Pediatric Heart Transplant Study Research Articles

Paediatric heart transplantation: life-saving but not yet a cure.

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.

Worsening racial disparity in waitlist mortality for pediatric heart transplant candidates since the 2016 Pediatric Heart Allocation Policy revision.

The US Pediatric Heart Allocation Policy (PHAP) was revised in March 2016, with the goal of reducing waitlist mortality. We evaluated the hypothesis that these changes, which increased status exceptions, have worsened racial disparities in waitlist outcomes. Children in the Pediatric Heart Transplant Study database listed for first heart transplant from January 2012 - June 2020 were included and stratified by listing before (Era 1) or after (Era 2) the PHAP revision. A total of 4,089 children were listed during the study period. Compared with white children (n= 2648), non-white children (n= 1441) were more likely to have an underlying diagnosis of cardiomyopathy in both eras. Waitlist mortality was similar in white and non-white children in Era 1, but comparatively worse for non-white children in Era 2. In multivariable analysis controlling for diagnosis, age, and severity markers, non-white children had a significantly higher waitlist mortality only in Era 2 (Era 1: sHR 1.22 [95%CI 0.90-1.66] vs. Era 2: sHR 1.57 [95%CI 1.17-2.10]). Widening racial disparities in waitlist mortality may be an unintended consequence of the 2016 PHAP revision. Additional analyses may inform the degree to which this policy vs. unrelated changes in care differentially contribute to these disparities.

Abstract 10540: Worsening Racial Disparity in Waitlist Mortality for Pediatric Heart Transplant Candidates Since the 2016 Pediatric Heart Allocation Policy Revision

Introduction: The US Pediatric Heart Allocation Policy was recently revised with the goal of lowering waitlist mortality. Effective March 2016, these rules significantly changed the requirements for priority status. We evaluated the hypothesis that this change, which has led to an increase in status exceptions, has worsened known racial disparities in waitlist outcomes. Methods: Children in the Pediatric Heart Transplant Study database listed at a US center from January 2012 - June 2020 were included and stratified by listing before (Era 1) or after (Era 2) allocation policy change on March 22, 2016. Competing risk survival analysis was performed to evaluate endpoint of death or deterioration on the waitlist with transplant treated as a competing risk. Results: Compared with white children (n=2,648), non-white children (n=1,441) were more likely to have an underlying diagnosis of cardiomyopathy (49% vs. 39%, p<0.001), be currently hospitalized (81% vs. 71%, p=0.007) and supported with a ventricular assist device (VAD) (12% vs 9%, p=0.005) at the time of listing. Waitlist mortality was similar in white and non-white children in Era 1, but worse for non-white children compared to white children in Era 2 (Figure). In multivariable analysis controlling for diagnosis, age and severity markers, non-white children had a significantly higher waitlist mortality only if listed after the policy change (Era 1: sHR 1.18 [95%CI 0.88 - 1.59] vs. Era 2: sHR 1.52 [95%CI 1.14 - 2.02]). Hispanic ethnicity was not associated with waitlist mortality in either period when controlling for other risk factors. Conclusions: Widening racial disparities in waitlist mortality may be an unintended consequence of the 2016 Pediatric Heart Allocation Policy revision. Additional analyses may help the transplant community understand the degree to which this policy (i.e. prioritized listing status and exceptions) vs. unrelated changes in care differentially contribute to these disparities.

Relationship of ventricular assist device support duration with pediatric heart transplant outcomes

There is wide variability in the timing of heart transplant (HTx) after pediatric VAD implant. While some centers wait months before listing for HTx, others accept donor heart offers within days of VAD surgery. We sought to determine if HTx within 30 days versus ≥ 30 after VAD impacts post-HTx outcomes. Children on VAD pre-HTx were extracted from the Pediatric Heart Transplant Study database. The primary endpoints were post-HTx length of hospital stay (LOS) and one-year survival. Confounding was addressed by propensity score weighting using inverse probability of treatment. Propensity scores were calculated based on age, blood type, primary cardiac diagnosis, decade, VAD type, and allosensitization status. A total of 1064 children underwent VAD prior to HTx between 2000 to 2018. Most underwent HTx ≥ 30 days post-VAD (70%). Infants made up 22% of both groups. Patients ≥ 12 years old were 42% of the < 30 days group and children 1 to 11 years comprised 47% of the ≥ 30 days group (p < 0.001). There was no difference in the prevalence of congenital heart disease vs. cardiomyopathy (p=0.8) or high allosensitization status (p=0.9) between groups. Post-HTx LOS was similar between groups (p=0.11). One-year survival was lower in the < 30 days group (adjusted mortality HR 1.76, 95% CI 1.11-2.78, p=0.016). A longer duration of VAD support prior to HTx is associated with a one-year survival benefit in children, although questions of patient complexity, post-VAD complications and the impact on causality remain. Additional studies using linked databases to understand these factors will be needed to fully assess the optimal timing for post-VAD HTx.

