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BACKGROUND: While sex-related differences in transplant outcomes have been well characterized amongst adults, there are no sex-specific pediatric heart transplant studies over the last decade and none evaluating waitlist outcomes. In a contemporary cohort of children undergoing heart transplantation in the United States, this analysis was performed to determine if there were sex disparities in waitlist and/or post-transplant outcomes. METHODS: Retrospective review of Scientific Registry of Transplant Recipients database from December 16, 2011 to February 28, 2019 to compare male and female children after listing and after transplant. Demographic, clinical characteristics and outcomes were compared unadjusted and after 1:1 propensity matching for selected covariates. RESULTS: Of 4089 patients, 2299 (56%) were males. At listing, males were more likely to be older, have congenital heart disease (58% vs 48%), renal dysfunction (49% vs 44%) and implantable cardioverter defibrillator (9% vs 7%). At transplant, males were more likely to have renal (42 % vs 35%) and liver dysfunction (13% vs 10%), PRA >10% (29% vs 22%) and ischemic time >3.5 hours (p

BACKGROUND: There is a paucity of data regarding the antibody response to SARS-CoV-2 vaccination in children after solid organ transplant.We retrospectively reviewed the SARS-CoV-2 Anti-Spike IgG antibodies measured following SARS-CoV-2 vaccination at our pediatric heart transplant (HTx) center.Among patients (median age 17.1 years) in whom antibody testing was performed (median 118 days post-vaccine completion), a SARS-CoV-2 Anti-Spike IgG antibody was detected in 28 of 40 (70%) post-HTx recipients (median antibody level 10.9 AU/ml). Neutropenia, diabetes mellitus, and previous use of rituximab were associated with absence of a detectable antibody. All 7 post-HTx patients with a known pre-vaccination SARS-CoV-2 viral infection had a detectable SARS-CoV-2 Anti-Spike IgG. All 12 vaccinated pre-HTx patients had a detectable antibody (median antibody level 11.6 AU/ml) including 5 patients that maintained detectable antibodies post-HTx. There were no cases of myocarditis among the total of 17 pre-HTx and 81 post-HTx patients that underwent SARS-CoV-2 vaccination.Our data suggest that a significant proportion of pediatric HTx recipients have no detectable antibody response after SARS-CoV-2 vaccination and support the recommendation to complete the vaccination series prior to HTx in those pediatric patients waiting for HTx.

Endomyocardial biopsy (EMB) is the current standard for rejection surveillance in heart transplant recipients. The quantification of donor-specific cell-free DNA (cfDNA) may be an appropriate biomarker for non-invasive rejection surveillance. A multicenter prospective blinded study (DNA-Based Transplant Rejection Test, DTRT) investigated the value of donor fraction (DF), defined as the ratio of cfDNA specific to the transplanted organ to the total amount of cfDNA present in a blood sample.A total of 241 heart transplant patients were recruited from 7 centers. Age at transplant ranged from 8 days to 73 years, with 146 subjects18 years and 95 ≥18 years. All the patients were followed for at least 1 year, with blood samples drawn at routine and for-cause biopsies. A total of 624 biopsy-paired samples were included for analysis through a commercially available cfDNA assay (myTAIDF in acute cellular rejection (ACR) 1R/2R (n = 15) was higher than ACR 0R (n = 42) (p = 0.02); DF in antibody-mediated rejection pAMR1 (n = 8) and pAMR2 (n = 12) (p = 0.05) were higher than pAMR0 (n = 466) (p = 0.04 and p = 0.05 respectively). An optimal DF threshold was determined by the use of an ROC analysis, which ruled out the presence of either ACR or antibody-mediated rejection.The cell-free DNA DF holds promise as a non-invasive diagnostic test to rule out acute rejection in both adult and pediatric heart transplant populations.

The number of potential pediatric heart transplant recipients continues to exceed the number of donors, and consequently the waitlist mortality remains significant. Despite this, around 40% of all donated organs are not used and are discarded. This document (62 authors from 53 institutions in 17 countries) evaluates factors responsible for discarding donor hearts and makes recommendations regarding donor heart acceptance. The aim of this statement is to ensure that no usable donor heart is discarded, waitlist mortality is reduced, and post-transplant survival is not adversely impacted.

In this study we sought to quantify hazards associated with various donor factors into a cumulative risk scoring system (the Pediatric Heart Donor Assessment Tool, or PH-DAT) to predict 1-year mortality after pediatric heart transplantation (PHT).PHT data with complete donor information (5,732) were randomly divided into a derivation cohort and a validation cohort (3:1). From the derivation cohort, donor-specific variables associated with 1-year mortality (exploratory p-value0.2) were incorporated into a multivariate logistic regression model. Scores were assigned to independent predictors (p0.05) based on relative odds ratios (ORs).The final model had an acceptable predictive value (c-statistic = 0.62). The significant 5 variables (ischemic time, stroke as the cause of death, donor-to-recipient height ratio, donor left ventricular ejection fraction, glomerular filtration rate) were used for the scoring system. The validation cohort demonstrated a strong correlation between the observed and expected rates of 1-year mortality (r = 0.87). The risk of 1-year mortality increases by 11% (OR 1.11 [1.08 to 1.14]; p0.001) in the derivation cohort and 9% (OR 1.09 [1.04 to 1.14]; p = 0.001) in the validation cohort with an increase of 1-point in score. Mortality risk increased 5 times from the lowest to the highest donor score in this cohort. Based on this model, a donor score range of 10 to 28 predicted 1-year recipient mortality of 11% to 31%.This novel pediatric-specific, donor risk scoring system appears capable of predicting post-transplant mortality. Although the PH-DAT may benefit organ allocation and assessment of recipient risk while controlling for donor risk, prospective validation of this model is warranted.

