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In the 1980s, heart transplantation was the first successful treatment for infants born with hypoplastic left heart syndrome. Infants who have required heart transplantation benefit from immunologic "advantages," including long-term survival free from cardiac allograft vasculopathy. Currently ∼ 90% of children undergoing a heart transplant are reaching their first-year anniversary and the clinical practices of paediatric heart transplantation have dramatically improved. These successes are largely attributed to research sponsored by the Pediatric Heart Transplant Study Group, the International Society of Heart and Lung Transplantation and, more recently, the Non-profits Enduring Hearts and Additional Ventures. Despite these successes, the field is challenged to increase progress to achieve long-term survival into adulthood. The wait-list mortality, especially among infants, is unacceptably high often leading to palliative measures that can increase post-transplant mortality. Cardiac allograft vasculopathy remains a major cause for progressive graft loss of function and sudden death. The relative tolerance seen in immature recipients has not been translated to modifying older recipients' post-transplant outcomes. The modifiable cause(s) for the increased risks of transplantation in children of different ethnicities and races require definition. Addressing these challenges faces the reality that for-profit research favours funding adult recipients, with ∼ 10-fold greater numbers, and their more modest longevity goals. Advocacy for funding "incentives" such as the Orphan Drug rules in the United States and upholding principles of equity and inclusion are critical to addressing the challenges of paediatric heart transplant recipients worldwide.

Pediatric heart transplant recipients have been expected to be at higher risk of adverse events from developing COVID-19 infection. COVID-19 RNA PCR and antibody testing has been performed in our cohort of patients since March 15, 2020 and outcomes were reviewed. COVID-19 infection in our population of pediatric heart transplant recipients is common (21%), despite recommendations to avoid contact with others. Asymptomatic COVID-19 infection is common as well (55%). Despite the frequency of infection, COVID-19 is well tolerated in this population (5% admission from home; 0% mortality). A suppressed immune system does not significantly inhibit an antibody response in pediatric heart transplant recipients (>70% antibody seroconversion) and appears to persist, similar to those without transplantation (>90 days). Routine testing for COVID-19 via PCR and antibody testing enhances the ability to detect COVID-19 infection in asymptomatic patients and may help reduce unintended transmission to more susceptible individuals., (Copyright © 2021 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

Background: Primary transplantation was developed in the 1980s as an alternative therapy to palliative reconstruction of uncorrectable congenital heart disease. Although transplantation achieved more favorable results, its utilization has been limited by the availability of donor organs. This review examines the long-term outcomes of heart transplantation in neonates at our institution., Methods: The institutional pediatric heart transplant database was queried for all neonatal heart transplants performed between 1985 and 2017. Follow-up was obtained from medical records and an annually administered questionnaire. Overall survival and time to development of complications were estimated using the Kaplan Meier method. Univariate and multivariate analyses were performed to identify independent predictors of survival., Results: Heart transplantation was performed in 104 neonates. Median age was 17 days. Hypoplastic left heart syndrome (classic or variant) was the primary diagnosis in 77.8% of patients. Survival at 10 years and 25 years was 73.9% and 55.8%, respectively. At 20 years, freedom from allograft vasculopathy and lymphoproliferative disease was 72.0% and 81.9%, respectively. Freedom from re-transplantation was 81.4% at 20 years. Eight patients (7.6%) developed end-stage renal disease. By multivariate analysis, lower glomerular filtration rate and allograft vasculopathy were the only significant predictors of death., Conclusions: Neonatal heart transplantation remains a durable therapy with very acceptable long-term survival. Children transplanted in the newborn period have the potential to reach adulthood with minimal need for reintervention., (Copyright © 2019 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Background: Young-adult heart transplant recipients transferring to adult care are at risk for poor health outcomes. We conducted a pilot randomized controlled trial to determine the feasibility of and to test a transition intervention for young adults who underwent heart transplantation as children and then transferred to adult care., Methods: Participants were randomized to the transition intervention (4 months long, focused on heart-transplant knowledge, self-care, self-advocacy, and social support) or usual care. Self-report questionnaires and medical records data were collected at baseline and 3 and 6 months after the initial adult clinic visit. Longitudinal analyses comparing outcomes over time were performed using generalized estimating equations and linear mixed models., Results: Transfer to adult care was successful and feasible (ie, excellent participation rates). The average patient standard deviation of mean tacrolimus levels was similar over time in both study arms and < 2.5, indicating adequate adherence. There were no between-group or within-group differences in percentage of tacrolimus bioassays within target range (> 50%). Average overall adherence to treatment was similarly good in both groups. Rates of appointment keeping through 6 months after transfer declined over time in both groups., Conclusions: The feasibility of the study was demonstrated. Our transition intervention did not improve outcomes., (Copyright © 2019 Elsevier Inc. All rights reserved.)

The newborn infant with severe cardiac failure owed to congenital structural heart disease or cardiomyopathy poses a daunting therapeutic challenge. The ideal solution for both might be cardiac transplantation if availability of hearts was not limiting and if tolerance could be induced, obviating toxicity of immunosuppressive therapy. If one could safely and effectively exploit neonatal tolerance for successful xenotransplantation of the heart, the challenge of severe cardiac failure in the newborn infant might be met. We discuss the need, the potential for applying neonatal tolerance in the setting of xenotransplantation and the possibility that other approaches to this problem might emerge., (© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Young adult solid organ transplant recipients who transfer from pediatric to adult care experience poor outcomes related to decreased adherence to the medical regimen. Our pilot trial for young adults who had heart transplant (HT) who transfer to adult care tests an intervention focused on increasing HT knowledge, self-management and self-advocacy skills, and enhancing support, as compared to usual care. We report baseline findings between groups regarding (1) patient-level outcomes and (2) components of the intervention. From 3/14 to 9/16, 88 subjects enrolled and randomized to intervention (n = 43) or usual care (n = 45) at six pediatric HT centers. Patient self-report questionnaires and medical records data were collected at baseline, and 3 and 6 months after transfer. For this report, baseline findings (at enrollment and prior to transfer to adult care) were analyzed using Chi-square and t-tests. Level of significance was p < 0.05. Baseline demographics were similar in the intervention and usual care arms: age 21.3 ± 3.2 vs 21.5 ± 3.3 years and female 44% vs 49%, respectively. At baseline, there were no differences between intervention and usual care for use of tacrolimus (70 vs 62%); tacrolimus level (mean ± SD = 6.5 ± 2.3 ng/ml vs 5.6 ± 2.3 ng/ml); average of the within patient standard deviation of the baseline mean tacrolimus levels (1.6 vs 1.3); and adherence to the medical regimen [3.6 ± 0.4 vs 3.5 ± 0.5 (1 = hardly ever to 4 = all of the time)], respectively. At baseline, both groups had a modest amount of HT knowledge, were learning self-management and self-advocacy, and perceived they were adequately supported. Baseline findings indicate that transitioning HT recipients lack essential knowledge about HT and have incomplete self-management and self-advocacy skills.

