Immunologic risk stratification of pediatric heart transplant patients by combining HLAMatchmaker and PIRCHE-II.

BACKGROUND: Molecular-level human leukocyte antigen (HLA) mismatch is a powerful biomarker of rejection; however, few studies have explored its use in heart transplant recipients, and none have attempted to use the results of separate algorithms synergistically. Here we tested the hypothesis that a combination of HLAMatchmaker and Predicted Indirectly Recognizable HLA Epitopes (PIRCHE-II) can be used to identify more patients at low risk of rejection. METHODS: We studied 274 recipient/donor pairs enrolled in the Clinical Trials in Organ Transplantation in Children (CTOTC) performing class I and II HLA genotyping by next-generation sequencing to determine eplet mismatch (epMM) load and PIRCHE-II score. Correlation with clinical outcomes was performed on 131 cases. RESULTS: Of the 131 patients, 100 without pre-formed donor specific antibody (DSA) were used to identify cutoffs for the Class I, HLA-DR, and HLA-DQ epMM load and PIRCHE-II score for risk of developing post-transplant DSA (epMM: Class I/DR/DQ = 9/9/6; PIRCHE-II: 141/116/111) and antibody-mediated rejection (ABMR) (epMM: 9/8/8; PIRCHE-II: 157/80/201). Patients with above cut-off epMM load appear to be less likely to develop DSA and ABMR if their PIRCHE-II score is below cut-off (high epMM/high PIRCHE-II: 12.3%-20.3% DSA and 9%-13.5% ABMR vs high epMM/low PIRCHE-II: 4%-10% DSA and 0%-2% ABMR). CONCLUSION: For the first time in a pediatric heart transplant cohort, immunologic risk cut-offs for DSA and ABMR have been established. When used together, epMM load and PIRCHE-II score allow us to reclassify a portion of cases with high epMM load as having a lower risk for developing DSA and ABMR.

Lobar displacement following pediatric heart-lung transplantation: case report and review of literature.

Lobar displacement (LD) after heart-lung transplantation (HLT) has been reported in adults, but there are no reported pediatric cases. Its occurrence may cause vascular compromise of the displaced lung segment leading to necrosis, infection and bronchiectasis, as well as compression of contralateral lobes. We report two cases of LD in children following HLT, treated differently and with different outcomes. Assessment of pulmonary perfusion and weighing the risk of surgical repair may be considered for optimal patient management of this condition.

Post-transplant Burkitt lymphoma is a more aggressive and distinct form of post-transplant lymphoproliferative disorder.

BACKGROUND: Although the literature reports a low incidence of Burkitt lymphoma (BL) as a post-transplant lymphoproliferative disorder (PTLD), this entity appears to be different from other monomorphic PTLDs (M-PTLDs), both in its aggressive clinical presentation and its distinct pathologic profile. METHODS: Patients with BL, diagnosed in the post-transplant setting, (patients aged ≤ 18 years) were retrieved from the pathology archives at Children's Hospital of Pittsburgh of the University of Pittsburgh Medical Center from 1982 to 2010. Clinical outcomes were obtained along with pathologic review. RESULTS: Twelve patients with pediatric BL in the post-transplant setting (9 boys, 3 girls) were retrieved. The patients displayed a monomorphic population of small to intermediate-sized, noncleaved, lymphoid elements with a "starry-sky" pattern. The immunophenotype for patients available to the study was CD20+ (n = 9/10), CD10+ (n = 8/8), bcl-6+ (n = 11/11), with a near 100% Ki-67/MIB-1 proliferation index (n = 7/7), and negative for TdT (n = 7/7). Most pretransplant Epstein-Barr virus titers were negative (n = 8/10), with post-transplant titers positive in all tested patients (n = 11), and with positive Epstein-Barr-encoded RNA in situ hybridization in most cases (n = 9/11). The median time from transplantation to diagnosis was 52 months (range, 6-107 months). Nine patients were currently alive after immediate antineoplastic chemotherapy, with median disease-free time of 93 months from diagnosis (range, 2-199 months). CONCLUSIONS: BL-PTLD had a higher Epstein-Barr virus incidence compared with sporadic and immunodeficiency-associated BL and represented a distinct monomorphic PTLD. Although some M-PTLDs can be managed less aggressively with decreased immunosuppression alone, immediate lymphoma-specific chemotherapy was associated with a favorable outcome and was strongly recommended.

Pediatric heart transplantation for anthracycline cardiomyopathy: cancer recurrence is rare.

BACKGROUND: Although anthracycline therapy is invaluable for treating neoplastic disorders, morbidity includes severe cardiomyopathy that leads to heart transplantation. This multicenter study describes the course of children who experienced anthracycline cardiomyopathy (ACM) and who subsequently required heart transplantation. METHODS: We reviewed transplant databases/registries at 4 pediatric heart transplant centers to identify children with ACM who were listed for heart transplantation. We reviewed medical records to determine cancer therapy, clinical course, and outcome. RESULTS: Eighteen patients were listed, and 17 underwent transplantation. Mean age at cancer diagnosis was 6.0 years (SD, 3.7). The mean anthracycline dose was 361 mg/m2 (SD, 110). The median time from cancer diagnosis to listing for heart transplantation was 9.2 years (range, 0.4-15.2 years). Six transplantations were performed in patients who had disease-free intervals of <5 years. Two patients were lost to follow-up, and 8 are alive at 4.9 years (SD, 2.0; range, 1.3-7.4 years) after transplantation. Seven patients died at 4.7 years (SD, 2.0; range, 1.2-7.1 years) after transplantation. One patient had recurrent cancer. One-, 2- and 5-year survivals were 100%, 92%, and 60%, respectively. CONCLUSIONS: Cardiomyopathy that progresses to the need for heart transplantation occurs in patients receiving a wide range of cumulative anthracycline doses. The time from chemotherapy to ACM varies. Outcomes after transplantation are acceptable, and cancer recurrence is rare. Reconsideration of the 5-year disease-free wait period is warranted.

Cytokine gene polymorphisms in children successfully withdrawn from immunosuppression after liver transplantation.

BACKGROUND: Cytokine genetic polymorphisms have been associated with transplant outcome in some experimental and clinical studies, but the cytokine profile of patients who are clinically tolerant has not been investigated. AIM: Allelic variations in tumor necrosis factor (TNF)-alpha, interferon (INF)-gamma, transforming growth factor (TGF)-beta1, interleukin (IL)-6, and IL-10 were evaluated in patients successfully withdrawn from immunosuppression. METHODS: Pediatric liver transplant recipients who were successfully withdrawn from immunosuppression (n=12) or who are on minimal immunosuppression (n=7) were genotyped. A control group of liver recipients who required maintenance immunosuppression served as a control group (n=37). RESULTS: Compared to the control group, low TNF- alpha and high/intermediate IL-10 profiles were seen in all 12 children maintained off immunosuppression and in 6 of 7 children requiring minimal immunosuppression. CONCLUSION: Children successfully maintained off immunosuppression are more likely to have a genetic predisposition toward low TNF-alpha and high/intermediate IL-10 production. Children maintained on minimal immunosuppression exhibit a similar cytokine profile to those successfully weaned.