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We sought to characterize the shifting epidemiology and resource utilization of Lyme disease and associated carditis in US children’s hospitals. We hypothesized that the Lyme carditis burden has increased and that hospitalizations for Lyme carditis are costlier than those for Lyme disease without carditis. The PHIS database was queried for Lyme disease encounters between January 1, 2007 and December 31, 2013. Additional diagnostic codes consistent with carditis identified Lyme carditis cases. Demographic, clinical, and resource utilization data were analyzed. All costs were adjusted to 2014 US dollars. Lyme disease was identified in 3620 encounters with 189 (5%) associated with carditis. Lyme disease (360 cases in 2007 vs. 672 in 2013, p = 0.01) and Lyme carditis (17 cases in 2007 vs. 40 in 2013, p = 0.03) both significantly increased in frequency. This is primarily accounted for by their increase within the Midwest region. Carditis frequency among cases of Lyme disease was stable (p = 0.15). Encounters for Lyme carditis are dramatically costlier than those for Lyme disease without carditis [median $9104 (3741–19,003) vs. 922 (238–4987), p

Background:Investigations of ventricular dominance and outcomes after the Fontan procedure have shown conflicting results. This may be due to the inclusion of multiple modifications of the Fontan or the omission of recently identified complications of the procedure. We examined the association between right ventricular dominance (RVD) and morbidity/mortality in a contemporary cohort following the extracardiac (EC) Fontan.Methods:We studied all pediatric patients at our center who underwent a predominantly fenestrated EC Fontan from 2004 to 2016. Outcomes assessed were freedom from (1) Fontan failure (death, takedown, listing for transplantation) and (2) complication (arrhythmia requiring medication, postoperative pacemaker, or implantable cardioverter defibrillator requirement, stroke, thrombosis in the Fontan circuit, protein losing enteropathy, plastic bronchitis, New York Heart Association class >2). We defined the perioperative period as occurring before hospital discharge or within 30 days of the Fontan.Results:A total of 137 patients (median age: 34 months, 62% male, 60% RVD) underwent the EC Fontan. Median duration of follow-up was 5.8 years (interquartile range: 2.4-9.0). Freedom from any event was 82.5% (RVD = 77%, LVD = 91%, χ2(1) = 5.03, P = .025) and RVD was associated with reduced event-free survival (hazard ratio: 2.94, P = .02). No confounders were identified. In the perioperative period, RVD was associated with reduced complication-free survival ( P = .004). After this period, RVD was associated with reduced failure-free survival ( P = .003).Conclusions:In this contemporary, single-center cohort of EC Fontan patients, RVD was associated with inferior outcomes.

US Pediatric Heart Allocation Policy was recently revised, deprioritizing candidates with cardiomyopathy while maintaining status 1A eligibility for congenital heart disease (CHD) candidates on "high-dose" inotropes. We compared waitlist characteristics and mortality around this change. Status 1A listings decreased (70% to 56%, P < .001) and CHD representation increased among status 1A listings (48% vs 64%, P < .001). Waitlist mortality overall (subdistribution hazard ratio [SHR] 0.96, P = .63) and among status 1A candidates (SHR 1.16, P = .14) were unchanged. CHD waitlist mortality trended better (SHR 0.82, P = .06) but was unchanged for CHD candidates listed status 1A (SHR 0.92, P = .47). Status 1A listing exceptions increased 2- to 3-fold among hypertrophic and restrictive cardiomyopathy candidates and 13.5-fold among dilated cardiomyopathy (DCM) candidates. Hypertrophic (SHR 6.25, P = .004) and restrictive (SHR 3.87, P = .03) cardiomyopathy candidates without status 1A exception had increased waitlist mortality, but those with DCM did not (SHR 1.26, P = .32). Ventricular assist device (VAD) use increased only among DCM candidates ≥1 years old (26% vs 38%, P < .001). Current allocation policy has increased CHD status 1A representation but has not improved their waitlist mortality. Excessive DCM status 1A listing exceptions and continued status 1A prioritization of children on stable VADs potentially diminish the intended benefits of policy revision.