Exercise Recommendations in Pediatric HCM: Variation and Influence of Provider Characteristics.

Pediatric Hypertrophic Cardiomyopathy (HCM) is associated with sudden cardiac death (SCD) that can be related to physical activity. Without pediatric specific guidelines, recommendations for activity restriction may be varied. Therefore, our aim is to determine the current practice and variability surrounding exercise clearance recommendations (ER) in pediatric HCM referral centers as well as provider and patient characteristics that influence them. We designed a survey that was distributed to the Pediatric Heart Transplant Study (PHTS) providers and members of the Pediatric and Adult Congenital Electrophysiology Society (PACES) querying provider demographics and patient variables from 2 patient vignettes. The study is a multicenter survey of current practice of specialized providers caring for pediatric HCM patients. Survey of PHTS and PACES providers via email to the respective listservs with a response rate of 28% and 91 overall completing the entire survey after self-identifying as providers for pediatric HCM patients at their center. ER varies for pediatric HCM and is associated with provider training background as well as personal and professional history. Of the 91 providers who completed the survey, 42% (N = 38) trained in pediatric electrophysiology (EP), and 40% (N = 36) in pediatric heart failure (HF). Responses varied and only 53% of providers cleared for mild to moderate activity for the patient in Vignette 1, which is more in line with recent published adult guidelines. ER in both vignettes was significantly associated with type of training background. EP providers were more likely to recommend no restriction (27.8% vs 5.9%) than HF providers even when controlling for provider age and time out of training. Syncope with exercise was deemed "Most Important" by 81% of providers when making ER. ER for pediatric HCM are variable and the majority of providers make ER outside of previously published adult guidelines. Furthermore, ER are influenced by provider background and experience. Further study is needed for risks and benefits of physical activity in this population to inform the development of pediatric specific guidelines.

Favorable outcomes after heart transplantation in Barth syndrome

Barth Syndrome (BTHS) is a rare, X-linked disease characterized by cardioskeletal myopathy and neutropenia. Comparative outcomes after heart transplantation have not been reported. We identified BTHS recipients across 3 registries (Pediatric Heart Transplant Study Registry [PHTS], Barth Syndrome Research Registry and Repository, and Scientific Registry of Transplant Recipient-Pediatric Health Information System) and matched them 1:4 to non-BTHS, male heart transplant (HT) recipients listed with dilated cardiomyopathy in PHTS. Demographics and survival data were analyzed for all recipients, whereas post-HT infection, malignancy, allograft vasculopathy, and acute rejection were only available for analysis for individuals with PHTS data. Forty-seven BTHS individuals with 51 listings and 43 HTs (including 2 re-transplants) were identified. Age at primary HT was 1.7 years (IQR: 0.6-4.5). Mechanical circulatory support at HT was common (ventricular assist device 29%, extracorporeal membrane oxygenation 5%). Over a median follow-up of 4.5 years (IQR 2.7-9.1), survival for BTHS HT recipients was no different than non-BTHS HT recipients (HR 0.91, 95% CI 0.40-2.12, p=0.85). Among those with PHTS data (n=28), BTHS HT recipients showed no difference in freedom from infection (HR 0.64, 0.34-1.22; p=0.18), malignancy (HR 0.22, 0.02-2.01, p=0.18), and allograft vasculopathy (HR 0.58, 0.16-2.1, p=0.41). Freedom from acute rejection (HR 0.39, 0.17-0.86, p=0.02) was greater for BTHS HT recipients despite similar use of induction (61 vs 73%, p=0.20), steroids at 30-days (75 vs 62%, p=0.27), and dual/triple drug immunosuppression at 1-year (80 vs 84%, p=0.55). In this largest cohort yet reported, individuals with BTHS have equivalent survival with less acute rejection and no difference in infection or malignancy after HT. When indicated, HT for individuals with BTHS is appropriate.

