Eosinophilic esophagitis in children following cardiac transplantation: Association with post‐transplant lymphoproliferative disorder and other transplant outcomes

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.     

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.     

Induction regimens and post‐transplantation lymphoproliferative disorder after pediatric intestinal transplantation: Single‐center experience

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.     

Treatment and outcomes in classic Hodgkin lymphoma post‐transplant lymphoproliferative disorder in children

Classic Hodgkin lymphoma post‐transplant lymphoproliferative disorder (HL‐PTLD) has been rarely reported in children, with limited data available to guide treatment decisions. We report a retrospective review of five children diagnosed with classic HL‐PTLD following solid organ transplant between 2007 and 2013 at Stanford University. Patients were treated with Stanford V chemotherapy and involved field radiation therapy. With a median follow‐up of 7.2 years (range, 4.7–10.5 years) since diagnosis, all patients remain in remission from HL‐PTLD and free from graft failure. In this series, combined modality therapy with risk‐adapted chemotherapy and radiation therapy was a successful strategy for the treatment of classic HL‐PTLD.     

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.     

Clinicopathologic features of post‐transplant lymphoproliferative disorders arising after pediatric small bowel transplant

Few studies examined the clinicopathologic features of PTLD arising in pediatric SBT patients. Particularly, the association between ATG and PTLD in this population has not been described. Retrospective review of 81 pediatric patient charts with SBT – isolated or in combination with other organs – showed a PTLD incidence of 11%, occurring more frequently in females (median age of four yr) and with clinically advanced disease. Monomorphic PTLD was the most common histological subtype. There was a significant difference in the use of ATG between patients who developed PTLD and those who did not (p < 0.01); a similar difference was seen with the use of sirolimus (p < 0.001). These results suggested a link between the combination of ATG and sirolimus and development of more clinically and histologically advanced PTLD; however, the risk of ATG by itself was not clear. EBV viral loads were higher in patients with PTLD, and median time between detection of EBV to PTLD diagnosis was three months. However, viral loads at the time of PTLD diagnosis were most often lower than at EBV detection, thereby raising questions on the correlation between decreasing viral genomes and risk of PTLD.     

Prompt diagnosis and management of Epstein–Barr virus‐associated post‐transplant lymphoproliferative disorder and hemophagocytosis: A dreaded complication in a post‐liver transplant child

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.     

Various initial presentations of Epstein‐Barr virus infection‐associated post‐transplant lymphoproliferative disorder in pediatric liver transplantation recipients: Case series and literature review

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.     

Treatment of pediatric plasma cell myeloma type post‐transplant lymphoproliferative disorder with modern risk‐directed therapy

Post‐transplant lymphoproliferative disorder (PTLD) related plasma cell neoplasms are rare in pediatric patients. We report a pediatric liver transplant recipient with plasma cell myeloma type PTLD. Cytogenetics included 1q duplication, associated with poor prognosis in adult multiple myeloma, and t(8;14). High‐risk cytogenetics has not been reported in pediatric plasma cell myeloma type PTLD. The patient was treated with bortezomib, dexamethasone, and lenalidomide with subsequent autologous stem cell transplant. He achieved a 6‐year remission, demonstrating tolerance to and efficacy of this modern myeloma regimen in a pediatric patient. Unfortunately, he subsequently died from complications of repeat liver transplant.     

BK virus nephropathy in a pediatric heart transplant recipient with post‐transplant lymphoproliferative disorder: A case report and review of literature

BKV is known to cause allograft failure in kidney transplant recipients. It has been recently recognized to cause native kidney nephropathy in non‐kidney transplant recipients. This is a case report BKVN in a 15‐yr‐old HTx recipient who had PTLD and a review of pediatric cases in the literature. The patient was diagnosed with BKVN +189 months after transplantation and died thirty days after diagnosis of BKVN. We identified five other cases of BKVN in pediatric non‐kidney solid organ transplantation, of which all were HTx recipients. Overall, outcome was poor and BKV clearance was not achieved with reduction of immunosuppression and with current therapies. We strongly recommend that pediatric HTx recipients be tested for BKV infection if there is evidence of kidney dysfunction. We also recommend that they have an annual screening for BKV viruria and viremia with the assessment of kidney function.     

The value of 18F‐FDG PET in pediatric patients with post‐transplant lymphoproliferative disorder at initial diagnosis

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.     

Post‐transplant EBV‐related lymphoproliferative disorder complicating umbilical cord blood transplantation in patients of adrenoleukodystrophy

EBV‐associated post‐transplant lymphoproliferative disorder (PTLD) is a well‐recognized complication following solid organ transplantation and hematopoietic stem cell transplantation (HSCT) using bone marrow or peripheral blood as stem cell sources, but rarely reported in umbilical cord blood transplantation (UCBT). We report two cases in unrelated UCBT setting and added the following new information to the literature: (i) EBV‐related PTLD can be presented late in recipients of unrelated UCBT; (ii) in contrast to reported literatures that PTLD is a serious complication with unfavorable outcome, especially in monomorphic form, our cases showed that the clinical course may be relatively benign if treatment is initiated promptly. Pediatr Blood Cancer 2009; 53:1329–1331. © 2009 Wiley‐Liss, Inc.     

Post‐transplant lymphoproliferative disorder in pediatric intestinal transplant recipients: A literature review

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.