Background: Proliferation signal inhibitors, such as sirolimus, are increasingly used in solid-organ transplantation. However, limited data exist on sirolimus-treated pediatric patients. We aimed to describe sirolimus use in pediatric heart transplant patients and test the hypothesis that sirolimus use is associated with improved outcomes., Methods: A retrospective review and propensity-matched analysis of the Pediatric Heart Transplant Study database was performed on patients undergoing primary heart transplantation from 2004 to 2013 with at least 1 year of follow-up comparing patients treated vs not treated with sirolimus at 1 year after transplant. The primary outcome of interest was patient survival, with secondary outcomes including cardiac allograft vasculopathy, rejection, malignancy, and renal insufficiency., Results: Between 2004 and 2013, 2,531 patients underwent transplantation. At least 1 year of follow-up was available for 2,080 patients, of whom 144 (7%) were on sirolimus at 1 year post-transplant. Sirolimus-treated and non-treated patients had similar survival in the overall cohorts and in the propensity-matched analysis. The secondary outcomes measures were also similar, including a composite end point of all outcome measures. There was a trend toward increased time to cardiac allograft vasculopathy (p = 0.09) and decreased time to infection (p = 0.05) among sirolimus-treated patients in the overall cohort (p = 0.19) but not in the propensity-matched cohort (p = 0.17)., Conclusions: Sirolimus was used in less than 10% of patients at 1 year post-transplant. Overall outcomes of sirolimus treated and non-treated patients were similar with respect to survival and major transplant adverse events. Further study of sirolimus in pediatric heart transplant patients is needed., (Copyright © 2017 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

To evaluate social development of pediatric heart transplant (tx) recipients who have lived 15 or more years after transplantation. Among 498 pediatric patients, age less than 18 years, who underwent heart transplantation, at a single institution, 337 were performed between 1985 and 1998. We identified all who survived more than 15 years and engaged them in a survey regarding employment, education, marital, and social status. One hundred and eighty-three recipients (54.3%; 183/337) have survived greater than 15 years; of these, 150 (81.9%) subjects are alive with age ranging from 15.04 from 28 years (median, 23.6 years). Forty-two patients (23%) are independent, 127 (69%) were living at home, and 14 (8%) have been lost to follow-up. Ninety-nine survivors (66%) responded to the survey study. Currently, five recipients are married. Seventy-four completed high school, 21 are enrolled in high school, and four did not complete high school. Of the 47 recipients who started college, 27 are currently enrolled, 11 graduated, and nine did not finish college. Ninety-four patients have health insurance, 40 are employed, and 31 receive financial assistance for a disability. The majority of recipients of pediatric heart transplantation are able to reach reasonable academic milestones, achieve social well-being, and professional independence., (© 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Pediatric heart transplant patients at our institution are immunosuppressed with a CNI and another immune-modulating agent without utilizing corticosteroids. Patients whose renal function worsened and who did not respond to CNI minimization had their CNI discontinued. The clinical history of 35 pediatric heart transplant patients with significant renal insufficiency whose CNI was discontinued was retrospectively analyzed. Data including serum creatinine and weight were collected before, at time of, and every 3-6 months after CNI discontinuation. This was used to calculate an eGFR. Cardiac allograft rejection and mortality data were also collected. CNI discontinuation occurred 39 times in 35 patients. The median eGFR significantly increased by 14 mL/min 3 months after CNI discontinuation and the increase continued to be significant (P≤.05) at 5 years. Freedom from rejection analysis showed no difference between graft rejection 2 years before versus after CNI discontinuation (P=.437). No mortality was associated with CNI discontinuation. Immunosuppression free of CNIs and corticosteroids appears to be a safe alternative in pediatric heart transplant patients with significant renal insufficiency. Furthermore, this strategy can significantly reverse renal insufficiency, even late after transplantation., (© 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: We evaluated late survival among pediatric heart transplant patients who have lived more than 15 years., Methods: This is a retrospective chart review of the pediatric patients who underwent heart transplantation (HTx) between 1985 and 1998. Multivariate and univariate analyses were examined., Results: There were 183 recipients, of whom 151 are currently alive. Age at HTx ranged from 0 days to 17.48 years (median 56 days). Pretransplant diagnoses included congenital heart disease 142 (77.6%), cardiomyopathy 38 (20.8%), and tumor 3 (1.6%). Pretransplant renal dysfunction was present in 58 patients (31.7%). Perioperative peritoneal dialysis was instituted in 15 patients, all recovered. During the follow-up period (median 20.2 years), 17 (9.3%) have had renal transplants, and 2 require hemodialysis. There were 32 deaths from the following: cardiac allograft vasculopathy (CAV); 11 (34.3%); posttransplant lymphoproliferative disease 6 (18.8%); acute rejection 4 (12.5%); sepsis 2 (6.3%); multiorgan failure 1 (3.1%); and unknown 8 (25%). Immunosuppressive therapy for the living patients consists of monotherapy 25 (17.7%), dual therapy 87 (61.7%), triple therapy 24 (17%), quadruple therapy 5 (3.5%), and 10 unknown. Cardiac re-Tx was required for CAV in 30 patients and for graft failure in 6 patients. Four patients required a third transplant for CAV. For those who survived more than 15 years after HTx, actuarial survival to 20 years and 25 years is 82% and 78%, respectively., Conclusions: Pediatric HTx provides acceptable long-term survival. Cardiac re-Tx and renal transplantation offer reasonable palliation for recipients who develop CAV and renal dysfunction., (Copyright © 2014 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Background: Intentional blood group (BG)-incompatible (ABOi) heart transplantation in childhood is emerging in many centers. Safety limits remain undetermined. In this multicenter study we have compiled experience on clinical and immunologic boundaries., Methods: Data from six centers in Europe and North America on ABOi transplantation were collected in a standardized survey., Results: Fifty-eight ABOi transplants were performed in 57 patients. Median age at transplant was 6.8 months (0.03 to 90 months); post-transplant follow-up was 37.7 months (0.46 to 117 months), accumulating 188 patient-years. Forty-seven percent of the patients received pretransplant mechanical circulatory support. Donors were either blood group A (n = 25), B (n = 18) or AB (n = 15). The median peak antibody titer to the donor BG pretransplant was 1:8 (0 to 1:64) for anti-A and 1:4 (0 to 1:32) for anti-B. Titers against the donor BG were lower post- than pretransplant in B recipients (p = 0.02), whereas third-party antibodies in BG O recipients developed normally post-transplant. Induction immunosuppression included anti-thymocyte globulin (61%), basiliximab (32%) or none (7%). All patients received calcineurin inhibitors, including 62% with mycophenolate mofetil, 10% with azathioprine, 2% with everolimus and 24% with steroids. There were 4 episodes of cellular rejection (Grade≥2R) and 7 antibody-mediated rejections. Five patients underwent antibody removal post-transplant. One patient developed severe graft vasculopathy. Freedom from death or retransplantation was 100%/96%/69% at 1/5/10 years. No graft loss was attributed to BG antibodies., Conclusions: Successful ABOi heart transplantation can be performed at an older age and with higher isohemagglutinin titers than initially assumed and using similar immunosuppressive regimens as for ABO-compatible transplants. Rejection and graft vasculopathy are rare. Persistently low titers of antibodies to the donor BG post-transplant suggest elements of tolerance and/or accommodation., (Copyright © 2013 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

Background: Common genetic variations influence rejection, infection, drug metabolism, and side effect profiles after pediatric heart transplantation. Reports in adults suggest that genetic background may influence post-transplant renal function. In this multicenter study, we investigated the association of genetic polymorphisms (GPs) in a panel of candidate genes on renal function in 453 pediatric heart transplant recipients., Methods: We performed genotyping for functional GPs in 19 candidate genes. Renal function was determined annually after transplantation by calculation of the estimated glomerular filtration rate (eGFR). Mixed-effects and Cox proportional hazard models were used to assess recipient characteristics and the effect of GPs on longitudinal eGFR and time to eGFR < 60 mL/min/1.73m(2)., Results: Mean age at transplantation was 6.2 ± 6.1 years. Mean follow-up was 5.1 ± 2.5 years. Older age at transplant and black race were independently associated with post-transplant renal dysfunction. Univariate analyses showed FASL (C-843T) T allele (p = 0.014) and HO-1 (A326G) G allele (p = 0.0017) were associated with decreased renal function. After adjusting for age and race, these associations were attenuated (FASL, p = 0.075; HO-1, p = 0.053). We found no associations of other GPs with post-transplant renal function, including GPs in TGFβ1, CYP3A5, ABCB1, and ACE., Conclusions: In this multicenter, large, sample of pediatric heart transplant recipients, we found no strong associations between GPs in 19 candidate genes and post-transplant renal function. Our findings contradict reported associations of CYP3A5 and TGFβ1 with renal function and suggest that genotyping for these GPs will not facilitate individualized immunosuppression for the purpose of protecting renal function after pediatric heart transplantation., (Copyright © 2012 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