Purpose Routine surveillance biopsy (RSB) is performed to detect asymptomatic acute rejection (AR) after heart transplantation (HT). Variation in pediatric RSB across institutions is high. We examined center-based variation in RSB use and its relationship to graft loss, AR, coronary artery vasculopathy (CAV), and cost of care during the first year post-HT. Methods We linked the Pediatric Health Information System (PHIS) and Scientific Registry of Transplant Recipients (SRTR, 2002-2016), including all primary-HT aged 0-21. We scored institutional RSB strategy by the median number of first-year biopsies in recipients aged ≥12 months without rejection. Mixed effects regression analysis was used to adjust for potential confounders and center effects. Results Of 2,867 patients at 29 centers, we identified an inflection at the top-tertile of centers (834 patients at 10 centers with RSB-score≥4). Higher-RSB centers (i.e. those in the top-tertile) had more patients on pre-HT ventilator/ECMO (23% vs 18% p=0.04) and fewer with a positive crossmatch (13% vs 17% p=0.007). After adjusting for patient and center differences, higher RSB frequency was associated with diagnosed AR (OR 1.15 p=0.004), a trend toward treated AR (OR 1.09 p=0.083) and higher cost (US$450,708 vs 342,170, p Conclusion Higher RSB frequency is associated with increased diagnosis, but not treatment, of AR one-year post-HT. Graft survival and CAV appear unchanged at medium term follow-up. De-intensification at high-frequency institutions may be safe and reduce costs, but further study of differences in treated rejections are necessary.

Purpose The significance of atypical infiltrates, defined as eosinophils or plasma cells on endomyocardial biopsy (EMB) after pediatric heart transplant (HTx) is not known. We hypothesize that atypical infiltrates are associated with worse post-HTx outcomes. Methods We performed a retrospective cohort study of 96 consecutive patients status-post primary HTx (age Results Atypical infiltrates were seen in 24/96 (25%) patients. Of these patients, 14/24 (58%) had 1 EMB and 10/24 (42%) had >2 EMB with atypical infiltrates. Atypical cells were abundant in 6/24 (25%), while they were a rare cell type in 18/24 (75%). The presence of atypical infiltrates on EMB was associated with higher likelihood of reaching the composite outcome compared to no atypical infiltrates (HR 6.9 [2.9-16.3], Fig 1A). Two or more EMBs with atypical infiltrates were associated with greater risk of composite outcome compared to no atypical infiltrates (HR 11.1 [4.2-29.1], Fig 1B). All patients with abundant atypical infiltrates met the composite outcome within the study period (HR 21.6 [7.7-60.2], Fig 1C, compared to no atypical infiltrates). Conclusion Atypical infiltrates on EMB are associated with increased risk of CAV, graft failure, or death after HTx. The risk is higher with increasing frequency and greater extent of atypical infiltrates on EMB. Patients with atypical infiltrates are an at-risk population that require close follow up.

Purpose Recent data in adult solid organ transplantation suggest that epitope-based human leukocyte antigen (HLA) matching may permit better risk assessment of de novo donor‐specific antibody (dnDSA) development compared to antigen-based HLA matching, but data in pediatric heart transplantation (PHTx) are scarce. We evaluated the association between epitope mismatches and dnDSA in PHTx. Methods We performed high resolution HLA typing and epitope mismatch analysis (HLA Matchmaker) in children undergoing primary PHTx at a single center from 2014 - 2020. DSA >1000 MFI (Luminex Single Antigen Bead Assay; One Lambda) were considered positive. Data are presented as median (interquartile range). Results Epitope and dnDSA data were available in 109 transplants (age 5.8 years [1-12], 66% male, 32% non-Hispanic White, follow-up 2.5 years [1.3 - 4.7]). There was significant diversity in the number of epitope mismatches within each HLA locus (Fig 1A), and the number of mismatches were: A 20 (13-28), B 17 (12-22), C 10 (6-15), DR 16 (8-30), DQ 12 (8-16), and DP 8 (3-13). The number of epitope mismatches did not differ among any donor-recipient race combination (not shown). The development of dnDSA was not associated with a higher number of epitope mismatches at any HLA-loci (Fig 1B). However, patients with antibody mediated rejection (AMR) had more DQ mismatches (15 vs 11; p=0.04) than those without AMR, and there were more anti-DQB1 DSA than any other DSA in the cohort (Figure 1C). Conclusion There is significant variability in the number of HLA epitope mismatches within each HLA locus. These data suggest that it may not be the total number of epitope mismatches but rather epitope mismatches at specific loci that vary in location and function that are of immunogenic importance. Further investigation of epitope-matching in PHTx may permit a more personalized immunosuppressive approach based on individualized alloimmune risk assessment in the future.

Purpose Studies on the efficacy of pre-recovery donor thyroxine (T4) treatment for adult heart transplant recipients report inconsistent results. Guidelines for T4 therapy in donors designated for pediatric heart transplantation (PHT) remain undefined. This study investigates the age-dependent impact of donor T4 therapy on the survival of PHT recipients. Methods The UNOS Registry was queried for PHT recipients ( Results A total of 7,999 PHT recipients were identified. 51.5% received a T4-treated donor heart. Median age of patients receiving a T4-treated heart (5 yrs) was significantly higher than those transplanted with non-treated hearts (3 yrs; p Conclusion Survival benefit of donor T4 treatment in PHT depends mainly on recipient age, demonstrating a nonlinear relationship according to donor age. Better survival is seen in infants transplanted with T4-treated hearts. Future clinical trials are warranted to confirm indications for T4 therapy.

Donors are matched for weight in pediatric heart transplantation (PHT), yet age differences are not considered in this decision. In this study we attempt to identify the effect of age differences in weight-matched patients and the effect these differences have on post-transplant survival.The United Network of Organ Sharing (UNOS) database was queried for the period from October 1987 to March 2014 for all pediatric heart transplant patients. Transplants with donor-to-recipient (D-R) weight ratios of 0.8 to 1.5 were identified (weight-matched). D-R age differences were categorized as: donors 5 years younger than recipients (DR-5); donors within 5 years of recipients (D=R±5); and donors 5 years older than recipients (DR+5).A total of 4,408 patients were identified as weight-matched transplants. Of these transplants, 681 were DR+5, 3,596 were D=R±5 and 131 were DR-5. DR+5 transplants were found to be associated with decreased post-transplant survival compared with D=R±5 (p = 0.002). Rates of acute rejection were similar among all groups but post-transplant coronary allograft vasculopathy (CAV) was more prevalent in DR+5 than D=R±5 patients (28% and 18%, respectively; p0.001). Increasing age difference by each year was associated with decreasing median post-transplant survival time (p0.001; hazard ratio 1.018, range 1.011 to 1.025). The overall negative association with mortality was due to the adolescent cohort (11 to 17 years), specifically DR+5 transplants, utilizing organs from donors25 of age.In PHT, increasing D-R age difference decreases survival; however, this effect is driven by recipients 11 to 17 years old and donors25 years old. Allocation of younger donor organs to adolescent recipients should be a priority.

