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Background Endomyocardial biopsy (EMB) is costly and discomforting yet remains a key component of surveillance after pediatric heart transplantation (HT). Donor-derived cell-free DNA (dd-cfDNA) has been histologically validated with high negative predictive value, offering an alternative to surveillance EMB (sEMB). Methods We implemented an alternative surveillance protocol using commercially available dd-cfDNA assays in place of sEMB after pediatric HT. Recipients ≧7 months post-HT with reassuring clinical assessment were referred for dd-cfDNA. When not elevated above the manufacturers' threshold, sEMB was deferred. Subsequent clinical status and results of follow-up EMB were analyzed. Results Over 17 months, 58 recipients [34% female, median age at HT 3.1 years (IQR 0.6-10.6)] had dd-cfDNA assessed per protocol. Median age was 14.8 years (8.4-18.3) and time from HT 6.0 years (2.2-11.2). Forty-seven (81%) had non-elevated dd-cfDNA and 11 (19%) were elevated. During a median of 8.7 months (4.2-15), all are alive without allograft loss/new dysfunction. Among those with non-elevated dd-cfDNA, 24 (51%) had subsequent sEMB at 12.1 months (6.9-12.9) with 23 showing no acute rejection (AR): grade 0R/pAMR0 (n = 16); 1R(1A)/pAMR0 (n = 7). One had AR (grade 2R(3A)/pAMR0) on follow-up sEMB after decreased immunosuppression following a diagnosis of PTLD. All 11 with elevated dd-cfDNA had reflex EMB at 19 days (12-32) with AR in 4: grade 1R(1B-2)/pAMR0 (n = 3); 1R(1B)/pAMR2 (n = 1). Conclusions dd-cfDNA assessment in place of selected, per-protocol EMB decreased surveillance EMB by 81% in our pediatric HT recipient cohort with no short-term adverse outcomes. Individual center approach to surveillance EMB will influence the utility of these findings.

Background Our pediatric heart transplant center transitioned from post-bypass basiliximab (BAS) induction to either anti-thymocyte globulin (ATG) or pre-bypass BAS. The purpose of this study was to compare first-year rejection rates before and after this change. Methods A single center retrospective analysis was conducted of pediatric heart transplant recipients from 2010-2019. Primary outcome was first-year rejection. Bivariate analysis, Kaplan-Meier curves, and multivariable regression were performed across eras. Results Forty-three early era patients (55%) received post-bypass BAS, and 35 late era patients (45%) received pre-bypass BAS (n=17) or ATG (n=18). First-year rejection decreased in the late era (31% vs 53%, p = 0.05). This finding was more pronounced after excluding infants (38% vs 73%, p = 0.006). Late era was associated with a decreased likelihood of rejection (all cohort OR 0.19, 95%CI 0.05-0.66; infants excluded OR 0.17, 95%CI 0.04-0.61). No differences in post-transplant lymphoproliferative disease, donor specific antibody, or infection were observed. Conclusions Fewer late era patients receiving ATG or pre-bypass BAS induction had first-year rejection compared to the early era patients receiving standard post-bypass BAS induction. This programmatic shift in induction strategy was readily achievable and potentially effective in reducing first-year rejection.

A 16-year-old with new-onset dilated cardiomyopathy underwent VAD placement, later complicated by low flow from outflow graft kinking. To expedite heart transplantation, TCV was calculated and compared with 141 normal patients pinpointing the upper weight threshold. He was transplanted 2 days later within the expanded weight range with no post-transplant complications.

BACKGROUND There is limited information about HRQL after pediatric heart transplantation at a young age. METHODS Prospective follow-up study of children who received a heart transplant at age ≤4 years. HRQL was assessed using the PedsQLTM 4.0 at age 4.5 years. This cohort was compared with healthy children, children with CHD, and with chronic conditions. Peri-operative factors associated with HRQL were also explored. RESULTS Of 66 eligible patients, 15 (23%) died prior to the HRQL assessment and 2 (3%) were lost to follow-up, leaving 49 patients. Indication for transplantation was CHD in 27 (55%) and CMP in 22 (45%). Median age (IQR) at transplant was 9 (5-31) months. HRQL was significantly lower in transplanted children compared to population norms (65.3 vs 87.3, P