Background: Late (occurring >1 year) rejection (LR) has been shown to increase mortality and morbidity after pediatric heart transplantation (HTx). The incidence of rejection has decreased in the first year after pediatric HTx in the current era. We hypothesized a similar phenomenon has occurred with LR., Methods: The Pediatric Heart Transplant Study database was used to analyze the effects of era (1993 to 1998 vs 1999 to 2007) and other factors on the prevalence of LR and its relationship to mortality, moderate-severe coronary vasculopathy (CAV) and retransplantation., Results: Freedom from first LR (59% vs 69% 5-year post-HTx, p < 0.001) and recurrent LR (p < 0.001) was significantly lower in the current vs earlier era. LR was significantly (p < 0.001) associated with early rejection (ER; rejection <1 year post-HTx) in both eras. Independent risk factors for LR were: earlier era (hazard ratio [HR] 1.47, 95% confidence interval [CI] 1.25 to 1.73, p < 0.001); non-white race (HR 1.41; 95% CI 1.19 to 1.67, p < 0.001); older recipient age (HR 1.05, 95% CI 1.03 to 1.06, p < 0.001); recipient Status 2 at transplant (HR 1.21, 95% CI 1.01 to 1.45, p = 0.037); and male donor (HR 1.17; 95% CI 1.0 to 1.37, p = 0.055). Late rejectors had a similar higher risk of mortality (odds ratio [OR] 4.20, 95% CI 3.04 to 5.81, p < 0.001) and incidence of moderate-severe CAV or retransplantation (OR 2.63, 95% CI 1.78 to 3.90, p < 0.001) in both eras., Conclusions: LR has decreased in the recent era in pediatric HTx recipients. Its effect on mortality and the development of CAV has not changed over time, suggesting an ongoing need for improved primary prevention strategies., (Copyright © 2012 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

The introduction of cyclosporine revolutionized the practice of immunosuppression for solid organ transplant recipients, and has resulted in a significant increase in survival. While CNI use has been the mainstay of immunosuppressive therapy in pediatric heart transplantation, CNIs have been associated with an increased risk of nephropathy leading to significant morbidity and mortality. We evaluated the effect on renal function of a CNI minimization protocol using SRL in pediatric heart transplant patients with CNI induced renal insufficiency. An IRB approved retrospective chart review and case control study was performed. There were 20 patients identified with renal insufficiency who had been converted to SRL (target 5-8 ng/mL) and cyclosporine (target 50-75 vs. 125-150 ng/mL). Renal insufficiency was defined as isotopic (Indium 111 DTPA) GFR <60 mL/min per 1.73 m(2) or sCr >1 mg/dL. Outcome variables evaluated were GFR and sCr at time of conversion and at two yr post conversion. Comparison was made with case control subjects matched for age at Tx, time from Tx to conversion, and initial GFR. The median age at Tx = 81 days (S.D. ±26), median time of conversion after Tx = 10 yrs (s.d. ±0.65). Self-limited/treatable side effects included hypercholesterolemia (10), neutropenia (6), aphthous ulcer (3), edema (2), anemia (2), and tremor (1). One patient rejected in the two yr prior to conversion, and one patient had two rejection episodes following conversion. GFR at conversion for study group was 51 ± 14 vs. 60 ± 2 at two yr, p = 0.018. GFR at inclusion for control group was 56 ± 20 vs. 53 ± 21, p = 0.253. This report demonstrates that minimizing CNI exposure by addition of SRL to the immunosuppressant regimen in pediatric heart transplant recipients result in improved renal function in comparison to historically managed patients. Furthermore, immunotherapy with SRL and lower-dose CNI can effectively prevent rejection with an acceptable side-effect profile., (© 2011 John Wiley & Sons A/S.)

Background: Rejection with hemodynamic compromise (RHC) is associated with high mortality in heart recipients. This study investigates the association between genetic polymorphisms and RHC in pediatric heart recipients., Methods: Data from 532 pediatric heart recipients from six centers in the Pediatric Heart Transplant Study were analyzed for time to RHC by recipient race, age at transplantation, and genotype at 13 genetic polymorphisms (TNF-α A-308G, IL-6 G-174C, INF-γ T+874A, IL-10 G-1082A, C-819T, and C-592A; FAS A-670G, FASL C-843T, and ACE I/D; and VEGF A-2578C, C-1451T, C+405G, and -2549 I/D)., Results: RHC occurred in 126 (23.7%) patients during the study period. Adjusting for age and race, IL-10 G-1082A, FAS A-670G, and ACE I/D genotypes were associated with RHC. IL-10 G-1082A GG genotype was associated with decreased risk of RHC with an adjusted hazard ratio (HR) of 0.49 (95% confidence interval [CI], 0.27-0.90; P=0.020). FAS A-670G AA genotype was associated with increased risk of RHC with an adjusted HR of 1.84 (95% CI, 1.25-2.69; P=0.002). ACE II genotype was associated with decreased risk of RHC with an adjusted HR of 0.58 (95% CI, 0.36-0.95; P=0.031)., Conclusions: Recipients with a high anti-inflammatory and immune-regulatory genetic profile (high interleukin-10) were protected from RHC. Conversely, recipients with a pro-apoptotic genetic profile (high Fas) or high angiotensin-1-converting enzyme producing genotype were at increased risk of RHC. This represents progress toward understanding the genetic risk factors of posttransplantation outcomes in pediatric heart recipients.

Background & Objectives: As more heart transplant recipients survive into late adolescence, research addressing long-term psychosocial and neurodevelopmental outcomes is imperative. The limited literature available suggests risk for psychosocial difficulties and lower cognitive, academic, and neuropsychological functioning. This paper reviews topic-related literature and provides preliminary data examining psychosocial and neuropsychological functioning of adolescents who received their heart transplant during infancy., Method: This paper offers a literature review AND presents preliminary data from studies conducted through Loma Linda University Children's Hospital (LLUCH). Study one examined psychosocial functioning and quality of life of adolescent infant heart transplant recipients. In study two, cognitive, academic, and neuropsychological data were analyzed., Results: Study 1: Overall psychosocial functioning fell in the Average range, however, a significant percentage of participants presented with difficulties on one or more of the psychosocial domains. Quality of life was also within normal limits, though concerns with general health and bodily discomfort were noted. Study 2: Cognitive functioning was assessed to be Below Average, with 43-62% of the participants demonstrating significant impairments. Neuropsychological functioning yielded significant weakness on language functioning, and mild weakness on visual-motor integration and executive functioning., Conclusion: While the majority of the participants demonstrate psychosocial resiliency, a subgroup present with difficulties suggesting the need for intervention. Cognitive/neuropsychological functioning suggests poorer functioning with patterns similar to other high-risk pediatric populations. These results are preliminary and further research on long-term psychosocial and neuropsychological development of pediatric heart transplant recipients is needed to better understand and ameliorate developmental trajectories.