The effect of age at transplant on rejection detected by routine surveillance biopsy (RSB) in pediatric heart transplant (HT) recipients is unknown. We hypothesized there would be low diagnostic yield and decreased prevalence of rejection detected on RSB in infants (age1 year) when compared with children (age 1 to 9 years) and adolescents (age 10 to 18 years).We utilized Pediatric Heart Transplant Study (PHTS) data from 2010 to 2013 to analyze moderate-to-severe (ISHLT Grade 2R/3R) cellular rejection (MSR) detected only on RSB (RSBMSR).RSB detected 280 of 343 (81.6%) episodes of MSR. RSBMSR was detected in all age groups even5 years after HT. Infant RSBMSR had a greater proportion (p = 0.0025) occurring5 years after HT (39.2 vs 18.4 vs 10.8%) and a lower proportion (p = 0.0009) occurring in the first year after HT (25.5 vs 60.6 vs 51.7%) compared with children and adolescents, respectively. Freedom from RSBMSR was 87 ± 7% in infants, 76 ± 6% in children and 73 ± 7% in adolescents 4 years after HT. In 1-year survivors who had RSBMSR in the first year after HT, the risk of RSBMSR occurring in Years 2 to 4 was significantly (p0.0001) greater than patients without RSBMSR in the first year (hazard ratio 21.28, 95% confidence interval 10.87 to 41.66), regardless of recipient age.RSBMSR exists in all age groups after pediatric HT with long-term follow-up. The prevalence in infant recipients is highest5 years after HT. Those with RSBMSR in the first year after HT are at a high risk for recurrent rejection regardless of age at HT.

Purpose Currently there are no-FDA approved immunosuppressants specific to pediatric heart transplantation (HT). In recent years, everolimus (EVL) has emerged as an alternative to tacrolimus (TAC) as a primary immunosuppressant to prevent rejection that may also prevent kidney and coronary disease. However, the two regimens have never been evaluated systematically. Methods The TEAMMATE Trial (IND 127980) is designed to evaluate the safety and efficacy of EVL and low-dose (LD-TAC) compared to standard-therapy TAC and mycophenolate mofetil (MMF). The study design and rationale are reviewed in light of challenges inherent in rare disease research. Results The TEAMMATE trial is the first multicenter randomized clinical trial (RCT) in pediatric HT. The primary purpose is to evaluate the risk-benefit profile of the two regimens to prevent major adverse transplant events (MATE), and to support FDA approval of 1 or both regimens for pediatric HT. Children Conclusion The TEAMMATE trial is the first RCT in pediatric HT. It is anticipated that the study will provide important information about the safety and effectiveness of EVL and TAC and provide valuable lessons into the design and conduct of future trials in pediatric HT.

Purpose Donor utilization rates continue to be low for pediatric heart transplantation (pHT) however efforts to expand the donor acceptance criteria have shown mixed results in single institution studies in pediatric and adult transplantation. Methods We analyzed pHT UNOS data (2008-2018) to compare the recipient characteristics, donor characteristics and outcomes, based on donor ejection fraction of less than 50% (low EF) and or ischemic time of greater than 4 hours (prolonged IT). Results A total of 4345 pHT were performed of which 1309 (30.1%) were with prolonged IT and 122 (2.8%) in low EF. Additionally, 58 (1.3%) were performed with both low EF and prolonged IT (combined risk). Recipients of combined risk were more likely to be younger, have post-surgical congenital heart disease, be on ECMO or ventilator but less likely on VAD (all p l 0.01). Figure 1. There was no significant difference in donor characteristics such as mode of death, gender mismatch, race mismatch or inotrope use. Waitlist time was significantly lower for low EF (mean 39 days, range 15-109) or combined risk group (36 days, 15-80) compared to other groups (60 days, 23-125) (p=0.01). 1 year mortality was 8% in low risk group, 12% in prolonged IT, 14% in reduced EF and 28% in combined risk patients (p l 0.01). Additionally, 9% of low risk patients had episode of treated rejection, while 15% of prolonged IT, 5% of low EF and 15% in combined group had rejection (pl0.01).The KM survival analysis performed is shown in the figure 1. Conclusion Lower EF donors performed similar to prolonged IT donor, but were uncommonly used. Acceptance of risk was common in recipients deemed higher risk for waitlist mortality and led to shorter wait times. However, episodes of treated rejection as well as 1 year mortality was higher with the higher risk transplants, specifically with combined risk donors. Caution should be used in accepting combined risk transplants and further analysis will help balance the waitlist mortality with post-transplant outcomes.

Purpose Pediatric lung transplantations (LTx) consists of a relatively small but significant population. Without pooling of multi-institutional data, setting expectations for length of stay (LOS) is difficult. This study aims to investigate the LOS in LTx over the last 20 years to help benchmarking and quality improvement work. Methods The United Network for Organ Sharing (UNOS) database was used to identify patients ages 0-18 at time of listing for LTx between 2000 and 2019. This timeframe was divided into two eras: first (2000-2009) and second (2010-2019) eras. LOS was defined as number of days from LTx to discharge. Results 905 LTx were identified. 471 transplantations occurred in the first era and 434 in the second. Overall length of stay [median days (IQR)] was 19 (13-31) and comparable between the eras [18 (13-29) vs 20 (14-35), p=0.082]. Specifically by age, LOS for infants was 44 (29-80), for ages 2-11 was 21 (13-37), and for ages 12-18 was 17 (12-26). Compared to patients who did not have each of the following, LOS was increased in patients on ECMO (p Conclusion Over the past two decades, lung transplantation patients who are younger or who have pre- or post-transplantation end-organ dysfunction consistently have longer LOS. With these stable patterns, healthcare moving towards a bundled-care system, and an increase in UNOS required & institutional Quality Improvement projects, establishing benchmarks and expectations in pediatric post-lung transplant LOS is important.