Hypertension is a known complication of pediatric heart transplantation. We sought to identify factors associated with anti-hypertensive use in pediatric heart transplant recipients immediately post-transplant and oral anti-hypertensive use at discharge and 1-year post-transplant. Retrospective chart review was conducted of patients ≤18 years who underwent heart transplantation at two major heart transplant centers between August 1, 2009 and December 31, 2017 with ≥1-year follow-up. Exclusion criteria included re-transplant, multi-organ recipients, survival

TDI is considered superior to conventional echocardiography for detecting changes in graft function during rejection in adults but has not demonstrated after pediatric OHT. We retrospectively analyzed echocardiograms performed within 24 hours of biopsy in 122 recipients with median age of 8.7 years. Using biopsy findings as the gold standard, we compared paired rejection and non-rejection echocardiograms using each patient as their own control. We included pairs of LV dimensions, FS, volumes, mass, mass/volume, sphericity, wall stress, SSI, SVI, and TDI velocities in this comparison. C-statistic was used to assess discrimination for individual echo variables and combinations of variables. Overall, 647 non-rejection and 24 rejection biopsy-echo pairs were identified. There was a significant decline in TDI velocities and their Z-scores during rejection but not in conventional variables (P ≤ .005). The variable that best discriminated rejection from non-rejection was LV S', with C-statistic = 0.93. Conventional echo variables performed less well with C-statistic range 0.65-0.67 for LV EF, shortening fraction, and mass. TDI is superior to conventional echocardiography measures for discriminating rejection from non-rejection. The use of newer non-invasive parameters to detect myocardial dysfunction and shifting the paradigm of rejection surveillance to detection of non-rejection together provide a promising approach to reducing the need for biopsy in pediatric heart recipients.

Vasoactive inotrope score (VIS) is scarcely studied in pediatric orthotopic heart transplantation (pOHT). We conducted a retrospective review of pOHT (21 years) recipients. Max VIS and mean VIS were calculated at 0-24 and 24-48 hours post-pOHT. Patients were divided into groups based on ISHLT guidelines: high (10) and low (≤10). In our group (n = 104), patients with high max and mean VIS groups at 0-24 and 24-48 hours had longer bypass times (high:130 minutes; low:108 minutes; P .05) and high max and mean VIS groups at 0-24 hours had longer ischemic times (high:215 minutes; low:192 minutes; P .05). Patients with high max and mean VIS at 0-24 and 24-48 hours had longer hospital stay, ventilation, inotrope duration, more cardiac events, and acute kidney injury postoperatively (P .05). High max VIS at 24-48 hours and high mean VIS at 24-48 hours had higher 3-year mortality (P = .04; P = .02). Multivariate analysis confirmed the association of VIS with short-term outcomes. However, VIS was not identified as an independent predictor of mortality. The ROC curve exhibits 10 as the ideal cutoff with area under the curve0.8 for primary graft dysfunction (PGD).

Pediatric heart transplant patients face the highest waitlist mortality in solid organ transplantation. Given the relatively fixed number of donor organs becoming available each year, improving donor organ utilization could potentially have significant impact on reducing waitlist mortality. Donor to recipient weight ratio has historically been used to identify suitable donors; however, this method does not take into account the potential for significant variance in heart size due to complex congenital heart disease or underlying cardiomyopathy. We believe, based on our experience to date, that donor matching based upon weight ratios should be augmented by improved methodologies that provide a more accurate assessment of heart volumes. Herein we describe the rationale for these methodologies and our single-center experience using volumetrics as an alternative for donor fit assessments.

We aimed to review current literature on the discard rate of donor hearts offered to pediatric recipients and assess geographical differences. Consequences and ways to reduce the discard rate are discussed. A systemic review on published literature on pediatric transplantation published in English since 2010 was undertaken. Additionally, a survey was sent to international OPOs with the goal of incorporating responses from around the world providing a more global picture. Based on the literature review and survey, there is a remarkably wide range of discard and/or refusal for pediatric hearts offered for transplant, ranging between 18% and 57% with great geographic variation. The data suggest that that the overall refusal rate may have decreased over the last decade. Reasons for organ discard were difficult to identify from the available data. Although the refusal rate of pediatric donor hearts seems to be lower compared to that reported in adults, it is still as high as 57% with geographic variation.

