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.

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.

Patterns of kidney injury in pediatric nonkidney solid organ transplant recipients.

The incidence of acute kidney injury (AKI) and its impact on chronic kidney disease (CKD) following pediatric nonkidney solid organ transplantation is unknown. We aimed to determine the incidence of AKI and CKD and examine their relationship among children who received a heart, lung, liver, or multiorgan transplant at the Hospital for Sick Children between 2002 and 2011. AKI was assessed in the first year posttransplant. Among 303 children, perioperative AKI (within the first week) occurred in 67% of children, and AKI after the first week occurred in 36%, with the highest incidence among lung and multiorgan recipients. Twenty-three children (8%) developed CKD after a median follow-up of 3.4 years. Less than 5 children developed end-stage renal disease, all within 65 days posttransplant. Those with 1 AKI episode by 3 months posttransplant had significantly greater risk for developing CKD after adjusting for age, sex, and estimated glomerular filtration rate at transplant (hazard ratio: 2.77, 95% confidence interval, 1.13-6.80, P trend = .008). AKI is common in the first year posttransplant and associated with significantly greater risk of developing CKD. Close monitoring for kidney disease may allow for earlier implementation of kidney-sparing strategies to decrease risk for progression to CKD.

Right ventricular function during exercise in children after heart transplantation.

Aims: Right ventricular (RV) dysfunction is a common problem after heart transplant (HTx). In this study, we used semi-supine bicycle ergometry (SSBE) stress echocardiography to evaluate RV systolic and diastolic reserve in paediatric HTx recipients. Methods and results: Thirty-nine pediatric HTx recipients and 23 controls underwent stepwise SSBE stress echocardiography. Colour tissue doppler imaging (TDI) peak systolic (s') and peak diastolic (e') velocities, myocardial acceleration during isovolumic contraction (IVA), and RV free wall longitudinal strain were measured at incremental heart rates (HR). The relationship with increasing HR was evaluated for each parameter by plotting values at each stage of exercise versus HR using linear and non-linear regression models. At rest, HTx recipients had higher HR with lower TDI velocities (s': 5.4 ± 1.7 vs. 10.4 ± 1.8 cm/s, P < 0.001; e': 6.4 ± 2.2 vs.12 ± 2.4 cm/s, P < 0.001) and RV IVA values (IVA: 1.2 ± 0.4 vs. 1.6 ± 0.8 m/s2, P = 0.04), while RV free wall longitudinal strain was similar between groups. At peak exercise, HR was higher in controls and all measurements of RV function were significantly lower in HTx recipients, except for RV free wall longitudinal strain. When assessing the increase in each parameter vs. HR, the slopes were not significantly different between patients and controls except for IVA, which was lower in HTx recipients. Conclusion: In pediatric HTx recipients RV systolic and diastolic functional response to exercise is preserved with a normal increase in TDI velocities and strain values with increasing HR. The blunted IVA response possibly indicates a mildly decreased RV contractile response but it requires further investigation.

Risk factors for specific causes of death following pediatric heart transplant: An analysis of the registry of the International Society of Heart and Lung Transplantation.

We sought to determine temporal changes in COD and identify COD-specific risk factors in pediatric primary HTx recipients. Using the ISHLT registry, time-dependent hazard of death after pediatric HTx, stratified by COD, was analyzed by multiphasic parametric hazard modeling with multivariable regression models for risk factor analysis. The proportion of pediatric HTx deaths from each of cardiovascular cause, allograft vasculopathy, and malignancy increased over time, while all other COD decreased post-HTx. Pre-HTx ECMO was associated with increased risk of death from graft failure (HR 2.43; p < 0.001), infection (HR 2.85; p < 0.001), and MOF (HR 2.22; p = 0.001), while post-HTx ECMO was associated with death from cerebrovascular events/bleed (HR 2.55; p = 0.001). CHD was associated with deaths due to pulmonary causes (HR 1.78; p = 0.007) or infection (HR 1.72; p < 0.001). Non-adherence was a significant risk factor for all cardiac COD, notably graft failure (HR 1.66; p = 0.001) and rejection (HR 1.89; p < 0.001). Risk factors related to specific COD are varied across different temporal phases post-HTx. Increased understanding of these factors will assist in risk stratification, guide anticipatory clinical decisions, and potentially improve patient survival.

Development and Impact of De Novo Anti-HLA Antibodies in Pediatric Heart Transplant Recipients.