Purpose In adults, female (F) and African American (AA) heart transplant (HT) recipients have higher waitlist (WL) and post-transplant (PT) mortality. Our study aims to evaluate gender and racial disparities in pediatric recipients and its effect on survival in the WL and PT period in the current era. Methods Pediatric ( Results 1435 (44%) F were listed for HT during the study period. Compared to males (M), F recipients listed for HT were younger, more likely AA (19 vs. 22%), and cardiomyopathy [CMP] (41.3 vs. 51.4%) [p 0.05 for all]. 663 (20%) AA HT candidates were listed. Compared to Caucasian, AA recipients more likely had CMP (41.3 vs. 49.5%), listed Status 1A (68.7 vs. 72.9%), had renal dysfunction (47.4 s. 53.4%) and were on Medicaid (33.3 vs. 65%) [p Conclusion In the current era, pediatric heart transplant recipients who are F and AA continue to have higher waitlist mortality. Such disparities do not exist post-transplant.

Purpose PRES is an uncommon complication of organ transplantation. Little is known about its clinical course and risk factors. We sought to examine the natural history and risk factors for PRES in pediatric heart transplant (HTx) recipients. Methods 14-center international retrospective study of 46 pediatric PRES cases between 2000-2018, compared with 1372 HTx recipients without PRES between 2000-2018. Demographic and clinical data were entered into a central database. PRES diagnosis was based on a combination of seizures, headache, altered mental status or focal neurological deficits, and required confirmation, either by MRI or resolution of neurological symptoms after CNI withdrawal. Factors associated with PRES were identified by Cox Proportional Hazard multivariable analysis. Results Median onset of symptoms was 16 days (R, 2-2468 d) after HTx; 23 (50%) developed PRES in the first 2 weeks, 32 (70%) in the first month, and 40 (87%) within the first year after HTx. Symptoms at presentation included seizures (40/46, 87%), altered mental status (27/46, 59%), headache (18/46, 39%), focal neurological deficits (16/46, 35%), and lasted for a median of 4 days (R 1-1772d), with almost all recipients (44/46, 96%) making a full recovery. MRI was obtained in 43/46, showing a vasogenic pattern of edema characteristic of PRES in 37 recipients (80%). Recipients with PRES tended to be older (9.1 y vs 5.9 y, p=0.06). Hypertension (SBP>95%ile) was present in 40/44 (91%) recipients with PRES at presentation, with severe hypertension (SBP>99%ile plus 5mmHG) in 37 (85%). Though all cases occurred in the setting of CNI use (TAC 40, CSA 6), levels were supratherapeutic in only 13/42 (31%). Cox analysis revealed a 5.3x increased hazard for PRES with Glenn (CI 1.54,18.01; p=0.008) and a 3.8x increased hazard with Fontan (1.08,13.00; p=0.038), while age, underlying cardiac diagnosis, BMI, ischemic time and type of CNI did not appear to contribute significantly. Conclusion 2/3 of pediatric PRES cases occur in the first month after HTx with seizures as the most common presenting symptom. An overwhelming majority of patients were severely hypertensive, whereas less than a third had supratherapeutic CNI levels. Almost all recipients recovered fully within days. Recipients with pre-existing Glenn or Fontan have a higher rate of developing PRES after HTx.

Purpose Pediatric heart transplant (PHT) patients have the highest waitlist mortality of all solid organ transplants yet more than 40% of viable hearts are unutilized. A tool for risk prediction is therefore necessary to improve organ matching in PHT. This study aims to compare and validate the PHT risk scores found in the literature. Methods The literature was searched for PHT risk prediction models. The UNOS registry was used to validate the models with a pediatric cohort ( Results Five recipient and one donor risk scores were published between 2008-2019 (Davies et al 2008, Almond et al 2012, Butts et al 2015, Zafar et al 2018, Fraser III et al 2019 and Choudhry et al 2019). The validation cohort included 1,003 PHT identified in UNOS. 50.5% of patients had a diagnosis of CHD and 42.8% of cardiomyopathy. With exception of Butts et al's model, all other models significantly predicted 1-year mortality for low- vs high-risk patients. Choudhry et al (ROC=0.70) and Davies et al (ROC=0.66) models had the highest predictive power (figure 1). Fraser III et al model was the best predictor for non-CHD patients (ROC=0.71) compared to Choudhry et al (ROC= 0.68) and Davies et al (ROC=0.67) models. Conclusion The risk model by Choudhry et al provided the best prediction for 1-year mortality. However, all published validated studies lacked advanced analytical approaches in their models. Using machine learning algorithms is important to develop an advanced tool that can risk stratify a given donor-to-recipient match for any PHT candidate.

Purpose Functional status at listing predicts waitlist survival in adult heart transplant candidates including those on mechanical circulatory support. This has not been studied in pediatric heart transplantation although it is an independent predictor of outcomes in pediatric liver transplantation. We aimed to determine the association of: 1) functional status at listing with waitlist and post-transplant outcomes, and 2) functional status at transplant with post-transplant outcomes in pediatric heart transplant candidates. Methods Retrospective registry study of 5754 patients ≤18 years old listed for heart transplant between 1995 and 2019 with Lansky/Karnofsky Play Performance Scale (LPPS) scores in the UNOS database. Standard statistical methods were used to assess relationships of LPPS scores at listing and transplant with waitlist and post-transplant outcomes. A positive waitlist outcome was defined as transplantation, removal from waitlist due to clinical improvement, or remaining on waitlist. Results At listing, 1463 patients had the ability to carry out normal activities (LPPS 80-100), 2338 had mild-moderate restriction in functional status (LPPS 50-70), and 1953 had moderate-severe restriction (LPPS 10-40). Normal activity and mild-moderate restriction at listing were associated with a higher positive waitlist outcome rate compared with moderate-severe restriction (90% vs 80%, p Conclusion Candidate functional status is associated with waitlist as well as post-transplant outcomes. Improvement in functional status between listing and transplant is associated with better outcomes 1-year post-transplant. These data suggest that interventions targeting functional impairment (e.g. physical rehabilitation) have the potential to improve pediatric heart transplant outcomes.

