Incidence, characterization, and impact of newly detected donor-specific anti-HLA antibody in the first year after pediatric heart transplantation: A report from the CTOTC-04 study.

Data on the clinical importance of newly detected donor-specific anti-HLA antibodies (ndDSAs) after pediatric heart transplantation are lacking despite mounting evidence of the detrimental effect of de novo DSAs in solid organ transplantation. We prospectively tested 237 pediatric heart transplant recipients for ndDSAs in the first year posttransplantation to determine their incidence, pattern, and clinical impact. One-third of patients developed ndDSAs; when present, these were mostly detected within the first 6 weeks after transplantation, suggesting that memory responses may predominate over true de novo DSA production in this population. In the absence of preexisting DSAs, patients with ndDSAs had significantly more acute cellular rejection but not antibody-mediated rejection, and there was no impact on graft and patient survival in the first year posttransplantation. Risk factors for ndDSAs included common sensitizing events. Given the early detection of the antibody response, memory responses may be more important in the first year after pediatric heart transplantation and patients with a history of a sensitizing event may be at risk even with a negative pretransplantation antibody screen. The impact on late graft and patient outcomes of first-year ndDSAs is being assessed in an extended cohort of patients.

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

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

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

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

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

Human leukocyte antigen (HLA) molecular mismatch is a powerful biomarker of rejection. Few studies have explored its use in assessing rejection risk in heart transplant recipients. We tested the hypothesis that a combination of HLA Epitope Mismatch Algorithm (HLA-EMMA) and Predicted Indirectly Recognizable HLA Epitopes (PIRCHE-II) algorithms can improve risk stratification of pediatric heart transplant recipients. Class I and II HLA genotyping were performed by next-generation sequencing on 274 recipient/donor pairs enrolled in the Clinical Trials in Organ Transplantation in Children (CTOTC). Using high-resolution genotypes, we performed HLA molecular mismatch analysis with HLA-EMMA and PIRCHE-II, and correlated these findings with clinical outcomes. Patients without pre-formed donor specific antibody (DSA) (n=100) were used for correlations with post-transplant DSA and antibody mediated rejection (ABMR). Risk cut-offs were determined for DSA and ABMR using both algorithms. HLA-EMMA cut-offs alone predict the risk of DSA and ABMR; however, if used in combination with PIRCHE-II, the population could be further stratified into low-, intermediate-, and high-risk groups. The combination of HLA-EMMA and PIRCHE-II enables more granular immunological risk stratification. Intermediate-risk cases, like low-risk cases, are at a lower risk of DSA and ABMR. This new way of risk evaluation may facilitate individualized immunosuppression and surveillance.

Bartonella henselae-mediated disease in solid organ transplant recipients: two pediatric cases and a literature review.

Bartonella henselae, the etiologic agent of cat-scratch disease, causes a well-defined, self-limited syndrome of fever and regional lymphadenopathy in immunocompetent hosts. In immunocompromised hosts, however, B. henselae can cause severe disseminated disease and pathologic vasoproliferation known as bacillary angiomatosis (BA) or bacillary peliosis. BA was first recognized in patients infected with human immunodeficiency virus. It has become more frequently recognized in solid organ transplant (SOT) recipients, but reports of pediatric cases remain rare. Our review of the literature revealed only one previously reported case of BA in a pediatric SOT recipient. We herein present 2 pediatric cases, one of which is the first reported case of BA in a pediatric cardiac transplant recipient, to our knowledge. In addition, we review and summarize the literature pertaining to all cases of B. henselae-mediated disease in SOT recipients.

Survival after reconstructive surgery for hypoplastic left heart syndrome: A 15-year experience from a single institution.

BACKGROUND: There are limited data regarding the long-term survival of patients who have undergone reconstructive surgery for hypoplastic left heart syndrome (HLHS). We reviewed the 15-year experience at our institution to examine survival in the context of continued improvements in early operative results. METHODS AND RESULTS: Between 1984 and 1999, 840 patients underwent stage I surgery for HLHS. From review of medical records and direct patient contact, survival status was determined. The 1-, 2-, 5-, 10-, and 15-year survival for the entire cohort was 51%, 43%, 40%, 39%, and 39%, respectively. Late death occurred in 14 of the 291 patients discharged to home after the Fontan procedure, although only 1 patient has died beyond 5 years of age. Heart transplantation after stage I reconstruction was performed in 5 patients. Later era of stage I surgery was associated with significantly improved survival (P:<0.001). Three-year survival for patients undergoing stage I reconstruction from 1995 to 1998 was 66% versus 28% for those patients undergoing surgery from 1984 to 1988. Age >14 days at stage I and weight <2.5 kg at stage I were also associated with higher mortality (P:=0.004 and P:=0.01, respectively). Other variables, including anatomic subtype, heterotaxia, and age at subsequent staging procedures, were not associated with survival. CONCLUSIONS: Over the 15-year course of this study, early- and intermediate-term survival for patients with HLHS undergoing staged palliation increased significantly. Late death and the need for cardiac transplantation were uncommon.