There is increasing evidence that de novo anti-HLA antibodies, more specifically de novo donor-specific antibodies (DSA) following solid organ transplantation may be associated with negative outcomes including rejection in the first year and graft loss. Limited data are available in pediatric heart transplant recipients. We sought to prospectively determine the incidence, class and early impact of de novo anti-HLA antibodies in a cohort of pediatric heart transplant recipients. Serial panel reactive antibody testing posttransplant was performed in 25 patients (14 males) transplanted between January 2008 and June 2010. Five patients were sensitized pretransplant; all patients had negative direct crossmatch. Seventy-two percent developed de novo anti-HLA antibodies at a median of 2.6 weeks (IQR 1.2 weeks to 6.2 months) posttransplant; 67% of these were DSA. The majority of recipients in our cohort developed de novo anti-HLA antibodies within the first year posttransplant, with two-thirds being donor-specific. Acute cellular rejection, though frequent, was not different in patients with antibody development regardless of class or specificity, and there was no antibody-mediated rejection, graft loss or early cardiac allograft vasculopathy.

Report from a forum on US heart allocation policy.

Since the latest revision in US heart allocation policy (2006), the landscape and volume of transplant waitlists have changed considerably. Advances in mechanical circulatory support (MCS) prolong survival, but Status 1A mortality remains high. Several patient subgroups may be disadvantaged by current listing criteria and geographical disparity remains in waitlist time. This forum on US heart allocation policy was organized to discuss these issues and highlight concepts for consideration in the policy development process. A 25-question survey on heart allocation policy was conducted. Among attendees/respondents were 84 participants with clinical/published experience in heart transplant representing 51 US transplant centers, and OPTN/UNOS and SRTR representatives. The survey results and forum discussions demonstrated very strong interest in change to a further-tiered system, accounting for disadvantaged subgroups and lowering use of exceptions. However, a heart allocation score is not yet viable due to the long-term viability of variables (used in the score) in an ever-developing field. There is strong interest in more refined prioritization of patients with MCS complications, highly sensitized patients and those with severe arrhythmias or restrictive physiology. There is also strong interest in distribution by geographic boundaries modified according to population. Differences of opinion exist between small and large centers.

A 16-year multi-institutional study of the role of age and EBV status on PTLD incidence among pediatric heart transplant recipients.

The objective was to determine the incidence and hazard for posttransplant lymphoproliferative disease (PTLD) in a study of 3170 pediatric primary heart transplants between 1993 and 2009 at 35 institutions in the Pediatric Heart Transplant Study. 147 of 151 reported malignancy events were classified as PTLD. Overall freedom from PTLD was 98.5% at 1 year, 94% at 5 years and 90% at 10 years. Freedom from PTLD was lowest in children (ages 1 to < 10 years) versus infants (<1 year) and adolescents (10 to < 18 years) with children at highest risk for PTLD with a relative risk of 2.4 compared to infants and 1.7 compared to adolescents. Positive donor EBV status was a strong risk factor for PTLD in the seronegative recipient, but risk magnitude was dependent on recipient age at the time of transplantation. Nearly 25% of EBV seronegative recipients of EBV+ donors at ages 4-7 at transplantation developed some form of PTLD. The overall risk for PTLD declined in the most recent transplant era (2001-2009, p = 0.003). These findings indicate that EBV status and the age of the recipient at the time of transplantation are important variables in the development of PTLD in the pediatric heart transplant recipient.

Effects of an acute, outpatient physiotherapy exercise program following pediatric heart or lung transplantation.

This prospective interventional study investigated the impact of a three-month, ambulatory HA or HB, semi-individualized, PT-prescribed exercise program following pediatric HTx or LTx. SMW distance, strength, and flexibility were assessed at start and completion of the program and one yr after enrollment. Subjects received either an HB or HA exercise program three times per week. The cohort demonstrated clinically and statistically significant improvements in SMW distances at three months (425.7 ± 109.4-500.6 ± 93.6 m, p < 0.001) and at one yr (528.5 ± 66.6 m, p = 0.001), although there was no difference between the two groups at any time. Similar improvements were also observed in strength and flexibility measures. Correlates with higher SMW distance at three months and one yr included older age, male gender, and underlying diagnosis other than CHD. Male gender and diagnosis other than CHD were associated with a slower improvement in the SMW distance. This is the first report of institutionally based, outpatient exercise rehabilitation in the recovery following pediatric thoracic transplantation. We found similar improvements to HB interventions up to one yr after surgery. Further study of the role of exercise rehabilitation and long-term fitness outcomes is needed.