There is increasing evidence that donor-specific anti-HLA antibodies (DSA) are associated with poor outcomes after cardiac transplantation in adults, but data are limited in children. The objective of this study was to examine the development and consequences of de novo DSA in pediatric recipients of heart transplants.We analyzed 105 pediatric patients who received heart transplants at our center from January 2002 to December 2012. All patients had negative T-cell and B-cell post-transplant crossmatches. Patients underwent HLA antibody screening at 1, 2, 3, 6, and 12 months post-transplant and annually thereafter unless there was suspicion for rejection. HLA class I and II antibodies were identified using Luminex assay. Coronary angiography was performed at 1 year and annually thereafter. Acute cellular rejection, antibody-mediated rejection, and treated clinical rejections were included together as rejection events.Of 105 patients, 45 (43%) developed de novo DSA. DSA-positive patients had significantly higher rates of coronary artery vasculopathy (CAV) compared with DSA-negative patients (36% vs 13%). CAV-free survival at 1 year and 5 years post-transplant for DSA-negative patients was 90% and 25%, respectively, compared with 70% and 0%, respectively, for DSA-positive patients (p0.01). DSA-positive patients had 2.5 times more rejection events per year than DSA-negative patients. The 5-year graft survival rate was 72.4% for DSA-negative patients and 21% for DSA-positive patients (p0.001).De novo DSA has a strong negative impact on CAV, rejection, and graft survival in pediatric recipients of heart transplants.

Purpose Donor-recipient age matching has been introduced into the new French allocation system launched on January 2018. The allocation score is currently weighted by the age difference between the donor and the candidate. The score decreases for candidates 15 to 40 years older than the donor from 100% to 0%. The aim of this study was to evaluate the effect of the new system on pediatric heart transplantation. Methods The study included all new pediatric candidates added to the French waiting list between January 2014 and March 2019 (n=179). The profile and waitlist outcomes of the candidates registered before (2014-2017, n=128) and after (January 2018- March 2019, n=51) the introduction of the new system were compared. The main outcomes were 3-month cumulative incidence (CI) of transplantation, and of waitlist mortality or delisting for worsening medical condition. The CI were estimated using the competing risk analyses and were compared using the Gray's test. Results The medical characteristics of the patients were similar between the 2 periods except for mechanical ventilation which tended to be more frequent in the first cohort (33% vs 18%, p=0.05). The number of new registrations per year increased by 28% in the second period. Donor heart donations decreased in 2018-2019 period but pediatric donor hearts were more often allocated to pediatric candidates (63% vs 48%). The 3-month CI of transplantation was similar between the 2 periods (53% vs 54%, p=0.41). The 3-month waitlist mortality or delisting for worsening medical condition tended to be lower in 2018-2019 (8% vs 17%, p=0.09). Conclusion While access to transplantation remains unchanged, a non-significant decrease in 3-month waitlist mortality has been observed since the implementation of the new system.

Purpose Three-dimensional (3D) echocardiography for the assessment of LV size, function and myocardial mechanics has been commonly used after heart transplantation (HT) in adults, but not yet in children. We purposed to explore the feasibility of 3D echocardiography for these parameters in children after HT. Methods We analyzed data from 33 pediatric HT recipients with median age 10 yrs at HT (3 mos -17yrs) who had ≥ 2 echocardiograms with 3D LV full volume image within 24 hours of routine biopsy at BCH between March 2013 and December 2015. Rejection was defined by biopsy as acute cellular rejection Grade ≥2R or antibody mediated rejection (ISHLT-2004). We analyzed 3D LV volumes, ejection fraction (EF), mass and mass/volume, global longitudinal, circumferential and radial strains (GLS, GCS and GRS), twist and torsion at first, 6 and 12 months after HT; and compared with corresponding values in 30 age- and BSA-matched controls with median age 7.2 yrs (2 mos-17yrs). Results During the initial 30 days post HT, all HT recipients had smaller end-diastolic volumes than controls (median EDV: 38 vs. 47 ml/m2) resulting in mild LV hypertrophy (Mass: 50 vs. 43 gr/m2) and impairment in LV systolic function (EF: 56 vs. 65%, GLS: 21 vs. 26%, GCS: 26 vs. 33%, GRS: 39 vs. 48%, for all P Among 23 rejection free recipients, EDV, ESV, Mass and GRS gradually increased within 1 year after HT (ANOVA P=0.015, P=0.022, P=0.015, P Conclusion 3D echocardiography can assess LV size, function and myocardial mechanics and reflects LV post-transplant recovery in rejection-free pediatric recipients. There were changes in LV size, function and myocardial mechanics associated with rejection and deserve further assessment in larger pediatric heart recipient cohorts.

Purpose Heart transplantation (HT) in children consumes substantial health care resources. However, little is known regarding the financing of pediatric HT in the US and whether there have been changes in the nature of pediatric HT financing over time. Methods The United Network for Organ Sharing thoracic organ transplant database was queried for all HTs performed in patients Results During the study period, 8289 HTs were performed in patients Conclusion Currently, pediatric HT in the US is funded predominantly by Medicaid. In recent years, the proportion of patients with private insurance has fallen with a commensurate increase in Medicaid as primary payer. These findings have implications in view of recent threats to Medicaid funding nationally. Further study is necessary to better understand the causes and impacts of these temporal changes.

Purpose ABO-incompatible (ABO-I) heart transplantation (HT) is used in children Methods Two MP (Prismaflex) and two CP (Spectra Optia, Terumo BCT) circuits were incorporated into four separate CBP circuits primed with high titer type O donor whole blood. Assays were performed to determine baseline isohemagglutinin titers and then at 30 minute increments until completion of the run (two plasma volume exchanges) at two hours. Results There was a decrease in anti-A and anti-B IgM and IgG titers with both MP and CP. Mean anti-A and anti-B titer reduction was 4.625 titers (93.7% change) and 4.375 titers (93.8% change) using MP and CP, respectively. At 2 hours of apheresis, CP reduced 62.5% of all ITs to ≤ 1:4, while MP reduced 50% of ITs to ≤1:4. Both demonstrated similar hemolytic and thrombotic profiles. Conclusion In this in vitro plasmapheresis model of IT reduction, both MP and CP incorporated into the CPB circuit can be used quickly and effectively to reduce circulating IT. While CP may have some greater efficiency, further study is necessary to verify this in vivo.