Abstract 13291: Impact of VAD Support Duration on Pediatric Heart Transplant Outcomes

Introduction: There is wide variability in the timing of heart transplant (HT) listing and consideration of organ offers after ventricular assist device (VAD) implant in children. While some centers wait weeks or months before proceeding with HT, others accept donor hearts within days of VAD surgery. We sought to determine if HT within 30 days of VAD implant impacts post-HT outcomes when compared to HT after ≥30 days of VAD support. Methods: Patients on VAD support prior to HT were extracted from the Pediatric Heart Transplant Study database. The primary endpoints were post-HT length of hospital stay (LOS) and one-year survival. Confounding was addressed by propensity score weighting using inverse probability of treatment. Propensity scores were calculated based on age at VAD implant, blood type, primary cardiac diagnosis, decade, VAD type, and allosensitization status. Group balance was verified with standardized differences. Results: A total of 1138 children underwent VAD implant prior to HT between 2000-2019 (Table 1). Most underwent HT ≥30 days after VAD (71%). The majority (70%) had an LVAD alone. Infants accounted for 22% of both groups, while those 1-11 years were 46% of the ≥30-day group and patients ≥12 years made up 42% of &lt;30-day group (p=0.001). There was no difference in the prevalence of congenital heart disease vs. cardiomyopathy (p=0.7) or high allosensitization status (p=0.8) between groups. Post-HT LOS was similar between groups (23 vs. 21 days in &lt;30 vs. ≥30 days, p=0.07). One-year survival was 90.5% in the &lt;30-day group vs. 94.5% in ≥30 days (adjusted mortality HR 1.81, 95% CI 1.15-2.86, p=0.01). Conclusions: In this large study of children undergoing HT after VAD, we found lower one-year survival in patients on VAD support for &lt;30 days prior to HT compared to those on VAD for ≥30 days before HT. These findings suggest that a strategy of delayed HT listing following VAD implant may favorably impact post-HT survival in the pediatric population.

Characteristics, risks, and outcomes of post-transplant lymphoproliferative disease >3 years after pediatric heart transplant: A multicenter analysis.

Post-transplant lymphoproliferative disorder (PTLD) is a significant complication after pediatric heart transplantation (HT), occurring in 5%-15% of patients within 3years. Data >3years from HT are limited. We sought to describe the prevalence, risk factors, and outcomes of PTLD occurring late (>3years) after pediatric HT in the Pediatric Heart Transplant Study from 1993 to 2010. Among 3844 primary HT patients, 110 (3%) developed late, nonrecurrent PTLD. The hazard rate for late PTLD was constant at 0.01 events/year out to 20years after HT. Risk factors for late PTLD were younger age at HT (HR 1.06, P=0.003) and Epstein-Barr virus (EBV) naivety (HR 1.65, P=0.02). Survival after late PTLD was 86% and 68% at 1 and 5years, with nonwhite race (HR 2.27, P=0.03) and earlier year of HT (HR 1.03, P=0.04) independently associated with mortality. Acute rejection and infection were both common after late PTLD, occurring in 26% and 34% of patients. The constant late hazard and contribution of EBV to late PTLD suggest that vigilance for development of PTLD, including for EBV conversion, should persist indefinitely after pediatric HT. The reasons for elevated risk of death for nonwhites after late PTLD are unclear and warrant further investigation.

Cardiac allograft vasculopathy and graft failure in pediatric heart transplant recipients after rejection with severe hemodynamic compromise.