Enhanced exercise performance and survival associated with evidence of autonomic reinnervation in pediatric heart transplant recipients.

Following heart transplantation (HTx), loss of autonomic input to the allograft results in elevated resting heart rate (HR) and decreased chronotropic reserve. As enhanced exercise capacity and HR recovery post exercise are suggestive of reinnervation in pediatric cohorts, we used heart rate variability (HRV) analysis to assess autonomic reinnervation in pediatric HTx recipients. Pediatric patients transplanted between 1996 and 2010 and with serial 24-hour Holter recordings post-HTx were analyzed for HRV using time and frequency domain measures. Of 112 patients, 68 (57%) showed evidence of autonomic reinnervation that was not associated with age at HTx. Evidence of reinnervation was associated with a significant increase in low-frequency power spectrum (p<0.001), suggesting sympathetic reinnervation. Patients with evidence of reinnervation showed higher percent-predicted maxVO(2) on performing an exercise test (+10.2 ± 3.6%, p = 0.006) and improved HR recovery at 3 minutes (-11.4 ± 3.9 bpm, p = 0.004), but no difference in percent-predicted maximal HR. Cox hazards modeling using presumed sinus reinnervation criteria at last Holter recording as a time-dependent covariate was associated with decreased hazard of mortality and/or retransplantation (HR: 0.2, 95% CI 0.04-1.0, p = 0.05). In conclusion, a majority of pediatric HTx recipients demonstrate evidence of reinnervation that is associated with functional outcomes. Studies to assess graft reinnervation as a marker of long-term prognosis are warranted.

Development of donor-specific isohemagglutinins following pediatric ABO-incompatible heart transplantation.

Graft acceptance following pediatric ABO-incompatible heart transplantation has been associated with a deficiency of donor-specific isohemagglutinins (DSI) due to B-cell elimination. Recent observations suggest that some of these patients do produce DSI. The purpose of this study was to examine the pattern of, risk factors for development and clinical impact of DSI. All children who underwent an ABO-incompatible heart transplant (1996-2009) were included. Serial postheart transplantation DSI titers and clinical outcomes were reviewed. DSI were produced in 27% of the patients (n = 11/41). Anti-A production was significantly greater in "at risk" patients than Anti-B (39% vs. 8%; p = 0.04). Risk factors associated with the development of DSI included: older age at transplantation (HR: 1.15/month, p = 0.04), pretransplant Anti-B level ≥ 1:8 (HR: 9.61, p = 0.004) and HLA sensitization (HR: 2.80, p = 0.11). The presence of DSI did increase the risk of cellular rejection but not antibody-mediated rejection, allograft vasculopathy, graft loss or death. Although these antibodies do not result in any significant clinical consequences, their presence suggests that B-cell tolerance is not the sole mechanism of graft acceptance.

Equivalent outcomes for pediatric heart transplantation recipients: ABO-blood group incompatible versus ABO-compatible.

ABO-blood group incompatible infant heart transplantation has had excellent short-term outcomes. Uncertainties about long-term outcomes have been a barrier to the adoption of this strategy worldwide. We report a nonrandomized comparison of clinical outcomes over 10 years of the largest cohort of ABO-incompatible recipients. ABO-incompatible (n = 35) and ABO-compatible (n = 45) infant heart transplantation recipients (< or =14 months old, 1996-2006) showed no important differences in pretransplantation characteristics. There was no difference in incidence of and time to moderate acute cellular rejection. Despite either the presence (seven patients) or development (eight patients) of donor-specific antibodies against blood group antigens, in only two ABO-incompatible patients were these antibodies implicated in antibody-mediated rejection (which occurred early posttransplantation, was easily managed and did not recur in follow-up). Occurrence of graft vasculopathy (11%), malignancy (11%) and freedom from severe renal dysfunction were identical in both groups. Survival was identical (74% at 7 years posttransplantation). ABO-blood group incompatible heart transplantation has excellent outcomes that are indistinguishable from those of the ABO-compatible population and there is no clinical justification for withholding this lifesaving strategy from all infants listed for heart transplantation. Further studies into observed differing responses in the development of donor-specific isohemagglutinins and the implications for graft accommodation are warranted.

Perceptions of transitional care needs and experiences in pediatric heart transplant recipients.

