ABO-incompatible heart transplantation in early childhood: an international multicenter study of clinical experiences and limits.

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.

Cause of death in pediatric and infant heart transplant recipients: review of a 20-year, single-institution cohort.

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.

Postmortem intracranial neuropathology in children following cardiac transplantation.

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.

Effect of oversizing cardiac allografts on survival in pediatric patients with congenital heart disease.

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.

Post-transplant seizures in infants with hypoplastic left heart syndrome.

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.

Pediatric post-transplant diabetes: data from a large cohort of pediatric heart-transplant recipients.

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.

Duration of graft cold ischemia does not affect outcomes in pediatric heart transplant recipients.

BACKGROUND: Utilizing donor hearts with prolonged graft ischemia may extend the donor pool. METHODS AND RESULTS: The medical records of 363 infants and children, aged 1 day to 17 years, transplanted at Loma Linda University between November 1985 and March 2001, were retrospectively reviewed. Fourteen children received organs with prolonged ischemic times (>8 hours)(PIT) compared with 14 with short ischemic times (< or =90 minutes)(SIT). There were no significant differences when comparing donors for gender, age, weight, cause of death, or duration of cardiopulmonary resuscitation. Preoperative donor shortening fraction (%), as determined by echocardiography, was significantly higher in the SIT group (44.5 versus 36.5%; P=0.006). There were no significant differences between PIT and SIT recipients when comparing age at transplant, weight at transplant, waiting time, weight mismatch, postoperative days on ventilator, duration of inotropic support, and hospital stay. Cardiopulmonary bypass time was significantly longer in the PIT group (140.5 versus 80.5 minute; P=0.001). Median length of follow-up for both groups was approximately 5 years. Five grafts were lost in the PIT group; 7 were lost in the SIT group, with 1 early graft loss in each group. Significant posttransplant coronary artery disease was diagnosed in 2 recipients in each group (PIT: 80 and 42; SIT: 84 and 67 months posttransplant). There was no significant difference between groups in actuarial graft survival. Number of rejection episodes and hospital readmissions during the first posttransplantation year did not differ significantly between groups. CONCLUSION: Late outcomes were not adversely affected by donor hearts preserved by single dose cold crystalloid cardioplegia with greater than 8 hours of cold ischemia.

Usefulness of cardiac transplantation in children with visceral heterotaxy (asplenic and polysplenic syndromes and single right-sided spleen with levocardia) and comparison of results with cardiac transplantation in children with dilated cardiomyopathy.

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.