Purpose Routine surveillance biopsy (RSB) is performed to monitor for asymptomatic acute rejection (AR) after heart transplantation (HT). The optimal frequency of RSB in pediatrics is unknown and variation in RSB frequency is high. We hypothesized that higher frequency RSB centers have increased rates of AR and resource utilization, but no difference in graft survival. Methods We utilized a linked database (2002-2016) between Pediatric Health Information System (PHIS) and Scientific Registry of Transplant Recipients (SRTR). We designated centers as high- and low-RSB based on the observed median number of first-year biopsies (from procedural ICD and CPT coding) in recipients assumed to be standard risk: greater than 1 year old without rejection in their first year. The highest tertile of centers were classified as high-RSB and compared to the lowest two-thirds (low-RSB). We then compared outcomes amongst all primary recipients aged 0-21 by center type. Outcomes were HT admission length of stay (LOS), incidence of AR at one year, graft survival, estimated HT admission cost, and total cost in the first year. Regression analysis was used to adjust for potential confounders. Results We compared 834 patients at 10 high-RSB centers to 2,033 patients at 19 low-RSB centers. Baseline characteristics were similar except high-RSB center recipients had increased use of ventilator or ECMO at HT (23 vs 18%, p=0.039), fewer hispanic/asian/other race (20 vs 24% p=0.005), fewer positive crossmatch (13% vs 17% p=0.007). High-RSB centers had higher first-year incidence of all AR vs low-RSBs (36% vs 29%, p=0.001; OR 1.52 [95% CI 1.24-1.85] p Conclusion Centers with a high-frequency biopsy strategy during the first year diagnose AR more often during the first year after HT but have similar incidence of treated rejection. Early graft survival is unchanged. A low-frequency biopsy strategy is associated with lower cost. To determine the optimal biopsy frequency additional data are needed on long-term graft survival and graft performance.

Purpose Intravascular ultrasound (IVUS) has been used in adult heart transplant (HTX) recipients early after transplant to assess risk for long-term outcomes, along with differences in therapeutic targets for the treatment of cardiac allograft vasculopathy (CAV). Little is known about the utility of IVUS early after pediatric HTX. We evaluated the use of IVUS early ( Methods All pediatric HTX recipients at our hospital who underwent coronary evaluation via IVUS within 5 years after transplant were included. Maximal intimal thickness (MIT) and associated Stanford IVUS class (SIC) were analyzed and subjects were stratified into two groups [SIC 1-2 (trivial/mild) vs. 3-4(moderate/severe)]. Chi-square, t-test, and Kaplan Meier analyses were undertaken to evaluate association of SIC with long-term outcomes [CAV (diagnosed by angiography or pathology), graft loss from all causes, graft loss from CAV, and death]. Results Seventy-one subjects had IVUS performed within 5 years after HTX. Fifty-four (76%) were SIC 1-2, while 17 (24%) were SIC 3-4. Median time from transplant at IVUS was 3.8 & 3.5 years, respectively (p=0.59). Median age at transplant was 6.4 & 8.7 years, respectively (p=0.80). MIT was 0.17±0.06 & 0.53±0.23 mm, respectively (p Conclusion Early changes in IVUS (

Purpose Blood type ABO incompatibility (ABOi) is becoming increasingly utilized in heart transplantation. We sought to identify whether this increase was mostly in infants or older children as well. Methods Pediatric patients ( Results From 2000-2017, there were 415 ABOi transplants completed in children up to 13 years of age. ABOi transplantation volume over time is shown in Figure 1. Of ABOi transplants, 70% (n=291) were done in North America (NA) and 28% (n=115) in Europe. The proportion of ABOi transplants was 4.6% in NA and 4.5% in Europe (p=0.87). When examined by era, this proportion has increased from 3.5% (2000-2008) to 5.3% (2009-2017), p Conclusion Willingness to accept ABOi allografts has continued to increase in the recent era, especially among pediatric candidates >2 years old. The trends in ABOi transplants are similar between NA and Europe. In the U.S., 1/5th of the recipients listed as ABOi transplant acceptable ultimately received ABOi transplant. Survival among the expanding group of ABOi pediatric heart transplant recipients compares favorably to ABO compatible transplants. These outcomes should encourage centers to use ABOi donors, particularly in select older children.

Background Serial invasive cardiac catheterization with endomyocardial biopsies (EMBs) is the current standard of reference for evaluation after orthotopic heart transplant (OHTx). We developed a novel, non-invasive echocardiographic index of global left ventricular relaxation (LVRI) and assessed its sensitivity, specificity and predictive value for detecting rejection compared with EMB results in a prospective study conducted from September 2012 through May 2014. Methods LVRI was calculated as the sum of diastolic tissue Doppler imaging (TDI) velocities (E′) of the left ventricular lateral, septal and posterior walls divided by the percentage of left ventricular posterior wall (LVPW) thinning by M-mode. LVRI was measured in 47 OHTx patients and 50 patients with normal hearts. Of the 33 patients who underwent clinically indicated EMB, 22 patients had Grade 0R EMB, 6 had Grade 1R and 5 had Grade 2R to 3R biopsy results. Sensitivity, specificity and predictive value of LVRI for discriminating Grade 1R to 3R EMB were calculated. The LVRI was compared before and after OHTx rejection treatment and during the early and late post-transplant period. To characterize LVRI, 1-way analysis of variance was used to compare all groups, including non-OHTx patients. Results LVRI was lower in patients with Grade 0R EMBs compared with non-OHTx patients. Patients with Grade 1R to 3R EMBs had lower LVRI than those with Grade 0R EMBs. LVRI recovered after treatment for rejection. LVRI appeared to normalize between 40 and 90 days post-transplantation. After 90 days, sensitivity was 100% and specificity was 90.9% for detecting patients with Grade 1R to 3R EMBs using an LVRI of 0.8. Conclusion LVRI, a novel, non-invasive TDI index of global left ventricular diastolic dysfunction, appears to be useful for detecting rejection in children beyond 3 months post-OHTx.

In 2004, the United Network for Organ Sharing (UNOS) added the label "high-risk donor" (HRD) for any organ donor who met the Centers for Disease Control (CDC) criteria for high-risk behavior for infection. The aim of this study was to calculate the rate of HRD graft use in heart transplantation in children and determine the differences in outcome from those who received standard-risk donor (SRD) grafts.We reviewed information from the UNOS database regarding transplants performed between June 30, 2004 and July 31, 2012. Heart transplant recipients18 years old were divided into two groups based on the donor's risk status. Demographic data on donors and recipients were collected. Survival analysis was performed to compare survival based on donor status. We also compared episodes of rejection before hospital discharge and the length of stay after transplantation by donor status.During the study period, 2,782 pediatric heart transplantations were performed and 116 (4.1%) patients received a CDC HRD graft. Recipients of HRD grafts were significantly older and heavier than those who received an SRD graft (8.5 vs 6.5 years, p0.001 and 35.7 vs 26.9 kg, p0.001). There was no difference in patient survival (log rank, p = 0.88) between groups. There was no difference in rejection prior to discharge (17.2 vs 16.4%, p = 0.81) or length of stay after transplantation (26.1 vs 27.6 days, p = 0.58).CDC HRD graft status does not appear to significantly affect recipient outcome after heart transplantation in children.