Growth characteristics of the aortic arch after the Norwood operation.

OBJECTIVES: We sought to characterize the growth of the reconstructed aortic arch after the Norwood operation (NO). BACKGROUND: The first stage of surgical palliation of hypoplastic left heart syndrome (HLHS), the NO, includes augmentation of the aortic arch with homograft. Growth characteristics of the reconstructed aortic arch, which is comprised of both native aortic tissue and homograft, have not been characterized. METHODS: Retrospectively, we examined the serial echocardiograms of 50 patients with HLHS who underwent NO to determine the diameter of the reconstructed transverse arch. Measurements were taken immediately after NO and at two other points (1 to 11 years of age). In addition, the autopsy specimens of 10 other patients with HLHS who underwent NO were examined to determine the contribution of native aortic tissue to the overall size of the reconstructed arch at the time of death (12 to 34 months). RESULTS: The diameter of the transverse aorta increased after NO in all subjects. Its rate of growth paralleled that seen in the normal population, though the reconstructed arch had a significantly larger diameter throughout childhood. Examination of autopsy specimens demonstrated a mean increase in circumference of the native aortic tissue of 0.67 cm (p value <0.01), whereas there was no significant change in homograft circumference. CONCLUSIONS: After reconstruction of the aortic arch in HLHS, the diameter of the arch continues to increase throughout childhood, and this increase is due to growth of the native aortic tissue.

Impact of early ventricular unloading on exercise performance in preadolescents with single ventricle Fontan physiology.

OBJECTIVES: We sought to determine if early ventricular volume unloading improves aerobic capacity in patients with single ventricle Fontan physiology. BACKGROUND: Surgical strategies for patients with single ventricle include intermediate staging or early Fontan completion to reduce the adverse affects of prolonged ventricular volume load. The impact of this strategy on exercise performance has not been evaluated. METHODS: Retrospectively, we reviewed the exercise stress test results of all preadolescents with single ventricle Fontan physiology. "Volume unloading" was considered to have occurred at the time of bidirectional cavopulmonary anastomosis or at the time of Fontan surgery in those patients who did not undergo intermediate staging. Potential predictors of aerobic capacity were analyzed using multivariate regression. RESULTS: The patients (n = 46) achieved a mean percentage predicted of maximal oxygen consumption (VO2max) of 76.1% +/- 21.1%. The mean age at the time of volume unloading was 2.7 +/- 2.4 years, and the mean age at testing was 8.7 +/- 2 years. Intermediate staging was performed in 16 of 46 patients (35%). In multivariate analysis, younger age at volume unloading was associated with increased aerobic capacity (p = 0.003). Other variables were not predictive. The subgroup of patients who underwent volume unloading before two years of age achieved a mean percentage predicted VO2max of 88.6% +/- 24.1%. CONCLUSIONS: Preadolescents with single ventricle who undergo volume unloading surgery at an early age demonstrate superior aerobic capacity compared with those whose surgery is delayed until a later age.

Can echocardiography predict the presence or absence of endocardial fibroelastosis in infants <1 year of age with left ventricular outflow obstruction?

This study assesses the use of echocardiography in detecting endocardial fibroelastosis in 32 infants with obstructive left-sided lesions. The data demonstrate that neither endocardial echo-brightness nor geometric variables of the left ventricle allow for accurate prediction of the presence of endocardial fibroelastosis.

Exercise performance after the arterial switch operation for D-transposition of the great arteries.

Early- and intermediate-term results of the arterial switch operation for D-transposition of the great arteries (D-TGA) are encouraging. However, questions remain about the long-term outcome for these patients, especially with regard to exercise performance. Preliminary studies have demonstrated normal endurance time on treadmills. However, data regarding aerobic capacity and cardiopulmonary function are lacking. We report the cardiopulmonary performance of 22 school-age patients with D-TGA who underwent the arterial switch operation. Outcome variables included maximal oxygen consumption (VO2), maximal cardiac index, and peak heart rate. Patient and procedure-related variables were assessed for their association with outcome variables using linear and logistic regression. The mean values of maximal VO2 (113 +/- 19% predicted) and maximal cardiac index (96 +/- 18% predicted) were within normal limits for the pediatric population. Although the mean peak heart rate for the entire group (184 +/- 14 beats/min) was within normal limits, there were 7 subjects (32%) with chronotropic impairment. Significant ST-segment depression was seen in 2 subjects (9%). In regression analysis, surgery subsequent to the arterial switch was associated with lower maximal cardiac index (p = 0.01). Other variables were not significantly associated with maximal VO2, maximal cardiac index, and peak heart rate. In particular, chronotropic impairment was not significantly associated with maximal VO2 or maximal cardiac index. These findings demonstrate that cardiopulmonary performance during exercise is excellent after the arterial switch operation. The finding of ST-segment depression in some subjects supports the role of formal exercise testing in those patients participating in vigorous athletic activities.