Survival following pediatric heart transplantation (HTx) continues to improve. The transition from pediatric to adult care is becoming a pivotal stage in the ongoing medical management of this population. Published data support enhanced outcomes for adolescent patients with increased attention to transitional care. The purpose of this study was to explore the 'transition experience' of adolescent HTx recipients and families. All teens (12-18 years) and parents at a single-center HTx program were invited to participate in semistructured interviews. Qualitative, phenomenological methodology was used to build theoretical knowledge and guided the data collection and analysis. The study population included 14 patients (7 males) with a mean age of 15.7 +/- 1.8 years (11.7-17.8 years) and at a mean of 4.1 +/- 3.3 years post-HTx (0.3-9.2 years) at the time of study participation. Major themes identified included: (i) adolescent disinterest and apathy regarding transition to adult care versus parental anxiety about their child's eventual departure from the pediatric transplant center, (ii) perceived differences in pediatric versus adult care and (iii) identification of strategies described as helpful in facilitating the transition. Understanding the experiences and perceptions of adolescent HTx recipients and their parents is crucial to planning effective transitional care and necessary for evidenced-based practice.

Waiting before birth: outcomes after fetal listing for heart transplantation.

Following fetal diagnosis of a profound heart defect, transplantation (HTx) is an alternative to pregnancy termination or neonatal surgical palliation. Retrospective review of the cardiac and transplant databases of fetal listings for HTx between 1990 and July 2006 was undertaken to describe outcomes after listing. We identified 26 fetal listings (of 269 total listings). Diagnoses included congenital heart disease (n = 24) and cardiomyopathy (n = 2). Seven patients were delisted after birth: in five cases parents opted for surgical palliation, two clinically improved. One patient died wait-listed (stillborn). Time wait-listed as a fetus ranged from 1-41 days (median 19 days). Eighteen patients underwent HTx (median weight 2.8 kg, range 2.1-10.9 kg); median days wait-listed after birth was 22 (4 h-123 days). Two fetuses were surgically delivered at 36 weeks gestation when a donor organ became available; 11 were transplanted as neonates (<30 days). The median age at HTx was 1 month (4 h-2.6 months). Fetal listing for HTx increases the potential window of opportunity for a donor organ to become available; patients had low wait-list mortality and a fair intermediate-term outcome. Well-defined criteria for eligibility for fetal listing and priority allocation to infants over fetuses seem rational approaches for centers that offer fetal listing.

Anomalous origin of a coronary artery from the opposite sinus of Valsalva with an interarterial course: clinical profile and approach to management in the pediatric population.

An anomalous origin of a coronary artery from the opposite sinus of Valsalva with an interarterial course (interarterial coronary artery [IACA]) is a rare congenital anomaly associated with sudden cardiac death. The cardiac and surgical databases at a single pediatric institution were reviewed for a description of the clinical profiles and associated risk factors of this coronary anomaly. From 1994 to 2006, IACA was diagnosed for 31 patients with a median age of 6.2 years (range, birth to 16 years). The symptoms for 6 (19%) of the 10 patients (32%) presenting with symptoms were deemed to be cardiac in origin. The symptoms for the remaining 21 patients (68%) were incidental findings. Of the 31 patients, 29 (94%) had normal resting electrocardiograms (ECG). A total of 17 patients underwent dobutamine stress echo. None had wall motion abnormalities, but two had ECG changes indicating ischemia, and 4 had abnormal coronary flow, as detected by Doppler echocardiography. Seven patients, with either acute symptoms or testing suggestive of ischemia, underwent surgery. All seven had an interarterial left main coronary artery. There was one cardiac-related death. No sudden death was found in either the surgery or nonsurgery group during the mean follow-up period of 23 and 58 months, respectively. Whether surgical intervention modifies the natural history of the anomaly or not remains to be determined.

Quality of life and function following cardiac transplantation in adolescents.

Quality of life and functional status are important outcome measures following heart transplantation. The present study evaluated the quality of life and function of 10 adolescent heart transplant recipients at the Hospital for Sick Children. Subjects were surveyed using a visual analog quality of life scale, the Children's Depression Inventory, The Pediatric Quality of Life Scale 4.0, and the Functional Status IIR. Results demonstrated excellent perceived quality of life and psychologic well-being, comparable to healthy norms. Subscale results for physical, social, and emotional function provide evidence for positive responses to transplantation. As well, results on factors such as self-esteem, school, interpersonal function, and mood demonstrate gender differences that may influence outcomes. Studies are currently underway to further delineate these important quality of life, function, and psychosocial issues to ensure optimal outcomes are achieved in our patients.