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. Data from the Clinical Trials in Organ Transplantation for Children (CTOTC-04) multi-institutional collaborative study were utilized to determine incidence of, and risk factors for, hospital readmission within 30 days and 1 year from initial hospital discharge. 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 two or more readmissions. The 30-day and 1-year freedom from readmission were 70.5% (CI: 64.1%, 76.0%) and 42.2% (CI: 35.7%, 48.7%), respectively. 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. Factors independently associated with increased risk of first readmission within 1 year (Cox proportional hazard model) were as follows: 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). 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 factors are associated with higher risk of readmission. A fuller understanding of these risk factors may help tailor strategies to reduce unnecessary hospital readmission.

Height matching in pediatric HTx has been proposed as a superior method of evaluating graft size, but no studies have examined survival advantage for height-matched donor-recipient pairs. We hypothesized that in pediatric patients with DCM, an oversized donor improves survival and aimed to define the optimal height ratio in this patient group. Pediatric primary HTx recipients with DCM between 10/89 and 09/12 were identified in the OPTN database. Patients were stratified into three donor-recipient height and weight ratio categories. One- and five-yr survival was compared using Kaplan-Meier analysis and HRs were computed. A total of 2133 children with DCM who underwent HTx during the study period were included. Unadjusted one-yr survival was worse for DRHR

Background Listed pediatric heart transplant patients have the highest solid-organ waitlist mortality rate. The donor-recipient body weight (DRBW) ratio is the clinical standard for allograft size matching but may unnecessarily limit a patient's donor pool. To overcome DRBW ratio limitations, two methods of performing virtual heart transplant fit assessments were developed that account for patient-specific nuances. Method 1 uses an allograft total cardiac volume (TCV) prediction model informed by patient data wherein a matched allograft 3-D reconstruction is selected from a virtual library for assessment. Method 2 uses donor images for a direct virtual transplant assessment. Methods Assessments were performed in medical image reconstruction software. The allograft model was developed using allometric/isometric scaling assumptions and cross-validation. Results The final predictive model included gender, height, and weight. The 25th-, 50th-, and 75th-percentiles for TCV percentage errors were -13% (over-prediction), -1%, and 8% (under-prediction), respectively. Two examples illustrating the potential of virtual assessments are presented. Conclusion Transplant centers can apply these methods to perform their virtual assessments using existing technology. These techniques have potential to improve organ allocation. With additional experience and refinement, virtual transplants may become standard of care for determining suitability of donor organ size for an identified recipient.

DSA after HTx may have adverse effects on patient survival. The aim of this study was to assess risk factors for the development of DSA after pediatric HTx. All HTx recipients at our center with serial monitoring of DSA were identified. Cox proportional hazards model was used to estimate donor and recipient characteristics associated with the development of DSA. De novo DSA were detected in 40 (33%) of 121 HTx recipients. Characteristics associated with de novo DSA included older age, African American race, prior operations, prior ECMO, PRA > 10%, longer bypass time, mechanical support at transplant, and donor death from GSW. In a multivariable model, mechanical support (HR 3.23, 95% CI [1.02, 8.87]), African American race (HR 3.36, 95% CI [1.68, 7.32]), and donor death from GSW (HR 4.76, 95% CI [1.62, 14.01]) were significantly associated with DSA. Multiple factors appear to play a role in the development of DSA, knowledge of which may guide the frequency of post-transplant monitoring. DSA develop more frequently in those with prior sensitizing events, suggesting the possibility that these exposures predispose the immune system to respond to donor antigens, even in the presence of a negative cross-match.

Many children who undergo heart transplantation will survive into adulthood. We sought to examine the QOL and capacity for achievement in long-term adult survivors of pediatric heart transplantation. Adults >18 yr of age who received transplants as children (≤18 yr old) and had survived for at least 10 yr post-transplant completed two self-report questionnaires: (i) Ferrans & Powers QLI, in which life satisfaction is reported as an overall score and in four subscale domains and is then indexed from 0 (very dissatisfied) to 1 (very satisfied); and (ii) a “Metrics of Life Achievement” questionnaire regarding income, education, relationships, housing status, and access to health care. A total of 20 subjects completed the survey. The overall mean QLI score was 0.77 ± 0.16. Subjects were most satisfied in the family domain (0.84 ± 0.21) and least satisfied in the psychological/spiritual domain (0.7 ± 0.28). Satisfaction in the domains of health/functioning and socioeconomic were intermediate at 0.78 and 0.76, respectively. Most respondents had graduated from high school, reported a median annual income >$50 000/yr, and lived independently. Adult survivors of pediatric heart transplant report a good QOL and demonstrate the ability to obtain an education, work, and live independently.