Successful infant heart transplantation has now been performed for over 25 years. Assessment of long term outcomes is now possible. We report clinical outcomes for322 patients who received their heart transplant during infancy. Actuarial graft survival for newborn recipients is 59% at 25 years. Survival has improved in the most recent era. Cardiac allograft vasculopathy is the most important late cause of death with an actuarial incidence at 25 years of 35%. Post-transplant lymphoma is estimated to occur in 20% of infant recipients by25 years. Chronic kidney disease grade 3 or worse is present in 31% of survivors. The epidemiology of infant heart transplantation has changed through the years as the results for staged repair improved and donor resources remained stagnant. Most centers now employ staged repair for hypoplastic left heart syndrome and similar extreme forms of congenital heart disease. Techniques for staged repair, including the hybrid procedure, are described. The lack of donors is described with particular note regarding decreased donors due to newer programs for appropriate infant sleep positioning and infant car seats. ABO incompatible donors are a newer resource for maximizing donor resources, as is donation after circulatory determination of death and techniques to properly utilize more donors by expanding the criteria for what is an acceptable donor. An immunological advantage for the youngest recipients has long been postulated, and evaluation of this phenomenon may provide clues to the development of accommodation and/or tolerance.

Background: Late infections are common causes of morbidity and mortality after pediatric heart transplantation. In this multicenter study from 6 centers, we investigated the association between genetic polymorphisms (GPs) in immune response genes and late post-transplantation infections in 524 patients., Methods: Late infection was defined as a clinical infectious process occurring >60 days after transplantation and requiring hospitalization, intravenous antimicrobial therapy, or a life-threatening infection requiring oral therapy. All patients provided a blood sample for GP analyses of 18 GPs in cytokine, growth factor, and effector molecule genes by single specific primer-polymerase chain reaction and/or sequencing. Significant associations in univariable analyses were tested in multivariable Cox regression models., Results: Late infection was common, with 48.7% of patients experiencing ≥ 1 late infection, 25.2% had ≥ 1 late bacterial infection, and 30.5% had ≥ 1 late viral infection. Older age at transplantation was a protective factor for late infection, both bacterial and viral (hazard ratio [HR] 0.89-0.92 per 1-year age increase, p < 0.001). Adjusting for age, race, and transplant etiology, late bacterial infection was associated with HMOX1 A+326G AG and GG genotypes (HR, 2.41, 95% confidence interval [CI] 1.35-4.30; p = 0.003) and GZMB A-295G AA genotype (HR, 1.47; 95% CI; 1.03-2.1; p = 0.036). Late viral infection was associated with FAS A-670G GG genotype (HR, 1.42; 95% CI, 1.00-2.00; p = 0.050) in the adjusted model and with CTLA4 A+49G AA and AG genotypes (HR, 1.49; 95% CI, 1.02-2.19; p = 0.041) in univariable analysis., Conclusion: We found an association between late bacterial infection and GP of HMOX1, which may control macrophage activation. A weaker association was also found between late viral infection and GP of CTLA4, a regulator of T-cell activation. This represents progress toward understanding the clinical and genetic risk factors of outcomes after transplantation., (Copyright © 2010 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

Background: Granzyme B has been associated with allograft rejection in solid organ transplantation. Single nucleotide polymorphisms (SNPs) in the granzyme B gene might impact its expression. The aims of this study were (1) to establish the frequency of two granzyme B SNPs (A-295G; Q-55R) in pediatric heart transplant (PHTx) recipients and (2) to determine their phenotypic expression in healthy individuals., Methods: Three hundred ninety-six PHTx patients (245 white non-Hispanic, 49 black non-Hispanic, 82 Hispanics, and 20 others) and 52 healthy controls were screened for Q-55R and A-295G. For the control samples, we assessed the frequency of granzyme B positive cells by ELISPOT assay after mitogen stimulation., Results: Among the PHTx recipients, 57% percent of the population carried the Q/Q genotype, whereas 6% were R/R homozygotes. Seven of 49 (14%) black non-Hispanics were R/R homozygotes, whereas 13 of 245 (5%) of white non-Hispanics and 5 of 82 (6%) Hispanics carried the R/R genotype (P=0.02). The A allele frequency of granzyme B A-295G (49.6%) was similar to that of the G allele (50.4%). However, 80% of Black non-Hispanics were A allele carriers compared with 68% of White non-Hispanics (P<0.0001). After mitogen stimulation, the frequency of granzyme B positive cells was higher in the Q/Q homozygotes compared with R/R carriers (P=0.006), whereas a similar frequency of granzyme B positive cells was noticed among the genotypes of A-295G SNP., Conclusions: These data indicate that 55 Q/Q genotype is associated with increased in vitro expression of granzyme B.

Background: There is always more demand than supply of organs in pediatric heart transplantation. Yet, potential donor organs are regularly declined for a variety of reasons, among them donor organ quality as determined by United Network for Organ Sharing (UNOS) refusal code 830 or its equivalent., Methods: For the study group institutional and UNOS databases (July 2000 to December 2008) were reviewed to examine outcomes of pediatric heart transplantation using donor hearts that had been previously refused one or more times because of organ quality. Variation between outcomes of this cohort and recipients who received primarily offered heart grafts in a single institution was analyzed., Results: In 29 recipients, transplantation or retransplantation was with heart grafts previously declined on the basis of quality. Recovery distances (p < 0.002) and graft cold ischemic times (p < 0.001) were significantly longer for declined hearts. Operative survival was 93% +/- 5.0% (27 of 29). Seven-year actuarial survival was 74% +/- 10.5%. At the present time, 24 of the 29 recipients (83%) are alive. These results do not vary statistically from those experienced by 84 recipients of 86 primarily offered donor organs during the same time., Conclusions: Despite longer distance recovery (ie, longer graft cold ischemic times), outcomes of pediatric heart transplantation using donor heart grafts refused on the basis of organ quality are highly competitive. Pediatric donor hearts should seldom be declined on the basis of organ quality (UNOS code 830).

Background: As infant and pediatric heart transplantation becomes more common, there is a growing need to better understand the causes of failure or death, if we are to continue to improve the outcome in these children., Methods: A multidisciplinary team reviewed all deaths occurring in the cohort of infants and children transplanted during the first 20 years of the Loma Linda Pediatric Heart Transplant program, with 2 additional years of follow-up beyond the 20-year accrual period, and classified them as to cause., Results: There were 169 deaths among 421 recipients, with a median follow-up of 9.7 years. Autopsy was performed in 128 cases. The causes of death, in decreasing order of frequency, included acute rejection (26.0%), infection (16.0%), cardiac allograft vasculopathy (CAV) (14.2%), technical issues (8.3%), acute graft dysfunction (6.5%), neoplasm (7.1%), chronic graft dysfunction (4.7%) and miscellaneous factors (10.1%), and in twelve deaths (7.1%) the cause was unclassified. Acute graft dysfunction and technical issues accounted for nearly two-thirds of the deaths in the first 30 days after transplant, while acute rejection resulted in the largest number of deaths after the first year (30.4%), with CAV a close second (23.5%)., Conclusions: Acute graft dysfunction and technical issues were the most frequent cause of early death. Late deaths were most often due to acute rejection and CAV, which differs somewhat from the experience reported in adults. Acute rejection was the single most important cause of late mortality, and resulted in a significant number of late sudden and unexpected deaths.

Background: Pediatric heart transplantation has now been successfully performed for more than 20 years. As survival rates have improved, more attention is now focused on long-term outcomes., Methods: This report reviews the literature on developmental outcomes after pediatric heart transplantation., Results: Pediatric patients undergoing heart transplantation generally can be expected to have developmental outcomes in the low-normal range, consistent with outcomes seen in other children with complex congenital heart disease requiring surgical intervention. When these children reach school age, or return to school, most can be expected to function reasonably well in mainstream school settings. A significant minority will require additional educational assistance. Approximately 10% will have significant neurologic impairment. In school, particular attention should be paid to evaluating the child for deficits in arithmetic and verbal skills. Performance may be better than predicted from IQ testing. Behavioral issues are common, with depression, concerns about social competence, and attention difficulties most frequently endorsed. This may pre-date transplantation in those who undergo transplantation during childhood and may improve with time. Parents more often report problem behaviors than teachers. Family resources and family coping skills are also strongly correlated with the child's emotions and coping skills., Conclusion: The pediatric heart transplant recipient's ability to transition from childhood into a happy and productive adult life can be significantly affected by his or her cognitive abilities, learning experiences, sense of self, and emotions. Attention to these factors is an important part of caring for these children.