Background The pediatric heart transplant literature contains little information regarding extracorporeal photopheresis (ECP), despite International Society for Heart and Lung Transplantation guidelines recommending it for recurrent/recalcitrant rejection. We report our experience with ECP in pediatric heart transplantation. Methods Data were obtained on heart transplant patients who were aged ≤ 18 years at the time of transplantation and received ECP between 1990 and 2012 at our institution. Results Twenty heart transplant patients underwent 22 courses of ECP. Median ages were 12.7 years (range, 0.3–18.5 years) at transplant and 15.3 years (range, 7.3–31 years) at initial ECP. Median time from transplant to ECP was 1.4 years (range, 0.1–12.6 years). The median ECP duration was 5.8 months (range, 1.9–16.1 months). Indications for ECP included rejection with hemodynamic compromise (HC) in 4 patients, rejection without HC in 12, and prophylaxis in 2. Eleven patients died at a median time of 3.1 years after the start of ECP. Survival after ECP was 84% at 1 year and 53% at 3 years. Eleven patients were considered non-compliant and had a trend toward lower survival of 75% at 1 year and 18% at 3 years ( p = 0.06 compared with compliant patients). One patient developed Pneumocystis carinii pneumonia during ECP and post-transplant lymphoproliferative disease 21 months after finishing ECP. No other adverse effects or infectious complications associated with ECP were noted. Conclusions This case series represents the largest reported experience with ECP in pediatric heart transplantation. ECP can be safely applied in this patient group. Despite EPC, non-compliant patients showed a trend toward lower survival than compliant patients.

Purpose Approximately 40% of potential pediatric heart donations go unused, while waitlist mortality remains high. The aim of our study was to investigate associations between center refusal rate and waitlist outcomes. Methods Retrospective analysis was performed using UNOS/OPTN pediatric ( Results 5,639 listed patients in 59 centers met inclusion criteria. The lowest quartile of center had a median RR of 75th percentile had a RR ≥ 4. There was no association between RR quartile and transplant center volume (p=0.4). Centers in the highest RR quartile were more likely to remove patients from the waitlist due to death or clinical deterioration versus those at lowest RR quartile (24.1% vs 14.6%, p Conclusion Patients listed at high RR centers had worse survival from listing. High RR centers are more likely to remove patients from the waitlist due to death or clinical deterioration and are less likely to transplant patients. Refusal rate is not associated with center transplant volume.

Purpose Total parenteral nutrition (TPN) allows for caloric, electrolyte, and mineral optimization of critically ill patients prior to and after surgery. However, prolonged use of TPN is associated with increased risk of infectious complications and metabolic dysregulation that can exacerbate post-transplant complications. We sought to evaluate the impact of TPN on the 1-year survival of pediatric heart transplant (HTx) patients. Methods The UNOS and Pediatric Health Information System were queried for heart transplantations performed from 2006 to 2017. A multivariate analysis of risk factors for TPN use and known risk factors for poor transplant outcomes was performed and patients were stratified into three groups: “pre-HTx TPN” (with/without post-HTx TPN), “post-HTx TPN” only, and “no TPN” during HTx admission. Pairwise comparisons were used to assess 1-year survival between each group and to identify risk factors impacting mortality. Results A total of 2,812 patients were identified, 1,410 (50.1%) had either pre-HTx TPN (N=970) or post-HTx TPN (N=440), while 1,402 (49.9%) patients received no TPN. Post-HTx TPN patients had significantly worse 1-year survival (85.5%) compared to both pre-HTx TPN and no TPN groups [89.2% and 93.3%, respectively, p≤0.001; (Figure)]. On multivariate analysis, post-HTx TPN group was twice as likely to die within 1 year as no TPN group (OR 2.2, CI 95% 1.5-3.2). Infants, ECMO, eGFR Conclusion TPN supplementation prior to transplantation portends a significantly worse 1-year survival, whereas post-operative TPN has even a stronger association with negative post-transplant outcomes. outcomes.

Purpose Hypertension (HTN) is a known complication of pediatric heart transplant (HTx) both immediately post-Tx and long-term. We sought to identify factors associated with antihypertensive medication (anti-HTN) use in pediatric HTx recipients in the ICU post-Tx, and need for oral anti-HTNs at post-Tx discharge (d/c) and 1 year (yr) post-Tx. Methods Retrospective chart review of patients (pts) ≤18 years who underwent initial HTx at UPMC Children's Hospital of Pittsburgh and Morgan Stanley Children's Hospital of NY between 8/1/09-12/31/17 with ≥1 yr follow-up. Exclusion criteria included re-Tx, multi-organ recipients, pts who survived Results There were 188 pts who met inclusion criteria. Anti-HTN drips were required in the ICU post-Tx in 46 pts (24.5%) for a median of 3 days (1-21 days). Drips were nitroprusside (28/46), calcium channel blocker (8/46), beta-blocker (1/46) and multiple (9/46). Oral anti-HTNs were required in 58 pts (30.9%) at d/c and 1 yr post-Tx. Figure 1 demonstrates significant associations by univariate and multivariate analyses. Anti-HTN drip in the ICU post-Tx was associated with donor-to-recipient weight ratio (wt ratio). Oral anti-HTN use at d/c was associated with wt ratio and pre-Tx VAD, and at 1 yr post-Tx was associated with age at Tx, steroid use at d/c and oral anti-HTN use at d/c. Conclusion HTN is common immediately and at 1 yr post-Tx, with over a quarter of pts requiring anti-HTNs. Wt ratio was the only independent predictor of anti-HTN use in the early post-Tx period, whereas VAD use was also associated with anti-HTN use at d/c. Interestingly, anti-HTN use at 1 yr post-Tx was not associated with those factors, but rather with age at Tx and steroid use.