Mycophenolic acid levels in pediatric heart transplant recipients receiving mycophenolate mofetil.

BACKGROUND: Mycophenolate mofetil (MMF) is an immunosuppressive agent that has shown promise in adult patients who have undergone heart transplantation. There have been a number of studies of the pharmacokinetics of MMF in adult solid organ transplant recipients, but there is very little information in the pediatric population. The purpose of this study was to review our experience with MMF dosing and the role of mycophenolic acid (MPA) levels for therapeutic drug monitoring in a population of pediatric heart transplant recipients. METHODS: Data were obtained by review of the pediatric heart transplant database between November 1, 1997 and October 15, 1998. The data included all serum trough MPA levels, patient age, weight, height, indication for and dose of MMF, other medications, and details of all episodes of graft rejection. RESULTS: Forty-four patients (27 males) had a total of 128 serum trough MPA levels. Median age at transplant was 2.7 years (7 days to 18.4 years), and at time of review was 6.3 years (29 days to 23.5 years). MMF treatment was used for induction in 18 patients, induction and rejection in 23 patients and graft vasculopathy in 3 patients. Dosing by body surface area (mg/m(2)), age and interval from transplantation were all independently associated with MPA level. There was a trend toward requiring higher doses to achieve desired levels (>3 ng/ml) in younger patients. The average dose to achieve desired levels was higher in the immediate post-transplant period. There was a trend that MPA levels for a given dose were higher in patients on concurrent tacrolimus therapy. CONCLUSIONS: (1) There is marked individual variation in pharmacokinetics of MMF in pediatric patients; (2) dosing by body surface area may be advantageous; (3) higher MMF doses may be required at younger ages and in the early period after transplantation; (4) lower MMF doses may be required with concurrent tacrolimus therapy; and (5) serum trough MPA levels may relate to efficacy. Therefore, therapeutic drug monitoring of serum trough MPA levels may be required for individualized MMF dosing in pediatric cases.

Mycophenolate mofetil in pediatric heart transplant recipients: a single-center experience.

Mycophenolate mofetil (MMF) is emerging as an effective agent for the treatment of both established rejection and primary rejection prophylaxis in solid-organ transplantation (Tx). However, little data is available on the use of MMF in the pediatric population. We therefore report on our experience with MMF in 21 pediatric heart transplant recipients. Data were obtained by retrospective chart review. Median age at time of review was 12.3 yr (range 11 months to 16.9 yr). Median age at Tx was 10.7 yr (range 55 days to 16.7 yr). MMF was started at a median of 4.3 months after Tx (range 1 day to 4.5 yr). At the time of MMF institution, all patients were concurrently on prednisone and azathioprine; 20 of these patients were also undergoing treatment with tacrolimus (median dose 0.18 mg/kg, range 0.03-0.64 mg/kg) and one with cyclo-sporin A (10 mg/kg). Azathioprine was discontinued at the time of commencing MMF. The average MMF dose was 40 +/- 14 mg/kg. The rationale for switching to MMF included rejection (International Society for Heart and Lung Transplantation [ISHLT] 3A/B), 66%; inability to wean steroids, 14%; ABO blood group donor-recipient mismatch, 10%; coronary artery disease (CAD), 5%; and side-effects of immuno-suppression, 5%. Of the patients switched for rejection, 93% demonstrated resolved or improving rejection. Both ABO donor-recipient mismatch patients were started on tacrolimus/MMF as primary therapy and had no significant episodes of rejection. Two patients had rejection classified as unchanged (one with CAD, one treated with addition of sirolimus prior to improvement). Corticosteroids were successfully discontinued in 28% of patients, and 20% are currently on a reduced dose. Fourteen per cent developed significant rejection while attempting to reduce the steroid dose. Steroid reduction has not yet been attempted in 38% of patients. The following side-effects were reported in 38% of the patients: diarrhea, 10%; gastrointestinal discomfort, 20%; and leukopenia, 20%. Dose reduction or temporary discontinuation was required in 63% of the patients who experienced side-effects (24% of the total number of patients). Opportunistic infections developed in 10% (cryptococcus, cytomegalovirus). Hence, MMF appears to be effective for treatment of rejection in the pediatric heart transplant population and has an acceptable side-effect profile. In addition, it may have a role in primary rejection prophylaxis and may facilitate a reduced steroid dosage or a steroid-free immunosuppression regimen.