Post-transplant lymphoproliferative disorder (PTLD) is a significant complication after pediatric heart transplantation (HT), occurring in 5%-15% of patients within 3 years. Data >3 years from HT are limited. We sought to describe the prevalence, risk factors, and outcomes of PTLD occurring late (>3 years) 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 20 years 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 5 years, 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.

Background Permanent pacemaker (PPM) placement in adults following orthotopic heart transplantation (OHT) has been well documented. However, studies concerning the need for PPM implantation in pediatric heart transplant recipients are less common. Methods Institutional transplant and pacing databases as well as patient medical records were reviewed for all pediatric patients undergoing OHT (n = 314; all with bicaval connection) at our institution between January 2000 and March 2018. Results A total of 16 patients (5.1%) were implanted with a pacemaker after transplantation. Donor age was the only significant risk factor for post-transplant PPM implantation, with a median age of 28.5 years (7.0-49.0) in the pacing group vs 15.5 years (0.4-56.0) in the non-pacing group (P = 0.009). Indication for pacemaker insertion was more often complete heart block (CHB) (12/16, 75%) than sinus node dysfunction (SND) (4/16, 25%). There was no significant difference in mortality between recipients who received a PPM and those who did not (log-rank test; P = 0.345). Conclusions Increasing donor age is associated with increased PPM placement following pediatric heart transplantation. Interestingly, a high proportion of CHB patients recovered sinus rhythm, and long-term outcomes for paced patients are similar to other heart transplant recipients.

As heart transplantation demand is increasing without subsequent growth of the donor pool, need for expansion of acceptance criteria is paramount, particularly when considering critically ill, highly sensitized patients. We present a case report of a pediatric heart transplant recipient of an organ refused by 197 prior potential recipients due to the donor being infected with influenza virus. We perform a literature review of recent solid organ transplant cases from influenza-positive donors and conclude that the donor pool may be expandable by allowing donors with treatable infections to be included.

EMB, the gold standard for diagnosis of ACR, poses unique risks in children. Limited cross-sectional data have associated LV MPI with ACR. We hypothesize that a relative change in MPI from baseline without ACR to the time of ACR will better detect ACR than an absolute threshold LV MPI value. We identified 40 children with ACR ≥60 days post-transplant matching them by age and time from transplantation to 40 children without ACR. There was a significant increase in LV MPI at time of ACR vs. baseline (0.59 ± 0.17 vs. 0.41 ± 0.11; p

Stendahl G, Bobay K, Berger S, Zangwill S. Organizational structure and processes in pediatric heart transplantation: A survey of practices. Abstract: Despite emerging literature on pediatric heart transplantation, there continues to be variation in current practices. The degree of variability among heart transplant programs has not been previously characterized. The purpose of this study was to evaluate organizational structure and practices of pediatric heart transplant programs. The UNOS database was queried to identify institutions according to volume. Coordinators from 50 institutions were invited to participate with a 70% response rate. Centers were grouped by volume into four categories. Some institutional practices were dominated by clear volume trends. Ninety-five percent of larger centers routinely transplant patients with known antibody sensitization and report a broader range and acuity of recipients. Ninety-four percent report problems with non-adherence. Sixty-nine percent of centers routinely require prospective crossmatches. There was dramatic variation in the use of steroids across all centers. Sixty-five percent of centers transition adolescents to an adult program. Prophylaxis protocols were also highly inconsistent. This survey provided a comprehensive insight into current practices at pediatric heart transplant programs. The results delineated remarkably variable strategies for routine aspects of care. Analysis of divergence along with uniformity across protocols is a valuable exercise and may serve as a stepping-stone toward ongoing cooperation and clarity for evidence-based practice protocols.

Summary The evolving demographics, outcomes, and anesthetic management of pediatric heart transplant recipients are reviewed. As survival continues to improve, an increasing number of these patients will present to our operating rooms and sedation suites. It is therefore important that all anesthesiologists, not only those specialized in cardiac anesthesia, have a basic understanding of the physiologic changes in the transplanted heart and the anesthetic implications thereof.

