Elevated ST2 Distinguishes Incidences of Pediatric Heart and Small Bowel Transplant Rejection.

Elevated serum soluble (s) suppressor of tumorigenicity-2 is observed during cardiovascular and inflammatory bowel diseases. To ascertain whether modulated ST2 levels signify heart (HTx) or small bowel transplant (SBTx) rejection, we quantified sST2 in serially obtained pediatric HTx (n = 41) and SBTx recipient (n = 18) sera. At times of biopsy-diagnosed HTx rejection (cellular and/or antibody-mediated), serum sST2 was elevated compared to rejection-free time points (1714 ± 329 vs. 546.5 ± 141.6 pg/mL; p = 0.0002). SBTx recipients also displayed increased serum sST2 during incidences of rejection (7536 ± 1561 vs. 2662 ± 543.8 pg/mL; p = 0.0347). Receiver operator characteristic (ROC) analysis showed that serum sST2 > 600 pg/mL could discriminate time points of HTx rejection and nonrejection (area under the curve [AUC] = 0.724 ± 0.053; p = 0.0003). ROC analysis of SBTx measures revealed a similar discriminative capacity (AUC = 0.6921 ± 0.0820; p = 0.0349). Quantitative evaluation of both HTx and SBTx biopsies revealed that rejection significantly increased allograft ST2 expression. Pathway and Network Analysis of biopsy data pinpointed ST2 in the dominant pathway modulated by rejection and predicted tumor necrosis factor-α and IL-1ß as upstream activators. In total, our data indicate that alloimmune-associated pro-inflammatory cytokines increase ST2 during rejection. They also demonstrate that routine serum sST2 quantification, potentially combined with other biomarkers, should be investigated further to aid in the noninvasive diagnosis of rejection.

Cost-effectiveness of pediatric heart transplantation across a positive crossmatch for high waitlist urgency candidates.

Allosensitized children listed with a requirement for a negative prospective crossmatch have high mortality. Previously, we found that listing with the intent to accept the first suitable organ offer, regardless of the possibility of a positive crossmatch (TAKE strategy), results in a survival advantage from the time of listing compared to awaiting transplantation across a negative crossmatch (WAIT). The cost-effectiveness of these strategies is unknown. We used Markov modeling to compare cost-effectiveness between these waitlist strategies for allosensitized children listed urgently for heart transplantation. We used registry data to estimate costs and waitlist/posttransplant outcomes. We assumed patients remained in hospital after listing, no positive crossmatches for WAIT, and a base-case probability of a positive crossmatch of 47% for TAKE. Accepting the first suitable organ offer cost less ($405 904 vs. $534 035) and gained more quality-adjusted life years (3.71 vs. 2.79). In sensitivity analyses, including substitution of waitlist data from children with unacceptable antigens specified during listing, TAKE remained cost-saving or cost-effective. Our findings suggest acceptance of the first suitable organ offer for urgently listed allosensitized pediatric heart transplant candidates is cost-effective and transplantation should not be denied because of allosensitization status alone.

Comparison of listing strategies for allosensitized heart transplant candidates requiring transplant at high urgency: a decision model analysis.

Allosensitized children who require a negative prospective crossmatch have a high risk of death awaiting heart transplantation. Accepting the first suitable organ offer, regardless of the possibility of a positive crossmatch, would improve waitlist outcomes but it is unclear whether it would result in improved survival at all times after listing, including posttransplant. We created a Markov decision model to compare survival after listing with a requirement for a negative prospective donor cell crossmatch (WAIT) versus acceptance of the first suitable offer (TAKE). Model parameters were derived from registry data on status 1A (highest urgency) pediatric heart transplant listings. We assumed no possibility of a positive crossmatch in the WAIT strategy and a base-case probability of a positive crossmatch in the TAKE strategy of 47%, as estimated from cohort data. Under base-case assumptions, TAKE showed an incremental survival benefit of 1.4 years over WAIT. In multiple sensitivity analyses, including variation of the probability of a positive crossmatch from 10% to 100%, TAKE was consistently favored. While model input data were less well suited to comparing survival when awaiting transplantation across a negative virtual crossmatch, our analysis suggests that taking the first suitable organ offer under these circumstances is also favored.

Posttransplantation lymphoproliferative disorders in pediatric thoracic organ recipients.