Rejection with severe hemodynamic compromise (RSHC) carries a mortality risk approaching 50%. We aimed to identify current risk factors for RSHC and predictors of graft failure after RSHC. Data from 3,259 heart transplant (HT) recipients between January 2005 and December 2015 in the Pediatric Heart Transplant Study (PHTS) were analyzed. Predictors for RSHC and outcome after RSHC were sought. Time to RSHC was analyzed using the Cox proportional hazards regression model. Cardiac allograft vasculopathy (CAV) after HT and CAV after RSHC were analyzed as time-dependent covariates. Timing of RSHC was analyzed as occurring before and after 4 years after RSHC. There were 309 patients (9.5%) with ≥ 1 RSHC episodes. In 143 patients with RSHC, the first episode was within 1 year after HT. Independent risk factors for RSHC were age 1 to 5 years at HT (hazard ratio [HR], 1.51; 95% confidence interval [CI], 1.04-2.18), age > 10 years at HT (HR, 1.83; 95% CI, 1.29-2.60), black race (HR, 1.64; 95% CI, 1.25-2.15), prior cardiac surgery (HR, 1.55; 95% CI, 1.03-2.31), ventricular assist device support at HT (HR, 1.65; 95% CI, 1.18-2.29), maintenance steroids (HR, 1.39; 95% CI, 1.06-1.82), and recipient on inotropes, pressors, or thyroid hormones (HR, 1.45; 95% CI, 1.09-1.94). Graft survival at 5 years after RSHC was 45.7%. RSHC was a greater risk factor for earlier CAV (HR, 7.78; 95% CI, 5.82-10.40) than other rejection types (HR, 2.31; 95% CI, 1.79-3.00). Patients with late RSHC, after 1 year after RSHC had increased risk of graft loss 4 years after RSHC (HR, 7.12; 95% CI, 2.18-23.22). The 5-year graft survival after RSHC was 50.5% for early RSHC and 39.0% for late RSHC. Mortality after RSHC is high in the current treatment era. Many patient risk factors for RSHC cannot be modified, including age, race, prior cardiac surgery, and ventricular assist device support. After RSHC, CAV is the only predictor of graft failure. Patients who have late RSHC fare worse than those who have RSHC within the first year after HT.

Invited Commentary

Models of posttransplant mortality are common. They are used frequently: for prognostic information for providers and families, benchmarking of individual center results, and public reporting of those results. Each model or score has strengths and weaknesses that are predominantly determined by the data source and the methodology. The score presented in this issue of The Annals of Thoracic Surgery by O’Connor and colleagues [1O'Connor M.J. Glatz A.C. Rossano J.W. et al.Cumulative effect of preoperative risk factors on mortality after pediatric heart transplantation.Ann Thorac Surg. 2018; 106: 561-567Abstract Full Text Full Text PDF Scopus (6) Google Scholar] is paradigmatic of both the potential and the limitations of a single-center retrospective study. By identifying a series of risk factors unavailable to larger datasets, it demonstrates how the use of large dataset models of posttransplant mortality has the potential to dissuade centers from transplanting high-risk pediatric patients. Most prior models and scores predicting posttransplant mortality in children have been developed using large datasets, commonly either the Pediatric Heart Transplant Study or the Organ Procurement and Transplantation Network/United Network for Organ Sharing data [2Almond C.S. Gauvreau K. Canter C.E. Rajagopal S.K. Piercey G.E. Singh T.P. A risk-prediction model for in-hospital mortality after heart transplantation in US children.Am J Transplant. 2012; 12: 1240-1248Crossref PubMed Scopus (66) Google Scholar, 3Schumacher K.R. Almond C. Singh T.P. et al.Predicting graft loss by 1 year in pediatric heart transplantation candidates: an analysis of the Pediatric Heart Transplant Study database.Circulation. 2015; 131: 890-898Crossref PubMed Scopus (49) Google Scholar, 4Davies R.R. Russo M.J. Mital S. et al.Predicting survival among high-risk pediatric cardiac transplant recipients: an analysis of the United Network for Organ Sharing database.J Thorac Cardiovasc Surg. 2008; 135 (155.e1–2): 147-155Abstract Full Text Full Text PDF PubMed Scopus (65) Google Scholar]. Organ Procurement and Transplantation Network/United Network for Organ Sharing data underlie the risk prediction models utilized by the Scientific Registry of Transplant Recipients to develop the publicly available program-specific reports (PSRs) evaluating individual center performance. These large-dataset models have the advantage of large sample sizes from multiple centers, but often lack relevant clinical information. Using a single-center retrospective analysis, O’Connor and colleagues [1O'Connor M.J. Glatz A.C. Rossano J.W. et al.Cumulative effect of preoperative risk factors on mortality after pediatric heart transplantation.Ann Thorac Surg. 2018; 106: 561-567Abstract Full Text Full Text PDF Scopus (6) Google Scholar] have identified several risk factors for posttransplant mortality that are not available in larger datasets, including single ventricle congenital heart disease, pulmonary vein stenosis, a history of greater than or equal to 4 prior sternotomies, and referral from another cardiac surgical center. Unfortunately, the methodology limits the practical applicability of the resultant score: the score is unvalidated, it suffers from the biases of the center (eg, there was only a single patient with renal insufficiency), and the increase in mortality occurred predominantly among patients with 4 or 5 risk factors (78% versus 7% to 14% in those with 0 to 3 risk factors). As the authors note, further study and validation of the score is required. However, the inclusion of these granular and specific clinical risk factors does point to the limitations of the current system of public reporting and program monitoring. Accurate models require accounting for all relevant risk models. The Scientific Registry of Transplant Recipients models used in generating PSRs fail to account for many factors that this study and others suggest are associated with high post-transplant mortality: pulmonary vein stenosis, specific congenital diagnoses, a high number of prior sternotomies, and other anatomic abnormalities. When PSRs and similar modeling are used for public reporting, regulatory oversight, and insurance contracting, centers become incentivized to avoid transplanting candidates whose risk factors are not accounted for in the modeling. Thus, while the specific score developed by O’Connor and colleagues [1O'Connor M.J. Glatz A.C. Rossano J.W. et al.Cumulative effect of preoperative risk factors on mortality after pediatric heart transplantation.Ann Thorac Surg. 2018; 106: 561-567Abstract Full Text Full Text PDF Scopus (6) Google Scholar] may have limited wider applicability, the identification of these granular risk factors and their inclusion in modeling is critical both to maximizing individual outcomes and to maintaining access to transplantation among high-risk patients. Cumulative Effect of Preoperative Risk Factors on Mortality After Pediatric Heart TransplantationThe Annals of Thoracic SurgeryVol. 106Issue 2PreviewRisk assessment in heart transplantation is critical for candidate selection, but current models inadequately assess individual risk of postoperative mortality. We sought to identify risk factors and develop a scoring system to predict mortality after heart transplantation in children. Full-Text PDF