Background: An increasing number of children are being referred for cardiac transplantation after (1) failing conventional corrective or palliative surgical reconstruction, (2) after stabilization with mechanical circulatory support devices, and (3) when primary graft failure or advanced cardiac allograft vasculopathy are established., Methods: The records of 417 infants and children (age range, 0-18 years) who underwent cardiac transplantation from November 1985 through December 2005 at Loma Linda University Children's Hospital were retrospectively reviewed. The pre-transplantation diagnosis was used to divide patients into 3 groups: primary cardiomyopathy (CM), 103; hypoplastic left heart syndrome (HLHS), 154; and other complex congenital heart disease (CCHD), 160. These groups were compared and analyzed for differences in early and late morbidity and mortality., Results: Operative mortality was significantly lower in the CM group compared with the HLHS (p < 0.02;) and CCHD groups (p < 0.01). Long-term actuarial recipient survival, however, was similar for all groups. The 15-year actuarial survival was 59% for the CM Group, 57% for the HLHS Group, and 50% for the CCHD Group. Actuarial survival after retransplantation is not statistically different from that with primary cardiac transplantation., Conclusion: Although peri-operative survival was lower in infants and children with HLHS and CCHD compared with those with CM, long-term survival has been the same for all groups. Late survival after retransplantation was not statistically different than among those with primary cardiac transplantation.

Objective: The objective of this study was to determine the association between the genetic polymorphisms of proinflammatory and regulatory cytokines and long-term rates of repeat and late acute rejection episodes in pediatric heart transplant (PHTx) recipients., Methods: Three hundred twenty-three PHTx recipients: 205 White non-Hispanic, 43 Black non-Hispanic, and 75 Hispanic were analyzed for time to first repeat and late acute rejection episodes by race, age at transplantation, and gene polymorphism (interleukin [IL]-6, -174 G/C, IL-10, -1082 G/A, -819 C/T, 592 C/A; vascular endothelial growth factor (VEGF) -2578 C/A, -460 C/T, +405 C/G; tumor necrosis factor alpha (TNF-alpha)-308 G/A)., Results: Recipient black race and older age at transplant were risk factors for both repeat and late rejections, though black race was more significantly related to late rejection (P=0.006). Individually, TNF-alpha high, IL-6 high, VEGF high, and IL-10 low phenotypes did not impact the risk of repeat or late rejection. However, the combination VEGF high/IL-6 high and IL-10 low was associated with increased estimated risk of late rejection (P=0.0004) and only marginally with repeat rejection (P=0.051). In a multivariate analysis, adjusting for age and race, VEGF high/IL-6 high and IL-10 low still remained an independent risk factor for late acute rejection (RR=1.91, P<0.001)., Conclusion: This is the largest multicenter study to document the impact of genetic polymorphism combinations on PHTx recipients' outcome. The high proinflammatory (VEGF high/IL-6 high) and lower regulatory (IL-10 low) cytokine gene polymorphism profile exhibited increased risk for late rejection, irrespective of age and race/ethnicity.

Objective: Children born with hypoplastic left heart syndrome (HLHS) may experience cardiac dysfunction after staged surgery or transplantation, which may worsen with age. We examined the hypothesis that exercise testing can address cardiovascular capacity and suggest interventions to improve quality of life., Study Design: Children with HLHS > or = 8 years old performed treadmill or bicycle ergometric testing at 4 centers. Results were compared with norms for age and sex., Results: Of the 42 participants, the mean age was 12.9 years (range, 8.5-17.0 years), 64% were boys, 20 had staged surgery, and 34 completed metabolic assessment. The percent of predicted maximal oxygen uptake (mVO2) was higher in younger children. Children aged 8 to 12 years achieved 70% of predicted mVO2; children aged 13 to 17 years achieved 60% of predicted mVO2 (P = .02). The percent of predicted peak heart rate trended higher in younger patients (83% versus 75%, P = .07). Electrocardiographic changes were more common in older children. In treadmill testing, patients who had a transplant had better exercise performance than patients who underwent staged surgery in percent of predicted exercise time (82% versus 54%, P < .0001) and peak rate-pressure product (241 x 10(3) versus 195 x 10(3), P = .02). The percent of predicted mVO2 did not differ between patients who had a transplant (66%) and patients who underwent staged surgery (61%, P = .25)., Conclusion: Children with HLHS showed considerable age-related decline in exercise performance, regardless of surgical strategy.

Background: Although tricuspid valve regurgitation (TR) after heart transplantation is a known complication, there has been little discussion of this subject in neonatal heart transplantation. We aim to elucidate the prevalence, etiology, and evolution of TR early after transplant in neonates., Methods: Eighty-five neonatal recipients were studied retrospectively by two-dimensional and Doppler echocardiography. The semiquantitative grading of TR was based on the ratio of regurgitation jet area to right atrial area., Results: Immediately after neonatal heart transplantation, TR was recognized in 47 patients (grade 1, n = 18; grade 2, n = 22; grade 3, n = 7; and grade 4, n = 0). Tricuspid regurgitation prevalence diminished from 55% to 19% with reduction in severity 1 year after transplantation. The prevalence of TR (grade 2 and grade 3) was affected by a donor/recipient body weight ratio of more than 2.0 (p = 0.004) and graft ischemia for more than 3 hours (p = 0.014). The ratio of donor and recipient right atria portion, which had a correlation with donor/recipient body weight ratio (r2 = 0.415, p < 0.0001), separated the four subgroups in terms of TR grade immediately after transplantation (p = 0.0064) and also at 1 year after transplantation in all surviving grafts from 1.48 +/- 0.54 to 0.8 +/- 0.32 (p < 0.0001). The Cox model found no significance for early posttransplant TR as a risk factor for graft survival., Conclusions: Early posttransplant TR was affected by atria geometrical disproportion and by graft ischemia. Tricuspid regurgitation was not a risk factor for graft survival because of its amelioration over time, perhaps induced by recipient growth and recovery of myocardial injury relating to graft procurement.

Background: Allograft failure in African-Americans remains higher than in Caucasians. Single nucleotide polymorphisms (SNPs) have been associated with altered allograft outcomes., Methods: In this multi-center study we compared SNP frequencies in 364 pediatric heart recipients from three ethnic/racial groups: Caucasian (n = 243), African-American (n = 39), and Hispanic (n = 82). The target genes were: tumor necrosis factor-alpha, interleukin (IL)-10, IL-6, interferon (IFN)-gamma, vascular endothelial growth factor (VEGF), transforming growth factor-beta1, Fas, FasL, granzyme B, ABCB1, CYP3A5., Results: Compared to Caucasians, African-Americans exhibited a higher prevalence of genotypes associated with low expression of IFN-gamma (24% vs. 45.7%, P < 0.001) and IL-10 (33% vs. 57.1%, P = 0.052). African-Americans also exhibited an increased prevalence of high IL-6 (82.9% vs. 38.1%; P < 0.001). VEGF -2578 C/C and -460 C/C genotypes were found more frequently in African-Americans and Hispanics as compared to Caucasians (P < 0.001). G/G genotype of Fas and T/T genotype of FasL were expressed more often by African-American recipients. The prevalence of Granzyme B (-295A/G) genotype was differentially distributed in the three groups. Compared with Caucasians, African-Americans were twice as likely to carry the ABCB1 2677 G/G genotype (78.6% vs. 33.7%, P < 0.0025), and they were more frequent carriers of the CYP3A5 *1/*1 genotype (35.7% vs. 0.6% in Caucasians and 7.2% in Hispanics; P < 0.001)., Conclusion: African-Americans have a genetic background that may predispose to proinflammatory/lower regulatory environment, reduced drug exposure and immunosuppressive efficacy. In this ongoing multicenter study, these gene polymorphisms differences among ethnic/racial groups are being documented so that therapeutic strategies can be devised to optimize outcomes for pediatric transplant recipients.