Atrioventricular valve replacement in patients with a single ventricle.

BACKGROUND: Significant atrioventricular valve (AVV) insufficiency has been associated with increased mortality and morbidity in patients with single ventricle. Although many patients can be managed with valvuloplasty alone, some patients require AVV replacement. The optimal timing, outcome, and risk factors for AVV replacement in this population have not been described. METHODS: We retrospectively reviewed our experience with AVV replacement in patients with single ventricle from January 1984 to August 2000. Outcome variables included mortality and valve-related complications. RESULTS: Seventeen patients required AVV replacement. Prosthetic valve types included: St. Jude's valve in 14, Bjork-Shiley in 1, Hall-Kaster in 1, and Carpentier-Edwards in 1. Valve size ranged from 17 to 33 mm, Median age at valve replacement was 3.0 years (range 7 days to 17.3 years). Of the 16 subjects with normal atrioventricular conduction preoperatively, 7 (44%) developed postoperative complete heart block. Hospital mortality was 29%. Hospital mortality decreased significantly from 56% in 1984 to 1993 to no deaths from 1994 to 2000 (p = 0.03). Younger age (less than 2 years) at operation was also a risk factor for hospital mortality (p = 0.03). There were four late deaths in this series and 1 patient underwent heart transplantation. Of the surviving patients, none has required replacement of the prosthetic valve. No patients have had cerebrovascular accident subsequent to AVV replacement. Functional status is New York Heart Association functional class I in 5, class II in 1, and Class III in 1. CONCLUSIONS: Atrioventricular valve replacement can be performed in patients with single ventricle with acceptable morbidity and mortality. The development of postoperative complete heart block is common. Survival after AVV replacement has improved in recent years, and intervention before patients develop ventricular dysfunction and atrial arrhythmias may further improve outcome.

Atrioventricular valve regurgitation in patients with single ventricle: impact of the bidirectional cavopulmonary anastomosis.

BACKGROUND: It is not known whether atrioventricular valve regurgitation (AVVR) can improve in some patients after the bidirectional cavopulmonary anastomosis (BCPA) without undertaking concomitant valvuloplasty. METHODS: We retrospectively reviewed our experience with patients who underwent the BCPA between June 1989 and June 2000 with specific attention to those patients with moderate or severe AVVR. The degree of AVVR was determined by color Doppler echocardiography. During the study period there were 576 patients who underwent BCPA at a median age of 6.8 months (range, 1.3 months to 4.8 years). The majority of subjects (66%) had a tricuspid valve as the systemic atrioventricular valve. Significant (moderate or severe) AVVR before BCPA was noted in 36 of 576 patients (6%) and was significantly more prevalent (8 of 52 patients, 15%; p = 0.01) in patients with a common atrioventricular canal. RESULTS: Of the 36 subjects with moderate or severe AVVR, 8 had interventions (6 valvuloplasty, 2 aortic arch dilation) at BCPA. There was 1 hospital death (2.8%). Of the remaining 27 survivors who did not undergo additional interventions at BCPA, improvement in AVVR (mild or none) was noted in 6 (22%) at intermediate follow-up (median, 2 years; range, 0.5 to 3.1 years). The presence of significant AVVR before BCPA was not significantly associated with hospital survival or intermediate-term freedom from death or transplantation. CONCLUSIONS: We conclude that AVVR improves in some patients after BCPA and that valvuloplasty is not justified in all patients with moderate preoperative AVVR.

Unexpected death after reconstructive surgery for hypoplastic left heart syndrome.