Ventricular Assist Device Support as a Bridge to Transplantation in Pediatric Patients

BackgroundPediatric ventricular assist device (VAD) use has evolved dramatically over the last 2 decades. ObjectivesThis study sought to describe the evolution of VAD support to heart transplantation (HTx) in children in a large international multicenter cohort. MethodsUsing data from the Pediatric Heart Transplant Study, comparisons were made between children (<18 years) supported to HTx (January 1, 1993 to December 31, 2015) with VAD or extracorporeal membrane oxygenation (ECMO) to VAD support. ResultsOf 7,135 listed patients, 5,145 underwent HTx; 995 (19.3%) were supported by a VAD (113 with congenital heart disease [CHD]). Patients with a VAD as their first device (n = 821) were older, larger, and more likely to have cardiomyopathy (80%) than patients transitioned from ECMO to VAD (n = 164). In the VAD-only cohort, 79% underwent HTx and 14% died, compared with 69% and 24% in the ECMO-to-VAD cohort, respectively. Patients with cardiomyopathy achieved HTx 84% of the time, with a 9% waitlist mortality rate compared with 55% and 36%, respectively, for CHD. Among VAD-treated patients, 79% were age >10 years in the earliest era, a percentage decreasing to 34% more recently, though neonates still represent <1%. Overall, survival at 2 and 20 years showed no difference between VAD and no support (2 years: 75% vs. 80%; 20 years: 55% vs. 54%). Post-HTx outcomes were better for durable versus temporary VADs (p < 0.01) and for continuous versus pulsatile VADs (p < 0.01) from 2005 onward; timing of VAD had no impact on post-HTx survival (p = 0.65). ConclusionsFor one-quarter of a century, major advances have occurred in mechanical support technology for children, thereby expanding the capability to bridge to HTx without compromising post-HTx outcomes. Significant challenges remain, especially for neonates and patients with CHD, but ongoing innovation portends improved methods of support during the next decade.

Practice Variation in the Diagnosis of Acute Rejection Among Pediatric Heart Transplant Centers: An Analysis of the Pediatric Heart Transplant Study (PHTS) Database

Practice Variation in the Diagnosis of Acute Rejection Among Pediatric Heart Transplant Centers: An Analysis of the Pediatric Heart Transplant Study (PHTS) Database

Association Between Thiopurine S-Methyltransferase (TPMT) Genetic Variants and Infection in Pediatric Heart Transplant Recipients Treated With Azathioprine: A Multi-Institutional Analysis.