OBJECTIVE: To determine the frequency, predisposing factors, clinical presentation, and outcome of posttransplantation lymphoproliferative disorders (PTLDs) in pediatric thoracic organ transplant recipients. METHODS: Retrospective review of the medical records of all 120 children who survived longer than 1 month after thoracic organ transplantation at our center. RESULTS: PTLD was diagnosed in 14 patients (11.7%), including 7.7% of heart and 19.5% of heart-lung/lung recipients. Presentation of PTLD was variable, ranging from asymptomatic lung nodules on chest radiograph to diffuse multiorgan failure. Treatment with a reduction of immunosuppression and antiviral therapy resulted in resolution of PTLD in eight patients. Eight patients died. PTLD contributed to death in five. No patient seropositive for Epstein-Barr virus (EBV) before transplantation had PTLD. There was a significant association between primary EBV infection after transplantation and the presence of PTLD. CONCLUSIONS: PTLD occurs with greater frequency in pediatric thoracic organ transplant recipients than in the adult transplant population. Primary EBV infection after transplantation is the major risk factor for the development of PTLD. Patients in whom primary EBV infection develops after transplantation should be managed with a reduction in immunosuppression and with heightened surveillance for the development of PTLD.

Long-term survivors of pediatric heart transplantation: a multicenter report of sixty-eight children who have survived longer than five years.

OBJECTIVE: Short-term survival after pediatric heart transplantation is now excellent, but ultimately the efficacy of this procedure will depend on duration and quality of survival. We sought to evaluate the clinical course of long-term survivors of heart transplantation in childhood. METHODS: Patients who had undergone heart transplantation at the university hospitals of Stanford, Columbia, and Pittsburgh between 1975 and 1989 and survived longer than 5 years from transplantation were identified and their clinical courses retrospectively reviewed. RESULTS: Sixty eight children have survived more than 5 years from transplantation, and 60 (88%) are currently alive with a median follow-up of 6.8 years (5 to 17.9 years). Thirteen have survived more than 10 years from transplantation. Renal dysfunction caused by immunosuppressive agents was common, and two patients required late renal transplantation. Lymphoproliferative disease or other neoplasm occurred in 12 patients, but none resulted in death. Coronary artery disease was diagnosed in 13 patients (19%), leading to retransplantation in eight. Death after 5 years was related to acute or chronic rejection in 5 of 8 cases. Two of the deaths were directly related to noncompliance with immunosuppressive medication. All survivors are in New York Heart Association class 1. CONCLUSIONS: Long-term survival with good quality of life can be achieved after heart transplantation in childhood, though complications of immunosuppression remain common. Posttransplantation coronary artery disease is emerging as the main factor limiting long term graft and patient survival.

Importance of microdeletions of chromosomal region 22q11 as a cause of selected malformations of the ventricular outflow tracts and aortic arch: a three-year prospective study.

OBJECTIVES: To assess the incidence of microdeletions of chromosomal region 22q11 in a population of infants coming to a regional pediatric cardiac center with selected abnormalities of the ventricular outflow tracts and aortic arch and, further, to provide phenotypic/genetic correlations to determine whether patients with 22q11 deletions can be clinically recognized in infancy. BACKGROUND: DiGeorge syndrome and velocardiofacial syndrome are frequently associated with malformations of the ventricular outflow tracts and aortic arch. Both are usually caused by microdeletions of chromosomal region 22q11. The overall importance of such deletions as a cause of these cardiac malformations remains to be established. STUDY DESIGN: All infants with the candidate cardiac phenotypes during a 34-month period were studied. Dysmorphic features, type of cardiac defect, serum calcium concentration, and thymic status were recorded. Cytogenetic studies, including high-resolution karyotyping and fluorescence in situ hybridization using cosmids (cEO or cH748) from the DiGeorge critical region, were performed after clinical assessment. RESULTS: Fifty infants (including 36 with tetralogy of Fallot with or without pulmonary atresia) were seen during the study period. Twenty-six infants (52%) were dysmorphic, including 19 who were considered to have a phenotypic appearance consistent with 22q11 deletion. Genetic analysis confirmed hemizygosity for 22q11 in 8 of these 19 cases. Results of fluorescence in situ hybridization studies were normal in 22 infants without dysmorphic features and in 5 infants with dysmorphic features not suggestive of a 22q11 deletion. CONCLUSIONS: Microdeletions of chromosomal region 22q11 are an important cause of selected malformations of the ventricular outflow tracts and aortic arch and account for about 15% to 20% of cases. These deletions may be clinically recognized in early infancy and can be rapidly confirmed by fluorescence in situ hybridization.

Autoantibody production after cardiopulmonary bypass with special reference to postpericardiotomy syndrome.

A prospective study of children undergoing open heart surgery with cardiopulmonary bypass showed that many of them produced autoantibodies. No association was found between these antibodies, including anticardiolipin antibodies, and the occurrence of postpericardiotomy syndrome.