BACKGROUND: Although operative mortality for reconstructive surgery for hypoplastic left heart syndrome continues to improve, nonoperative mortality, especially in the first year of life, remains relatively high. A number of patients who are thought to be clinically well at hospital discharge die unexpectedly. The goal of the present study was to determine the incidence of and risk factors for unexpected death in patients with hypoplastic left heart syndrome. METHODS: Retrospectively, we determined the incidence of unexpected death among 536 patients with hypoplastic left heart syndrome who were discharged to home after stage I surgical procedure. To identify potential risk factors, a nested case-control analysis was undertaken. RESULTS: Unexpected death occurred in 22 of 536 patients (4.1%) discharged to home after stage I surgical procedure. The median age at unexpected death was 79 days (range, 25 to 227 days). Seizures preceded cardiac arrest in 2 patients, and ventricular arrhythmias were documented in 3 additional patients during attempted resuscitation. Autopsy studies were performed in 12 patients and identified residual lesions that may have contributed to death in 2 patients. In multivariate analysis documented perioperative arrhythmia and earlier year of stage I surgical procedure were associated with an increased risk for unexpected death (p = 0.03 and p = 0.04, respectively). There were 4 additional patients who had unexpected death after subsequent cavopulmonary operation at a median age of 1.6 years (range, 0.9 to 3.8 years). CONCLUSIONS: Unexpected death occurred in more than 4% of patients with hypoplastic left heart syndrome who were discharged to home after stage I surgical procedure and was most common in the first several months of life. Factors that may contribute to unexpected death include residual lesions, arrhythmias, and neurologic events, although in the majority of cases the cause remains largely unknown.

Long-term developmental outcome of children with complex congenital heart disease.

As the mortality of neonatal and infant surgery for CHD continues to decrease, attention is now focused on long-term sequelae, especially later cognitive and neurologic function, in survivors. Although children with repaired or palliated CHD have an increased risk for neurocognitive deficits, most survivors are performing within the normal range for most standardized measures. Even those children at highest risk, such as patients with HLHS, are comparable with survivors of other congenital lesions, such as diaphragmatic hernia, or low-birth weight children. Continued efforts are underway to reduce cerebral injury before, during, and after congenital heart surgery.

Neurologic and cognitive outcomes in children with congenital heart disease.

Advances in congenital heart surgery have resulted in the increased survival of infants born with complex congenital heart disease. Questions remain, however, about how these patients will develop and whether they will have normal, productive lives. To date, studies have shown that although the vast majority of children with congenital heart disease have normal outcomes, as a group they generally have higher rates of neurodevelopmental problems. The developmental sequelae include mild problems in cognition, attention, and neuromotor functioning. The etiology of neurologic deficits in this population appears to be multifactorial with preoperative, operative, and postoperative factors all contributing to outcome. Continued research and attempts to minimize neurologic injury and associated sequelae are of primary importance. Recent data suggest that advances in care already may be improving outcome after congenital heart surgery. Ongoing documentation of the long-term outcome in this population needs to be mandated, as does the implementation of environmental enrichment programs to help ameliorate the long-term consequences of congenital heart disease.

A dangerous case of colic: anomalous left coronary artery presenting with paroxysms of irritability.

Anomalous left coronary artery originating from the pulmonary artery (ALCAPA) is a rare, but potentially lethal, cause for irritability in infancy. We present the case of a 12-week-old male infant who was managed as a colic patient for several weeks before the diagnosis of ALCAPA was established. A brief review of previous case reports demonstrated that paroxysms of irritability can be a presentation of this disorder. In the majority of cases the manifestations of ALCAPA can be differentiated from other diseases known to cause a infant to be colicky.

Exercise performance in tetralogy of Fallot: the impact of primary complete repair in infancy.

Primary complete repair (PCR) of tetralogy of Fallot (TOF) is now routinely performed in infancy. Although operative results are excellent, the impact on exercise performance is incompletely understood. We reviewed data of all children with TOF who underwent PCR at our institution and had subsequent maximal cycle ergometer exercise testing between January 1995 and December 2000. Of the 193 patients with TOF who underwent PCR, 57 (30%) underwent exercise testing; maximal tests were available for 50 of 57 (88%). Exercise performance of subjects who underwent PCR at <1 year of age was compared to that of those who underwent repair at >l year of age. The median age at PCR was 10.9 months; 28 subjects (56%) underwent PCR in infancy (<1 year). A transannular incision was employed in the repair in 41 subjects (82%). The mean age at exercise testing was 12.5 +/- 3.2 years. The mean maximal VO2 was 94.9 +/- 18.8% predicted and the mean maximal work rate was 98.0 +/- 20.8% predicted. In multivariate analysis PCR in infancy (age <1 year) was not associated with maximal VO2, peak work rate, peak heart rate, or arrhythmias. Only older age at testing and male gender were significantly associated with higher maximal VO2 (p = 0.005 and p = 0.002, respectively). Intermediate-term exercise performance in subjects who undergo PCR of TOF in early childhood is near normal. Performing PCR in the first year of life does not impact subsequent exercise performance.