Bone marrow suppression is a common adverse effect of the immunosuppressive drug azathioprine. Polymorphisms in the gene encoding thiopurine S-methyltransferase (TPMT) can alter the metabolism of azathioprine, resulting in marrow toxicity and life-threatening infection. In a multicenter cohort of pediatric heart transplant (HT) recipients, we determined the frequency of TPMT genetic variation and assessed whether azathioprine-treated recipients with TPMT variants were at increased risk of infection. We genotyped TPMT in 264 pediatric HT recipients for the presence of the TPMT*2, TPMT*3A, and TPMT*3C variant alleles. Data on infection episodes and azathioprine use were collected as part of each patient's participation in the Pediatric Heart Transplant Study. We performed unadjusted Kaplan-Meier analyses comparing infection outcomes between groups. TPMT variants were identified in 26 pediatric HT recipients (10%): *3A (n = 17), *3C (n = 8), and *2 (n = 1). Among those with a variant allele, *3C was most prevalent in black patients (4 of 5) and *3A most prevalent among white and Hispanic patients (16 of 20). Among 175 recipients (66%) who received azathioprine as part of the initial immunosuppressive regimen, we found no difference in the number of infections at 1 year after HT (0.7 ± 1.3; range, 0-6 versus 0.5 ± 0.9; range, 0-3; p = 0.60) or in freedom from infection and bacterial infection between non-variant and variant carriers. There was 1 infection-related death in each group. In this multicenter cohort of pediatric HT recipients, the prevalence of TPMT variants was similar across racial/ethnic groups to what has been previously reported in non-pediatric HT populations. We found no association between variant alleles and infection in the first year after HT. Because clinically detected cytopenia could have prompted dose adjustment or cessation, we recommend future studies assess the relationship of genotype to leukopenia/neutropenia in the pediatric transplantation population.

Post-transplant outcomes in pediatric ventricular assist device patients: A PediMACS–Pediatric Heart Transplant Study linkage analysis

Pediatric ventricular assist device (VAD) support as bridge to transplant has improved waitlist survival, but the effects of pre-implant status and VAD-related events on post-transplant outcomes have not been assessed. This study is a linkage analysis between the PediMACS and Pediatric Heart Transplant Study databases to determine the effects of VAD course on post-transplant outcomes. Database linkage between October 1, 2012 and December 31, 2015 identified 147 transplanted VAD patients, the primary study group. The comparison cohort was composed of 630 PHTS patients without pre-transplant VAD support. The primary outcome was post-transplant survival, with secondary outcomes of post-transplant length of stay, freedom from infection and freedom from rejection. At implant, the VAD cohort was INTERMACS Profile 1 in 33 (23%), Profile 2 in 89 (63%) and Profile 3 in 14 (10%) patients. The VAD cohort was older, larger, and less likely to have congenital heart disease (p < 0.0001). However, they had greater requirements for inotrope and ventilator support and increased liver and renal dysfunction (p < 0.0001), both of which normalized at transplant after device support. Importantly, there were no differences in 1-year post-transplant survival (96% vs 93%, p = 0.3), freedom from infection (81% vs 79%, p = 0.9) or freedom from rejection (71% vs 74%, p = 0.87) between cohorts. Pediatric VAD patients have post-transplant outcomes equal to that of medically supported patients, despite greater pre-implant illness severity. Post-transplant survival, hospital length of stay, infection and rejection were not affected by patient acuity at VAD implantation or VAD-related complications. Therefore, VAD as bridge to transplant mitigates severity of illness in children.

The Pediatric Heart Failure Workforce: An International, Multicenter Survey.

Our objective was to understand the scope of pediatric heart failure (HF) and the current staffing environment of HF programs. An online survey was distributed to members of the Pediatric Heart Transplant Study and the Pediatric Council of the International Society for Heart and Lung Transplantation. All participants received the primary 23-question survey. Additionally, HF program directors received a 32-question supplemental survey. Of 235 invitations sent, there were 69 (29%) primary surveys and 34 program director surveys completed (24 U.S. programs, 9 outside non-U.S., and one non-specified location). A formal HF program was reported by 88% of directors. There were 150 [IQR 50-200] outpatients/institution and 40% [25-50] of patients had congenital heart disease. Inpatient HF census was 3 [2-4] patients. Most programs (70%) used a consulting service model to provide HF specialty care, while only 10 (30%) utilized an inpatient HF service. Inpatient HF service programs had a higher daily inpatient census versus consult service model programs (4 [3-7] vs. 2 [1-4], respectively; p=0.022) and had a higher number of full-time equivalents dedicated to HF (5.5 [2-7] vs. 2.5 [1-4], respectively; p=0.024). Only 47% of programs report a general fellowship rotation devoted to HF. Advanced practice providers (APP) were utilized in 15 programs, nurse coordinators in 2, and both in 3. Most HF programs are formalized, utilize APP, and have inadequate HF staffing to utilize a separate inpatient HF service. Exposure of general pediatric cardiology fellows to HF care is variable between institutions.