Despite a limited supply of donors, potential donor hearts are often declined for subjective concerns regarding organ quality. This analysis will investigate the relationship between donor heart AR and patient outcome at pediatric transplant centers. The UNOS database was used to identify all match runs for pediatric candidates (age 18 years) from 2008 through March 2015 in which a heart offer was ultimately placed. Centers which received ≥10 offers/y were included (10 634 offers, 38 centers). Transplant centers were stratified based on their AR: low (20%, n = 13), medium (20%-40%, n = 16), or high (40%, n = 9). Low AR centers experienced worse negative WL outcome compared with medium (P = .022) and high (P = .004) AR centers. Low AR centers had similar post-transplant graft survival to medium (P = .311) or high (P = .393) AR centers; however, medium AR centers had better post-transplant graft survival than high AR centers (P = .037). E-F survival from listing regardless of transplant was worse for low AR centers compared with medium (P .001) or high (P = .001) AR centers. Low AR centers experience worse WL outcomes without improvement in post-transplant outcomes. High AR centers experience higher post-transplant graft failure than medium AR centers. AR of 20%-40% appears to have optimal WL and post-transplant outcomes.

Data are lacking on routine surveillance biopsy (RSB) intensity and outcomes after pediatric heart transplantation. Pediatric Heart Transplant Study (PHTS) centers received a survey on RSB practices from 2005 to present. PHTS data were obtained for 2010–2013 and integrated with center-matched survey responses for analysis. Survey response rate was 82.6% (38/46). Centers were classified as low, moderate, and high intensity programs based on RSB frequency (0 - more than 8 RSB/yr). RSB intensity decreased with increasing time from HT. Age at HT impacted RSB intensity mostly in year 1, with little to no impact in later years. Most centers have not replaced RSB with non-invasive methods, but many added ECHO and biomarker monitoring. Higher RSB intensity was not associated with decreased 4-year mortality (p= 0.63) or earlier detection of moderate to severe (ISHLT grade 2R/3R) cellular rejection (RSB-MSR) in the first year (p=0.87). First year RSB-MSR incidence did not differ with intensity or age at HT. Significant variability exists in RSB intensity, but with no impact on timing and incidence of RSB-MSR or 4-year mortality. Reduction in RSB frequency may be safe in certain patients after pediatric HT.

The broad range of topics relevant to pediatric heart transplantation makes it difficult to follow the published literature consistently. Moreover, as the field of pediatric heart transplantation overlaps with mechanical support and heart failure the realm of journals of relevance continues to expand. This review will provide succinct summaries of the recent medical literature in the field of pediatric transplantation. In this review, we summarize important articles in the field of pediatric heart transplantation that have been published over the last two yr (2006 and 2007).

To discuss the indications for and outcomes of cardiac retransplantation in childhood. The major challenge of pediatric heart transplantation is graft failure. The major causes of graft failure include coronary allograft vasculopathy and chronic rejection. Retransplantation may be considered in children or young adults who develop graft failure following pediatric heart transplantation. Retransplantation now accounts for 7% of all pediatric transplants. Recent studies have demonstrated that cardiac retransplantation has a poorer outcome than primary heart transplantation. However, the interval from primary transplant to retransplantation appears to impact significantly the success of retransplantation. When children undergo retransplantation for early graft failure, the survival is quite poor and the appropriateness of this strategy is questionable. However, children who undergo retransplantation many years after primary transplantation have outcomes that are similar to primary transplantation. The decision to pursue retransplantation depends on the severity of graft failure and recent data suggest that identification of mild graft dysfunction or coronary allograft vasculopathy does not imply impending graft failure. Novel therapies to extend the life of the primary graft and to stratify those at risk of severe graft dysfunction will improve the allocation of scarce organs for pediatric patients who might be candidates for cardiac retransplantation. Retransplantation can extend the lives of children who develop graft failure after primary transplantation. However, not all patients who develop graft dysfunction should necessarily be listed for retransplantation.

This is the third review in a series whose purpose is to provide succinct summaries and informative commentaries of the recent medical literature pertinent to pediatric heart transplantation and directed toward the practicing clinician. It is meant to be comprehensive but not all-inclusive. Important articles published during 2005 and 2006 are summarized.

This is the second review in a series aimed at providing succinct summaries of the recent medical literature pertinent to pediatric heart transplantation and aimed at the practicing clinician. It is meant to be comprehensive but not all inclusive. Important articles published over 2004 and 2005 are summarized.

We aimed to determine whether malignancy after pediatric HTx for ACM affects overall post-HTx survival. Patients