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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.)

Significant racial disparity remains in the incidence of unfavorable outcomes following heart transplantation. We sought to determine which pediatric posttransplantation outcomes differ by race and whether these can be explained by recipient demographic, clinical, and genetic attributes. Data were collected for 80 black and 450 nonblack pediatric recipients transplanted at 1 of 6 centers between 1993 and 2008. Genotyping was performed for 20 candidate genes. Average follow-up was 6.25 years. Unadjusted 5-year rates for death (p = 0.001), graft loss (p = 0.015), acute rejection with severe hemodynamic compromise (p = 0.001), late rejection (p = 0.005), and late rejection with hemodynamic compromise (p = 0.004) were significantly higher among blacks compared with nonblacks. Black recipients were more likely to be older at the time of transplantation (p < 0.001), suffer from cardiomyopathy (p = 0.004), and have public insurance (p < 0.001), and were less likely to undergo induction therapy (p = 0.0039). In multivariate regression models adjusting for age, sex, cardiac diagnosis, insurance status, and genetic variations, black race remained a significant risk factor for all the above outcomes. These clinical and genetic variables explained only 8-19% of the excess risk observed for black recipients. We have confirmed racial differences in survival, graft loss, and several rejection outcomes following heart transplantation in children, which could not be fully explained by differences in recipient attributes., (© 2016 The American Society of Transplantation and the American Society of Transplant Surgeons.)

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.

Background: The survival of recipients of cardiac allografts is limited by rejection, lymphoproliferative disease, and coronary vasculopathy. The purpose of this study in children who had received heart transplants was to evaluate the cardiac allografts for myocardial viral infections and to determine whether the presence of viral genome in the myocardium correlates with rejection, coronary vasculopathy, or graft loss., Methods: We enrolled heart-transplant recipients 1 day to 18 years old who were undergoing evaluation for possible rejection and coronary vasculopathy. Endomyocardial-biopsy specimens were evaluated for evidence of rejection with the use of standard criteria and were analyzed for the presence of virus by the polymerase chain reaction (PCR)., Results: PCR analyses were performed on 553 consecutive biopsy samples from 149 transplant recipients. Viral genome was amplified from 48 samples (8.7 percent) from 34 patients (23 percent); adenovirus was found in 30 samples, enterovirus in 9 samples, parvovirus in 5 samples, cytomegalovirus in 2 samples, herpes simplex virus in 1 sample, and Epstein-Barr virus in 1 sample. In 29 of the 34 patients with positive results on PCR (85 percent), an adverse cardiac event occurred within three months after the positive biopsy, and 9 of the 34 patients had graft loss due to coronary vasculopathy, chronic graft failure, or acute rejection. In 39 of the 115 patients with negative results on PCR (34 percent), an adverse cardiac event occurred within three months of the negative PCR finding; graft loss did not occur in any of the patients in this group. The odds of graft loss were 6.5 times as great among those with positive results on PCR (P=0.006). The detection of adenovirus was associated with considerably reduced graft survival (P=0.002)., Conclusions: Identification of viral genome, particularly adenovirus, in the myocardium of pediatric transplant recipients is predictive of adverse clinical events, including coronary vasculopathy and graft loss.

Objective: The study objectives were to determine posttransplant coronary artery disease (TxCAD) incidence, predisposing factors and optimal timing for retransplantation (re-Tx) in pediatric heart transplantation (Tx) recipients., Background: The TxCAD limits long-term survival following heart Tx, with re-Tx being the primary therapy. Information on risk factors and timing of listing for re-Tx is limited in children., Methods: The records of children who survived >1 year post-Tx at Loma Linda University were reviewed. Nonimmune and immune risk factors were analyzed., Results: TxCAD was documented in 24 of 210 children. Freedom from TxCAD was 92 +/- 2% and 75 +/- 5% at 5 and 10 years' post-Tx, respectively. The TxCAD diagnosis was established at autopsy in 10 asymptomatic patients who died suddenly within nine months following the most recent negative angiograms. The remaining 14 children had angiographic diagnoses of TxCAD and had symptoms and/or graft dysfunction (n = 10) or positive stress studies (n = 4). Three of 14 died within three months after the diagnosis was made. Eleven patients underwent re-Tx within seven months of diagnosis; nine survived. Univariate and multivariate analyses showed that only late rejection (>1 year posttransplant) frequency (p = 0.025) and severity (hemodynamically compromising) (p < 0.01) were independent predictors of TxCAD development. Freedom from TxCAD after severe late rejection was 78 +/- 8% one year postevent and 55 +/- 10% by two years., Conclusions: Late rejection is an independent predictor of TxCAD. Patients suffering severe late rejection develop angiographically apparent TxCAD rapidly and must be monitored aggressively. Both TxCAD mortality and morbidity occur early; therefore, we recommend immediate listing for re-Tx upon diagnosis.