At Loma Linda University Children's Hospital, the medical information of 405 pediatric patients who received orthotopic cardiac transplantation were reviewed. Of those who died (n=136), 86% (n=117) underwent postmortem examinations, and the brain was examined in 61% (n=82, male=39). The number and type of intracranial lesions present were compiled, and these were matched to underlying functional cardiac disease categories. Intracranial abnormalities were present in 87%. Infarct was the most common primary central nervous system pathology in hypoplastic left heart syndrome (41%) but was also observed frequently in children with obstructive lesions (37%), cyanotic disease (31%), or cardiac shunting (29%). Secondary findings included extraparenchymal hemorrhage in obstructive lesions (31%); hypoxic changes occurred in 15% of patients with cyanotic disease and in 14% of those with cardiac shunting. Thirty-three percent of children with restrictive lesions had no neuropathology reported. Postmortem examination brain weights were matched against age and sex norms, with 29% of females and 36% of males below two standard deviations. These findings revealed that intracranial pathology was present in the majority of transplanted children who underwent postmortem examination, and that infarctive changes constituted the most common neuropathologic abnormality. Additionally, a number of children had significantly reduced brain weight.

Most infants and children referred for cardiac transplantation have low cardiac output with concurrent renal hypoperfusion leading to renal insufficiency and failure. This article is a review of the literature of and a single center's experience with combined heart and kidney failure in infants and children less than 10 yr of age. While 39 infants less than 10 yr of age were dialyzed pre- or peri-operatively, none required dialysis support at the time of discharge or in 5-10 yr follow-up. Based on our experience we recommend heart transplant alone in infants and young children with primary heart disease even though they have renal dysfunction.

The Pediatric Heart Transplant Study (PHTS) group was founded in 1991 as a voluntary, collaborative effort dedicated to the advancement of the science and treatment of children following listing for heart transplantation. Since 1993, the PHTS has collected data in an international, prospective, event-driven database that examines risk factors for outcome events following listing for transplantation. The events include transplantation, death, rejection, infection, malignancy, graft vasculopathy, and retransplantation. Over its 12 years of existence, the PHTS has made major contributions to the field of pediatric heart transplantation, especially in the areas of outcome analysis and risk factor assessment for death and other major morbidities after listing and after transplantation. The new challenges facing the PHTS include how to implement the practice of evidence-based medicine in the field of pediatric heart transplantation and how to support ongoing data collection and analysis to provide long-term outcomes as the PHTS subjects enter their second decade after transplantation.

Metabolic parameters for coronary allograft vasculopathy (CAV) have not been well defined in children. CAV (by angiography or autopsy) was studied in 337 heart recipients on a cyclosporine-based steroid-sparing regimen. Freedom from CAV for all was 79% at 10 years. Fifty-nine patients (18%) developed CAV at a mean of 6.5 +/- 3 years post-transplant. First year rejections were significantly higher in CAV, mean 2.3 vs. 1.4, P = 0.003, odds ratio (OR) 1.8. Rejection with hemodynamic compromise beyond 1 year post-transplant was associated with CAV, P < 0.001, OR 8.4. There was no significant correlation among human leukocyte antigen DR (HLA DR) mismatch, pacemaker use or homocysteine levels and the development of CAV. Maximum cholesterol and low density lipoprotein (LDL) levels were not significantly different. Neither diabetes nor hypertension was significant predictors of CAV on multivariate logistic regression analysis. In conclusion, frequent and severe rejection episodes may predict pediatric CAV. Neither glucose intolerance nor lipid abnormalities appeared to alter risk for CAV in this population.

Background: There are few published data regarding the long-term outcome of "large" cardiac allografts in children. This study examines the effect of cardiac graft oversizing on the survival of pediatric patients with congenital heart disease (CHD)., Methods: Two hundred ninety-one children, age 1 day to 17 years (median 50 days), with CHD underwent primary cardiac transplantation between 1985 and 2002. Patients were analyzed according to donor-recipient weight ratio (D-R): Group (Gp) I (n = 252) with D-R <2.5 (range 0.59 to 2.49, median 1.4), and Gp II (n = 39) with D-R >/=2.5 (range 2.5 to 4.65, median 2.78). CHD diagnoses included hypoplastic left heart syndrome (138 in Gp I, 13 in Gp II), single ventricle (29 in Gp I, 1 in Gp II) and other (85 in Gp I, 13 in Gp II). Patients with cardiomyopathy were excluded. Pre-transplant cardiac palliation was performed in 36% of Gp I and 15% of Gp II patients. The average graft ischemic times (minutes) were 266 +/- 7.5 and 283 +/- 18.9 for Gp I and Gp II, respectively (p < 0.2)., Results: The operative mortality for Gp I was 10.3% and 10.2% for Gp II (p < 0.99). There was no significant difference between the 2 groups in length of hospital stay (p < 0.15) or duration of ventilator support (p < 0.6) post-transplantation. However, the incidence of open chest was higher (p < 0.003) in Gp II (28%) compared with Gp I (8%). The survival rates for Gp I and Gp II were: 82 +/- 2.4% vs 84 +/- 5.7% at 1 year; 71 +/- 2.9% vs 72 +/- 7.2% at 5 years; and 63 +/- 3.2% vs 65% +/- 7.4 at 10 years., Conclusions: Post-transplant morbidity and short- and long-term survival of pediatric recipients with CHD are not adversely influenced by the use of oversized cardiac allografts.

Background: Few data describe exercise performance after cardiac transplantation during infancy. The aim of this study was to compare the cardiorespiratory response to exercise in healthy subjects with that of subjects who had undergone heart transplantation during infancy to treat hypoplastic left heart syndrome., Methods: Subjects (24 heart transplant recipients and 25 healthy controls) exercised on a treadmill using pediatric ramp protocols. We measured heart rate (HR), blood pressure, and metabolic data. Median age at transplantation was 20 days (range, 4 to 97 days). Age of recipients at exercise testing was 9.7 +/- 2.3 years and in healthy subjects was 10.5 +/- 1.4 years (p=not significant [NS])., Results: Exercise duration was similar in both groups (10.3 +/- 2.0 minutes in recipients vs 11.1 +/- 1.5 minutes in healthy subjects, (p=NS). Heart rate at rest was greater in recipients (94 +/- 15 beats per minute [bpm] vs 85 +/- 11 bpm, p=0.02). Peak HR also was less in the recipient group (158 +/- 15 bpm vs 189 +/- 12 bpm, p <0.001). Peak oxygen consumption was 14% less in the recipients (32.3 +/- 5.6 ml/kg/min vs 36.8 +/- 5.5 ml/kg/min, p <0.01). Ventilatory anaerobic threshold was decreased in recipients, 27.6 +/- 9.6 vs 32.8 +/- 6.0, p <0.05. Respiratory exchange ratio at peak exercise was equal in both groups (1.06 +/- 0.06 vs 1.06 +/- 0.08). Oxygen pulse index did not differ significantly, 5.5 +/- 1.1 ml/beat/m2 in recipients and 6.1 +/- 1.7 ml/beat/m2 in healthy subjects (p=NS)., Conclusions: Overall, children who undergo cardiac transplantation in infancy have exercise capacities within the normal range. These recipients have a decreased heart rate reserve that may account for the differences in peak oxygen consumption when compared with healthy subjects.