Purpose Readmission is common following pediatric heart transplantation (HT), based on existing single center data. The nationwide incidence of rehospitalization after HT has not been reported. We aimed to assess the incidence, risk factors, and indications for rehospitalization in pediatric HT recipients using a nationwide multicenter linked database. Methods The Scientific Registry of Transplant Recipients and Pediatric Health Information System databases were linked at the patient level using indirect identifiers (2002-2016). All pediatric HT recipients who survived to discharge were included. The frequency, timing of, and indication for all-cause readmissions in the first year following initial discharge were assessed. Multivariable logistic regression examined risk factors for readmission with standard error estimates adjusted for clustering within centers. Results A total of 2870 HT recipients from 29 centers were included. Of these, 1835 (63.9%) were readmitted within the first post-HT year (total of 5428 admissions). Readmission rates varied across transplant centers from 46% (1 center) to 100% (3 centers). For patients who were rehospitalized, the median number of readmissions was 2 (IQR 1-4) and the median time to first readmission was 29 days (IQR 9-99 days). Risk factors independently associated with readmission included age 30 days (AOR 1.4, 95%CI 1.1-1.9). Cardiac diagnoses, including rejection and/or concern for rejection, were the most common indications for readmission (N=2213, 40.8%), followed by infection/fever (N=1222, 22.5%), and respiratory diagnoses (N=393, 7.2%). Conclusion Rehospitalization is common in the first year following pediatric HT, with considerable variation in readmission rates across centers. Younger age, congenital heart disease, and a more complicated post-HT course increase the risk for subsequent readmission. Risk stratification based on these factors may serve to guide decision-making in determining discharge readiness and planning.

Purpose Tracheostomy is often considered a contraindication to pediatric heart transplant (PHTX), however there is a paucity of information about clinical outcomes in this population. We sought to describe clinical outcomes for tracheostomy patients after PHTX at Loma Linda University (LLU). Methods Retrospective chart review of all PHTX recipients from 1985-2017 at LLU with a tracheostomy placed peri-PHTX. Cases were compared to propensity-matched controls (3:1). Baseline demographics, clinical co-variates, and post-PHTX outcomes [survival; freedom from infection, rejection, cardiac allograft vasculopathy (CAV), and malignancy] were assessed between the groups using the Kaplan-Meier method and were compared with the log-rank test (LRT) and Cox Proportional Hazards (CPH) model. Results Twenty (3.8%) PHTX tracheostomy patients and 504 PHTX patients without tracheostomies were identified, from which 60 matched pairs (3:1) were chosen. Seven (35%) had tracheostomy placement prior to PHTX, 8 (40%) were placed after PHTX prior to discharge, and 5 (25%) were placed after PHTX hospitalization discharge. Twelve (60%) were infants and 13 (65%) had congenital heart disease. After matching, there was lower freedom from infection (HR 2.10, 95% CI 1.12-3.95, CPH p=0.02, LRT p=0.0003, Figure 1a) in the tracheostomy group, however no difference in graft survival (CPH p=0.42, LRT p=0.07, Figure 1b) or death from infection (Chi-square p=0.18) was seen. No differences in freedom from rejection, CAV, nor malignancy (all p>0.05) were seen. Conclusion Tracheostomy in PHTX recipients is independently associated with increased risk of infection, though survival and freedom from other common co-morbidities is similar to matched peers.

Purpose The frequency, indications and outcomes for readmission following pediatric heart transplantation are poorly characterized. A better understanding of this phenomenon will help guide strategies to address the causes of readmission. Methods Data from the Clinical Trials in Organ Transplantation for Children (CTOTC-04) multi-institutional collaborative study were utilized to determine the incidence of, and risk factors for, hospital readmission within 30 days and 1 year from initial hospital discharge. Results Among 240 transplants at 8 centers, 227 subjects were discharged and had follow-up. 129 subjects (56.8%) were readmitted within one year; 71 had 2 or more readmissions. The 30 day and 1-year freedom from readmission was 70.5% (CI: 64.1%, 76.0%) and 42.2% (CI: 35.7%, 48.7%), respectively. The instantaneous hazard for first readmission was highest immediately following discharge and continued to decrease over the first year (Figure). The most common indications for readmissions were infection followed by rejection and fever without confirmed infection, accounting for 25.0%, 10.6% and 6.2% of readmissions, respectively . There were 4 deaths during readmissions due to pulmonary hemorrhage, infection, respiratory failure and rejection. Factors independently associated with increased probability of first readmission within 1 year (Cox proportional hazard model) were: transplant in infancy (p=.05), longer transplant hospitalization (p=.04), lower UNOS urgency status (2/IB vs 1A) at transplant (p=.04), and Hispanic ethnicity (p=.05). Conclusion Hospital readmission occurs frequently in the first year following discharge after heart transplantation with highest risk in the first 30 days. Infection is more common than rejection as cause for readmission, with death during readmission being rare. A number of patient and procedure-related factors are associated with higher risk of readmission. A fuller understanding of this risk factors may help tailor strategies to reduce unnecessary hospital readmission.

Allosensitization is associated with inferior waitlist outcomes in pediatric heart transplant candidates, presumably because of the requirement for a negative prospective crossmatch. However, there are no reports of heart transplant candidate outcomes according to prospective crossmatch requirements.We analyzed data on all children listed for isolated heart transplantation from 1995 to 2009 in the USA according to prospective crossmatch requirement (PXMR). Primary objectives were to describe the prevalence of PXMR at and during listing and to compare waitlist and post-transplant survival for patients based on PXMR. Patients with a PXMR during listing include those with a PXMR at the time of listing as well as those who were designated by the listing center as needing a prospective crossmatch at some point after being placed onto the waitlist.Among 6,343 listed children, 7.7% had a requirement for a prospective crossmatch at the time of listing and 11.8% had a requirement for a prospective crossmatch during listing. After controlling for risk factors associated with inferior survival, PXMR at listing was associated with increased waitlist mortality (HR 1.32, 95% CI 1.10 to 1.56; p = 0.003). Recipients with a PXMR during listing more commonly had a positive DSXM (22.1% vs 10.3%, p0.0001), as did recipients who carried a PXMR throughout listing (21.7% vs 11.3%, p = 0.004). However, there was no significant difference in post-transplant survival on the basis of a PXMR during listing (HR 1.04, 95% CI 0.87 to 1.25; p = 0.67). Nearly 30% of recipients with a PXMR during listing had a peak pre-transplant PRA ≤ 10%.PXMR increases the likelihood of death while awaiting, but not after, pediatric heart transplantation. Further study is necessary to understand how PXMR is applied, and changes, after listing for pediatric heart transplantation.