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.

Background: Inflammatory diseases of the heart, including myocarditis and cardiac transplant rejection, are important causes of morbidity and mortality in children. Although viral infection may be suspected in either of these clinical conditions, the definitive etiology is often difficult to ascertain. Furthermore, the histology is identical for both disorders. Coxsackievirus has long been considered the most common cause of viral myocarditis; however, we previously demonstrated by polymerase chain reaction (PCR) analysis that many different, and sometimes unexpected, viruses may be responsible for myocarditis and cardiac rejection. In this study, we describe the association of parvovirus genome identified through PCR analysis of cardiac tissue in the clinical setting of myocarditis and cardiac allograft rejection., Methods and Results: Myocardial tissue from endomyocardial biopsy, explant, or autopsy was analyzed for parvovirus B19 using primers designed to amplify a 699-base pair PCR product from the VP1 gene region. Samples tested included those obtained from patients with suspected myocarditis (n=360) or transplant rejection (n=200) or control subjects (n=250). Parvoviral genome was identified through PCR in 9 patients (3 myocarditis; 6 transplant) and no control patients. Of the 3 patients with myocarditis, 1 presented with cardiac arrest leading to death, 1 developed dilated cardiomyopathy, and the other gradually improved. Four of the 6 transplant patients had evidence of significant rejection on the basis of endomyocardial biopsy histology. All transplant patients survived the infection., Conclusions: Parvovirus is associated with myocarditis in a small percentage of children and may be a potential contributor to cardiac transplant rejection. PCR may provide a rapid and sensitive method of diagnosis.

Background: This study was performed to report causes of death or graft loss and to identify possible pretransplant risk factors for death or graft loss in infants after heart transplantation., Methods and Results: Pretransplant risk factors were compared for 153 infants registered for heart transplantation within 90 days of life and transplanted from November 1985 to June 1994. Factors assessed were diagnosis, age at transplantation, race, weight, blood type, sex, donor/recipient blood type match, sex match, weight ratio, fetal registration, locale of pretransplant waiting period, mechanical ventilation, ischemic time, and the need for atrial septostomy or septectomy pretransplantation. No factor was associated with death or graft loss at 1 month or 1 year. Causes of death or graft loss were determined using clinical course and pathology data when available. Death or grafts lost at 1 month, 1 year, and > 1 year were 14, 13, and 15, respectively. Causes of death or graft loss expressed as a percent (at 1 month, 1 year, and > 1 year, respectively) were acute rejection (14, 23, 27), chronic rejection and posttransplant coronary disease (0, 8, 47), infectious causes (21, 15, 13), early graft failure (21, 0, 0), technical issues (21, 23, 0), chronic graft dysfunction (0, 15, 0), and miscellaneous (21, 15, 13). The graft loss rate at 1 year was significantly correlated (linear regression, r2 = .66; P < .05) with the year of transplantation. Actuarial survival in this population was 91% at 1 month, 81% at 1 year, and 73% at 3 years., Conclusions: Heart transplantation in the young infant can be performed with acceptable short-term and midterm results. Causes of death or graft loss and survival are similar to adult data. No pretransplant risk factors were identified. The experience level of the transplant team members affects survival. The diagnosis and management of rejection remain a major challenge.

At Loma Linda University Medical Center, 210 heart transplant procedures have been performed on 207 newborns, infants, and children since 1985. Actuarial survival rate at 5 years is 72% for the entire population and 82% for those receiving a transplant during the first month of life. These patients have been managed with a regimen that minimizes long-term steroid use and emphasizes the noninvasive diagnosis of rejection. This article describes in some detail the mechanics of this process. In addition, the rejection history of 154 children undergoing transplantation from 1989 through 1992 was reviewed. The average number of rejection episodes was 1.67 (standard deviation 1.65; median, 1; mode, 0). The vast majority of rejections occur in the first 3 months after transplantation. Long-term freedom from rejection was 19% for newborn recipients, 42% for infants, 25% for older children. Donor/recipient mismatch for gender, race, blood type, Rh factor, and HLA typing did not correlate with rejection history. Older age at transplantation and cytomegalovirus disease were correlated with more frequent rejection episodes. Five patients had posttransplantation coronary artery disease. This was strongly correlated with greater rejection frequency and death from rejection. In addition, there was a trend toward less posttransplantation coronary artery disease with antibody induction therapy, younger age at transplantation, and absence of cytomegalovirus disease.(ABSTRACT TRUNCATED AT 250 WORDS)