Objective: To assess long-term neuropsychological outcomes of infant heart transplant recipients., Study Design: Fifty-five children (mean age, 6.4 years) with a primary diagnosis of hypoplastic left heart syndrome or other cardiac disorders participated in the study. Six areas of risk were assessed (birth; preoperative, intraoperative, and postoperative status; long-term medical complications; and socioeconomic factors). Neuropsychological evaluations included the following: Wechsler Scales of Intelligence, Wechsler Individual Achievement Test, Berry Visual Motor Integration Scale, Comprehensive Evaluation of Language Function, and Achenbach Child Behavioral Checklist., Results: Intellectual functioning scores revealed a mean full-scale IQ of 81 +/- 19. Intraoperative and postoperative variables (bypass time, hospital course, and lowest posttransplant pH), long-term medical complications (serious infections and posttransplant surgical procedures), and socioeconomic factors were associated with cognitive functioning. Visual-motor functioning was also related to bypass and total support time., Conclusions: Long-term outcomes reveal low-average neuropsychological functioning and are related to intrasurgical-postsurgical, long-term medical, and socioeconomic factors. The neuropsychological and psychosocial functioning of infant heart transplant recipients will be important to address as they mature during adolescence and adulthood.

Background: With improvement in medical outcomes, the current research has shifted toward understanding and enhancing the quality of life after pediatric heart transplantation. Previous research has indicated that infant heart transplant recipients are generally at risk for neurodevelopmental delays; however, no longitudinal studies exploring the patterns of development within this medical population have been performed., Methods: Using the Bayley Scales of Infant Development-II, 39 children (2 to 38 months of age) who underwent heart transplantation in infancy (<1 year) at Loma Linda University Children's Hospital were assessed consecutively over time., Results: Mean Mental Development Index (MDI) scores for all age groups were within normal limits, except for the age ranges of 18 to 23 and 24 to 35 months, which were mildly delayed. Average Psychomoter Development Index (PDI) scores for all age groups reflected mildly delayed performance, except for the 36- to 38-month age group, which was within normal limits. Repeated measures analyses of variance on a sub-set of participants with at least 4 consecutive assessments revealed within-subject effects on MDI scores (F = 5.7, p < 0.01), but not on PDI scores (F = 1.6, p = 0.22). Significant decreases in MDI scores at 18 and 28 to 36 months were noted., Conclusions: Motor development in this population was consistently mildly delayed. Age-dependent variability in cognitive skills was apparent. The delays appeared due to speech/language acquisition (18 months), and abstract reasoning/goal-directed behaviors (28 to 36 months). Possible etiologies for cognitive delays include test artifacts, auditory functioning and effects of immunosuppressive agents. Understanding risk factors in this patient population will allow for early and effective intervention.

A retrospective analysis of 381 pediatric heart-transplant recipients was performed to determine the frequency, characteristics, and risk factors for post-transplant diabetes. The rate of post-transplant diabetes was 1.8% with antithymocyte globulin, cyclosporine and azathioprine as primary immunosuppressive therapy. Time from transplant to diabetes was 0.25-13 years. Diabetes was characterized by reversibility, and lack of insulinopenia and autoimmunity. The post-transplant diabetes rate in tacrolimus-converted children (n = 45) was 8.8%. In tacrolimus-converted children, age at transplant, mean and maximum tacrolimus blood levels, and first-year rejection episodes were higher in the post-transplant diabetes group, which also consistently had DR-mismatched transplants and HLA DR3/DR4 haplotypes. Body mass index was not different between diabetic and control tacrolimus-converted children. In conclusion, pediatric post-transplant diabetes may be related to reversible insulin resistance. Tacrolimus levels, HLA DR mismatch, and older age at transplant may predispose to post-transplant diabetes.

Seizures are common in infants undergoing cardiac transplant and are usually attributed to a non-specific "post-pump" phenomenon. In this study, we determined which variables were associated with the occurrence of post-transplant seizures in infants with hypoplastic left heart syndrome and the need for continued treatment with antiepileptic medication. Of 127 infants studied over an 11-year period, 27 (21%), ages 9 to 90 days, had post-transplant seizures. These patients were compared to 27 age-matched transplanted infants without seizures. We compared multiple variables before, during, and after transplant including growth parameters, time of diagnosis, cyclosporine levels, maternal variables, circulatory and bypass parameters, laboratory data, neuroimaging and electroencephalographic studies, neurologic examination findings, and peri-operative complications. Post-transplant seizures were associated with total cardiopulmonary bypass time and the presence of post-transplant complications. Deep hypothermic circulatory arrest time was inversely correlated with seizure severity. Pre-transplant electroencephalographic abnormalities and total bypass time were associated with seizures requiring continued use of antiepileptic therapy. Post-transplant electroencephalograms were not associated with the need for continued treatment. Identification of variables associated with the development of post-transplant seizures is essential for early intervention to reduce long-term morbidity and mortality. Future studies to reduce risk of post-transplant seizures are warranted.

Background: Acute rejection commonly occurs within the first year after heart transplantation, and then decreases in frequency with time. Recently, the long-term utility of endomyocardial biopsy during routine annual catheterization has been questioned. The purpose of this study was to retrospectively review the prevalence of biopsy-proven rejection during routine annual catheterization in our patient population, determine whether biopsies late after transplant are useful, and identify factors that correlate with late unsuspected rejection., Methods: Biopsy results from the annual catheterization were evaluated from 1986 to August 2000. The prevalence of moderate rejection was evaluated and compared with the patient's immunosuppressive regimen; the prevalence of late rejection; and how late rejection correlated with recipient age, number of first-year rejections and presence of sub-therapeutic cyclosporine., Results: A total of 1108 biopsies were performed in 269 children with a mean follow-up of 5 +/- 3 years (median 5 years, range 1 to 11 years). Three-drug immunosuppressive therapy, including steroids, was used in 93 patients. There was a persistent 8% to 10% prevalence of moderate rejection at up to 10 years post-transplantation. Moderate rejection was more likely in patients: (1). on 3-drug immunosuppressive therapy; (2). with a recipient age >1 year; and (3). with a relatively lower cyclosporine level., Conclusions: These data suggest that continued surveillance of pediatric transplant patients for acute rejection is indicated for long-term follow-up.

Background: We evaluated the role of total lymphoid irradiation (TLI) in the management of refractory rejection among pediatric heart transplant patients., Methods: Eleven of 298 patients underwent TLI at 6 to 195 months of age and were divided into subgroups: those who survived (group A, n = 7) and those who did not survive beyond 1 year after TLI (group D, n = 4). Non-TLI recipient data were considered as the controls., Results: Six out of 11 patients died eventually (54%). TLI was initiated 3 to 107 months after transplantation with a dosage of 600 to 840 cGy. The pre-TLI rejection rate (0.62 +/- 0.40 per month) was higher (p < 0.0001); however, the post-TLI rejection rate (0.24 +/- 0.65 per month) showed no significant difference from the control rejection rate. The Cox proportional hazard model found significance for TLI as a risk factor for development of posttransplant coronary artery disease (relative risk, 4.8; 95% CI, 1.1 to 21.3) and posttransplant lymphoproliferative disease (relative risk, 47.9; 95% CI, 1.6 to 1,475.3), respectively. Although the rejection rate decreased after TLI in both groups (group A pre/post, 0.51 +/- 0.31/0.06 +/- 0.08 per month; group D pre/post, 0.82 +/- 0.49/0.57 +/- 1.09 per month), significance was obtained only in group A (p = 0.018)., Conclusions: TLI was an effective adjunct for reversal of refractory rejection in pediatric heart transplantation by reducing the rejection rate. Great care must be taken for the risk of development of coronary artery disease or lymphoproliferative disease.