The impact of flow PRA on outcome in pediatric heart recipients in modern era: An analysis of the Pediatric Heart Transplant Study database.

Data from patients in the Pediatric Heart Transplant Study (PHTS) registry transplanted between 2010 and 2014 were analyzed to determine the association between HLA antibody (PRA) determined by SPA using Luminex or flow cytometry with a positive retrospective cross-match and the post-transplant outcomes of acute rejection and graft survival. A total of 1459 of 1596 (91%) recipients had a PRA reported pretransplant; 26% had a PRA>20%. Patients with a PRA>20% were more likely to have CHD, prior cardiac surgery, ECMO support at listing, and waited longer for transplantation than patients with a PRA <20%. Patients with higher PRA% determined by SPA were predictive of a positive retrospective cross-match determined by flow cytometric method (P<.001). A PRA>50% determined by SPA was independently associated with worse overall graft survival after first month of transplant in both unadjusted and adjusted for all other risk factors. In this large multicenter series of pediatric heart transplant recipients, an elevated PRA determined by SPA remains a significant risk factor in the modern era.

Abstract 21298: Surveillance Invasive Hemodynamics in Pediatric Heart Transplant Patients: Utility or Futility?

Introduction: Although first year survival after pediatric heart transplant is improving, late-onset rejection, cardiac allograft vasculopathy (CAV), and graft failure remain significant challenges. Patients routinely undergo endomyocardial biopsy with invasive hemodynamics as the gold standard for rejection surveillance and assessment of long-term graft performance. However, it remains unclear how hemodynamic measures contribute to the monitoring of rejection, CAV, and graft dysfunction. This study aims to assess changes in hemodynamics as the graft ages in patients with or without a history of rejection or CAV. Hypothesis: We hypothesize that abnormal hemodynamics, particularly elevated filling pressures, are associated with CAV, rejection and graft aging. Methods: A total of 2,764 patients from the Pediatric Heart Transplant Study database from 1995-2014 met study criteria of survival to 1 year after transplant with available surveillance biopsy and hemodynamics. Retrospective analyses of 16,489 hemodynamic sets were performed. Results: The median age at transplant was 4.89 years [0.73, 12.95]. Average follow up time was 4.05 years [2.04, 7.17]. Fifty-six percent of patients were male, and 46% had history of congenital heart disease. When comparing hemodynamics collected at the first annual catheterization to 10 years after transplant, those who never had rejection or CAV showed statistically significant increases in right atrial pressure (RAP) (p=&lt;0.001), and pulmonary capillary wedge pressure (PCWP) (p = &lt;0.001) with concomitant decrease in cardiac index (p=0.01). When comparing hemodynamics from patients with a history of CAV or rejection to those without such events, patients with history of CAV or rejection had higher RAP (p=&lt;0.001) and PCWP (p = &lt;0.001), and lower cardiac index (p=0.003) and systemic vascular resistance (p=0.0001). Conclusions: Despite freedom from CAV or rejection, RAP and PCWP increase and cardiac index decreases as the graft ages. Additionally, the diagnosis of CAV or rejection during the life of the graft leads to further derangement in graft performance, which can be detected in hemodynamics. Serial hemodynamic assessment may contribute to the ongoing monitoring of graft function in pediatric recipients.

Haemodynamic profiles of children with end-stage heart failure.

