantitative polymerase chain reaction assays is an important aid in the surveillance and diagnosis of PTLD and early detection of EBV-induced PTLD, and aggressive treatment with rituximab is a key to survival in patients who have undergone liver transplantation. [ABSTRACT FROM AUTHOR]

Recently, it has been reported that Crohn's-like intractable colitis occurred in approximately 20% of the patients with XIAP deficiency, also known as X-linked lymphoproliferative disease type 2. Because treatment used for Crohn's disease is not always effective for Crohn's-like colitis related to XIAP deficiency, more effective treatment should be established. Although several studies reported allo- HSCT might be promising even for Crohn's-like colitis related to XIAP deficiency, the outcome of allo- HSCT using MAC for XIAP deficiency is extremely poor due to frequent TRM. In addition, there is little information about the outcome of allo-HSCT for intractable colitis related to XIAP deficiency. Herein, we describe a patient with intractable colitis related to XIAP deficiency who was successfully treated with allo-HSCT using a reduced-intensity conditioning regimen. Although allo-HSCT using the RIC regimen might be a curative therapeutic option for intractable colitis with XIAP deficiency, the prognostic factors that will determine the success of allo-HSCT require further clinical information of more patients. [ABSTRACT FROM AUTHOR]

We present the unique case of a pediatric patient who received chemotherapy for a diagnosis of CD, while mechanically supported with a Berlin EXCOR LVAD secondary to restrictive cardiomyopathy. A four-yr-old previously healthy male with restrictive cardiomyopathy required MCS after cardiac arrest but was diagnosed with multicentric CD, a non-malignant lymphoproliferative disorder fueled by excessive IL-6 production. Treatment with IL-6 blockade (tocilizumab) every two wk and methylprednisolone had no effect on his lymph nodes or cardiac function while on temporary RotaFlow. A Berlin LVAD was placed for treatment with rituximab, COP, vincristine, and methylprednisolone. After three courses of chemotherapy, his inflammatory markers normalized and his lymphadenopathy decreased but cardiac function remained severely depressed. He tolerated chemotherapy on the Berlin but required frequent titrations of his anti-coagulation regimen and he did suffer a hemorrhagic stroke. His clinical status improved significantly with rehabilitation, and he tolerated heart transplantation without further complications. MCS is a feasible option as a bridge to recovery or heart transplant eligibility for patients with hemodynamic collapse requiring chemotherapy but it does necessitate close titration of the anti-coagulation regimen to coincide with changes in the inflammatory state. [ABSTRACT FROM AUTHOR]

Although cardiac transplantation is life-saving, morbidities from immunosuppression are significant. EoE is a complication of calcineurin inhibitors following liver transplant causing feeding intolerance, weight loss, vomiting, and dysphagia. There are limited reports of EoE following heart transplantation. We performed a retrospective single-center review of pediatric cardiac transplant patients from 2000 to 2010. A case-control analysis of patients with and without EoE was performed evaluating heart transplantation outcomes such as rates of rejection, CAV, PTLD, and graft loss. Eighty-six transplants were performed in 84 patients; 34 (40%) underwent diagnostic endoscopy, and 10 (12%) had EoE. Median time to diagnosis of EoE was 3.7 yr ( IQR: 2.0-5.2). There were no differences in demographics or use of induction medications between patients with or without EoE. Patients with EoE had fewer episodes of treated rejection (1.0 vs. 2.5; p = 0.04). Four of 10 (40%) EoE patients had PTLD compared with only 2/24 (8%) of those without EoE (p = 0.048; OR 7.33 [95% CI: 1.1-50.2]). There were no differences in CAV or graft loss between groups. EoE should be considered as a cause of GI symptoms in children after cardiac transplantation and may be associated with fewer rejection episodes and increased rates of PTLD, thus representing a marker of over-immunosuppression. [ABSTRACT FROM AUTHOR]

Bartonella henselae (Bh) is the cause of cat-scratch fever. When infection is symptomatic, it typically presents with singular lymphadenitis and fever. Less commonly, the infection can become disseminated and cause endocarditis, osteomyelitis, and micro-abscesses in multiple sites including liver, spleen, eyes, and brain, especially in immunocompromised patients. Hemophagocytic lymphohistiocytosis (Hlh) is a rare and severe multisystem disorder that may be triggered by infections. In one prior case, Bh, like other infections, has induced Hlh, an immune-mediated disease that can be characterized by septic-like presentation with persistent fevers, hepatosplenomegaly, and pancytopenia. In an immunocompromised transplant recipient, the onset of Hlh can be difficult to discern from a severe presentation of Bh. We report a case of criteria-proven secondary Hlh occurring after Bh infection in an 11-yr-old girl who was 13 months post-renal transplant. The patient developed multi-organ failure, and her severe clinical presentation required a thorough evaluation for infectious and non-infectious possibilities including post-transplant lymphoproliferative disorder and rejection. Early recognition of Hlh allowed for better directed therapies, leading to recovery of the patient and resolution of both Bh and Hlh. [ABSTRACT FROM AUTHOR]