Surgical mortality is high in children with visceral heterotaxy (VH), particularly if atrioventricular valve insufficiency, ventricular dysfunction, or aortic atresia is present. This study reviews the outcome of cardiac transplantation (CT) in infants and children with VH and congenital heart disease who are at high risk for standard palliative or corrective surgery. We reviewed CT outcomes in 29 children with VH, congenital heart disease, atrioventricular valve insufficiency, ventricular dysfunction, and/or aortic atresia. Median age at CT was 3.1 years. Cardiac surgery had been performed in 20 patients (69%) before CT. Follow-up since CT has been 8.5 +/- 2.2 years. Outcomes were compared with 45 children who underwent transplantation for dilated cardiomyopathy. Actuarial graft survival in the VH group at 30 days and 1, 5, and 10 years was 100%, 86%, 68%, and 50%, respectively, compared with 100%, 96%, 83%, and 68% in children who underwent transplantation for dilated cardiomyopathy (p = 0.12). Splenic status, cardiac position, age at CT, number of prior cardiac surgeries, or systemic venous anomalies were not predictors of mortality after CT. Cardiopulmonary bypass and graft ischemic times were longer in the VH group; time on the ventilator after CT, length of hospitalization, and rejection, infection, post-transplant lymphoproliferative disease, and transplant coronary artery disease rates were equal. Thus, CT is a viable alternative therapy for high-risk patients with VH, possibly offering improved survival over standard surgical management.

Simple Summary: Post-transplant lymphoproliferative disorders (PTLD) are heterogenous lymphoproliferative disorders that develop in immunosuppressed transplant recipients. We performed a retrospective review of PTLD occurring in pediatric heart transplant recipients and sought to determine the correlation of PTLD subtypes with different characteristics. Our single institution retrospective study found that compared to older children, infant heart transplant recipients were less likely to develop PTLD. Infant heart transplant recipients who developed PTLD were diagnosed later than older children and had a lower rate of more aggressive PTLD. The overall survival of patients with more aggressive PTLD was significantly lower than patients with low-grade PTLD. Proper classification of the type of PTLD is important, as the subtypes of PTLD showed a significant correlation with the outcome. Post-transplant lymphoproliferative disorders (PTLD) are heterogenous lymphoproliferative disorders that develop as a consequence of immunosuppression in transplant recipients. We sought to determine if subtypes of PTLD correlated with different outcomes. We performed a retrospective review of PTLD occurring in pediatric heart transplant recipients. A total of 558 children and infants underwent cardiac transplantation at our institution between 1985 and 2019 and were followed until March 2021. Forty-nine of 558 patients developed PTLD (8.8%). As compared to older children (>one year of age), infant recipients (

Young adult solid organ transplant recipients who transfer from pediatric to adult care experience poor outcomes related to decreased adherence to the medical regimen. Our pilot trial for young adults who had heart transplant (HT) who transfer to adult care tests an intervention focused on increasing HT knowledge, self-management and self-advocacy skills, and enhancing support, as compared to usual care. We report baseline findings between groups regarding (1) patient-level outcomes and (2) components of the intervention. From 3/14 to 9/16, 88 subjects enrolled and randomized to intervention (n = 43) or usual care (n = 45) at six pediatric HT centers. Patient self-report questionnaires and medical records data were collected at baseline, and 3 and 6 months after transfer. For this report, baseline findings (at enrollment and prior to transfer to adult care) were analyzed using Chi-square and t-tests. Level of significance was p < 0.05. Baseline demographics were similar in the intervention and usual care arms: age 21.3 ± 3.2 vs 21.5 ± 3.3 years and female 44% vs 49%, respectively. At baseline, there were no differences between intervention and usual care for use of tacrolimus (70 vs 62%); tacrolimus level (mean ± SD = 6.5 ± 2.3 ng/ml vs 5.6 ± 2.3 ng/ml); average of the within patient standard deviation of the baseline mean tacrolimus levels (1.6 vs 1.3); and adherence to the medical regimen [3.6 ± 0.4 vs 3.5 ± 0.5 (1 = hardly ever to 4 = all of the time)], respectively. At baseline, both groups had a modest amount of HT knowledge, were learning self-management and self-advocacy, and perceived they were adequately supported. Baseline findings indicate that transitioning HT recipients lack essential knowledge about HT and have incomplete self-management and self-advocacy skills. [ABSTRACT FROM AUTHOR]

This review details the indications for heart transplantation in children. Contraindications have evolved from absolute to relative. Controversial issues remain and this paper represents a consensus of more than a dozen centers that have programs that remain active performing pediatric heart transplants. [ABSTRACT FROM AUTHOR]

Background: Cardiac transplantation (CTx) has been established as an effective therapy for a variety of inoperable cardiac conditions in infants and children. However, graft vasculopathy (GV) has emerged as the main limiting factor to long-term survival of CTx recipients. The only treatment of severe GV is cardiac retransplantation (re-Tx). Controversy exists regarding the use of scarce donor organs for cardiac re-Tx. Objective: To compare the outcome of cardiac re-Tx for GV with that of primary CTx in children. Design: A 12-year retrospective cohort review. Setting: A university-affiliated children's hospital. Patients: All infants and children who underwent CTx (group 1, n=322) had complete follow-up of 1389.7 patient-years. Graft vasculopathy was confirmed in 32 recipients (1.1-8.2 years after undergoing CTx). Thirteen patients died suddenly, 3 died waiting for cardiac re-Tx (1-17 days after relisting), 4 are pending cardiac re-Tx, and 12 (group 2) underwent cardiac re-Tx. Intervention: Cardiac re-Tx at a mean (±SD) interval from the first CTx of 6.3±1.8 years (range, 2.2-9.4 years). Two patients required additional aortic arch aneurysm repair with cardiac re-Tx. Results: When group 1 was compared with group 2, there was no significant difference in operative mortality (9.0% vs 8.3%; P=.9), rejection rate (0.98 vs 0.86; P =.1), and hospital stay (23.0±18.8 days vs 20.5±11.6 days; P =.65). Actuarial survival for groups 1 and 2 at 1 and 4 years was 84.3% vs 83.3% (P=.59) and 74.4% vs 83.3% (P=.85), respectively. Conclusions: The surgical outcome and intermediate survival of cardiac re-Tx for GV and primary CTx are similar. Children with severe cardiac GV are at risk of sudden death and can benefit from early cardiac re-Tx. [ABSTRACT FROM AUTHOR]

This study was undertaken to assess the incidence, indications, and predisposing factors for pacemaker placement in a pediatric heart transplant population. From November 1985 to May 1994, 246 pediatric patients have undergone cardiac transplantation at Loma Linda University Medical Center. Seven (2.8%) have received pacemaker placement with an 8-50 month follow-up period. Median age at transplant was 462 days (0 days to 2.5 years). The median time to pacemaker placement was 190 days (18-1,672 days) after transplantation. Indications were sick sinus syndrome (SSS) in 5 and heart block in 2 patients (1 during acute rejection). Three patients with SSS underwent electrophysiology studies (EPS); 1 was normal and 2 showed sinus node dysfunction. The mode of pacing was WIR in 6 patients and WI in 1 patient. All 6 survivors are doing well and 5 patients' pacemakers still provide support. These 7 patients were compared with 185 pediatric patients (0 days to 12-years-old) transplanted during 1985 through 1993 who survived at least 6 months after transplantation. There was no correlation between the receipt of a pacemaker and graft cold ischemic time, rejection history, donor age, or recipient age at transplantation. The 5 patients with SSS had significantly lower average heart rates in the first month after transplantation (108 ± 16 vs 130 ± 12; P = 0.0002). The need for permanent pacemakers in this population is uncommon. Pacemakers, however, can be safely performed when necessary with excellent clinical results. [ABSTRACT FROM AUTHOR]