To evaluate associations between haemodynamic profiles and symptoms, end-organ function and outcome in children listed for heart transplantation. Children <18 years listed for heart transplant between 1993 and 2013 with cardiac catheterization data [pulmonary capillary wedge pressure (PCWP), right atrial pressure (RAP), and cardiac index (CI)] in the Pediatric Heart Transplant Study database were included. Outcomes were New York Heart Association (NYHA)/Ross classification, renal and hepatic dysfunction, and death or clinical deterioration while on waitlist. Among 1059 children analysed, median age was 6.9 years and 46% had dilated cardiomyopathy. Overall, 58% had congestion (PCWP >15 mmHg), 28% had severe congestion (PCWP >22 mmHg), and 22% low cardiac output (CI < 2.2 L/min/m2). Twenty-one per cent met the primary outcome of death (9%) or clinical deterioration (12%). In multivariable analysis, worse NYHA/Ross classification was associated with increased PCWP [odds ratio (OR) 1.03, 95% confidence interval (95% CI) 1.01-1.07, P = 0.01], renal dysfunction with increased RAP (OR 1.04, 95% CI 1.01-1.08, P = 0.007), and hepatic dysfunction with both increased PCWP (OR 1.03, 95% CI 1.01-1.06, P < 0.001) and increased RAP (OR 1.09, 95% CI 1.06-1.12, P < 0.001). There were no associations with low output. Death or clinical deterioration was associated with severe congestion (OR 1.6, 95% CI 1.2-2.2, P = 0.002), but not with CI alone. However, children with both low output and severe congestion were at highest risk (OR 1.9, 95% CI 1.1-3.5, P = 0.03). Congestion is more common than low cardiac output in children with end-stage heart failure and correlates with NYHA/Ross classification and end-organ dysfunction. Children with both congestion and low output have the highest risk of death or clinical deterioration.

Risk stratification to determine the impact of induction therapy on survival, rejection and adverse events after pediatric heart transplant: A multi-institutional study

Induction therapy is increasingly being used in pediatric heart transplantation. General versus risk-adapted use remains controversial. We aimed to determine the impact of induction therapy on outcomes after stratifying patients by diagnosis and risk. The Pediatric Heart Transplant Study (PHTS) database was used to identify patients (age ≤18 years) who underwent transplantation between January 1, 2001 and December 31, 2014. Patients were excluded if they survived <48 hours or received multiple induction agents. Patients were stratified using a multivariable model to predict 1-year mortality. Patients within the top 25% risk of predicted mortality were defined as high risk (HR) and the bottom 75% as low risk (LR). Of the 2,860 patients studied, 1,370 received anti-lymphocyte antibody (ALA), 707 received an interleukin-2 receptor antagonist (IL-2RA) and 783 received no induction (NI) therapy. Overall, patients with NI had lower survival (p < 0.01); however, multivariable analysis did not demonstrate an association with graft loss. Freedom from rejection was greater among LR congenital heart disease (CHD) and all cardiomyopathy (CMP) patients who received induction therapy (p < 0.01, for both), as confirmed in a multivariable analysis for CMP patients. Frequency of graft vasculopathy was higher in LR CMP patients who received NI. Freedom from infection was lower with IL-2RA in the LR groups. Pediatric heart transplant survival has improved in the recent era, in concert with increased use of induction therapy. Although induction therapy is associated with decreased rejection, it was not found to directly influence survival on multivariable analysis. Lower risk patients may benefit the most from induction therapy, particularly IL-2RA, which may be correlated with decreased infection and rejection in this cohort.

Bacterial infections after pediatric heart transplantation: Epidemiology, risk factors and outcomes

Bacterial infections represent a major cause of morbidity and mortality in heart transplant recipients. However, data describing the epidemiology and outcomes of these infections in children are limited. We analyzed the Pediatric Heart Transplant Study database of patients transplanted between 1993 and 2014 to determine the etiologies, risk factors and outcomes of children with bacterial infections post-heart transplantation. Of 4,458 primary transplants in the database, there were 4,815 infections that required hospitalization or intravenous therapy, 2,047 (42.51%) of which were bacterial. The risk of bacterial infection was highest in the first month post-transplant, and the bloodstream was the most common site (24.82%). In the early post-transplant period (<30 days post-transplant), coagulase-negative staphylococci were the most common pathogens (16.97%), followed by Enterobacter sp (11.99%) and Pseudomonas sp (11.62%). In the late post-transplant period, community-acquired pathogens Streptococcus pneumoniae (6.27%) and Haemophilus influenzae (2.82%) were also commonly identified. Patients' characteristics independently associated with acquisition of bacterial infection included younger age (p < 0.0001) and ventilator (p < 0.0001) or extracorporeal membrane oxygenation (p = 0.03) use at time of transplant. Overall mortality post-bacterial infection was 33.78%, and previous cardiac surgery (p < 0.001) and multiple sites of infection (p = 0.004) were independent predictors of death. Bacteria were the most common causes of severe infections in pediatric heart transplant recipients and were associated with high mortality rates. The risk of acquiring a bacterial infection was highest in the first month post-transplant, and a large proportion of the infections were caused by multidrug-resistant pathogens.