Purpose Allograft rejection is driven by HLA disparity between donor and recipient despite of the use of various immunosuppression protocols. To better define the risk of allograft failure or complications from overt immunosuppression we applied the epitope-based mismatch approach to quantify the degree of HLA disparity in a in a large multi-center pediatric heart transplant (pHTX) cohort that has been followed for 3-5 years. Methods 274 pHTX recipient/donor pairs were retrospectively HLA genotyped by Next-Generation Sequencing and evaluated for HLA allele (alMM) and eplet mismatch (epMM) loads. HLAMatchmaker version 2.2 was used to determine epMM load at HLA-A/B/C, -DRB1/3/4/5, -DQA1/DQB1 and -DPA1/DPB1. Results Overall, the average total alMM was 13(±2). 76% were ≥5 HLA-A/B/C allele mismatches, 67% were ≥3 HLA-DRB and ≥3 HLA-DQ allele mismatch. The average epMM load was 60 (±17), range 16-112 (Table). 94% of cases had >11 HLA-DR or DQ epMM, a threshold previously shown to be associated with development of HLA donor-specific antibody in renal transplantation. While 159 cases (61.6%) had both DR and DQ epMM >11, only DR epMM or only DQ epMM >11 occurred in 31 (12.0%) and 50 (19.4%) cases, respectively (Figure). Therefore, this cohort can be divided into 3 groups for Class II epMM load: 6% (16) of cases with low, 36% (99) with intermediate and 58% (159) with high load. Conclusion Although this pHTx cohort is highly mismatched, for HLA alleles, there is a large range based on epMM, especially for HLA-DR and -DQ indicating that allele level typing is insufficient for determination of the true degree of mismatching. By correlating these data with clinical parameters, we aim to determine risk stratification based on epMM load in pediatric heart transplantation.

Purpose Reports focused on adult heart transplant (HT) recipients with COVID-19 suggest an increased risk of severe disease. It is unclear if this holds true for pediatric HT patients, given the reported milder course of illness in children in general with COVID-19. We sought to rapidly implement a system for multi-center data collection on pediatric HT recipients and candidates, with the aim of describing the patient population and infection related outcomes. Methods The Pediatric Heart Transplant Society (PHTS) is a multi-center collaboration whose main goal is to improve the outcomes of children who are listed and undergo HT. The society consists of pediatric HT centers in North America (n=53), UK (n=2), and Brazil (n=1). In response to the pandemic, PHTS developed a web-based platform to collect COVID-19 specific data in pediatric HT candidates and recipients. Non-PHTS centers were also invited to submit data. Data fields included pre-and post-HT patient characteristics, presumed vs. documented infection, need for hospitalization (including ICU and ventilator use), treatments administered, and 30-day outcome (death, resolution, sequelae, ongoing treatment). Results Data collection was initiated on 4/30/20. As of 9/28/20, there were 72 patients (7 pre-HT and 65 post-HT, median age 13 years) reported from 27 centers. Of these, 67 were PCR+ by nasal swab and 5 were presumed positive. Complete data with 30-day follow-up was available for 60 patients (7 pre and 53 post HTx). Hospitalization was common and occurred in 71% of the pre-HT and 32% of the post HTx patients. Of the pre-Tx patients, 43% required ICU and 14% were ventilated. In the post HTx group, 13% required ICU and 4% were ventilated. At 30 days a majority of pre-Tx had resolution of symptoms (n=6/7). Among post HTx patients, resolution occurred in 87%% (46/53) with 1 death at 30 days. Conclusion The PHTS remains the most robust source of data on pediatric HT and this effort shows the adaptability of the registry. Although likely limited by reporting bias, these data represent the first known report of characteristics and early outcomes for pediatric HT candidates and recipients with COVID-19. As data collection continues, we aim to better understand the characteristics of patients with more severe disease in order to improve risk characterization and decrease the knowledge gap that currently exists in this unique population.

Primary graft dysfunction following heart transplantation (HTx) is associated with significant morbidity and mortality. This study aimed to assess the incidence of, risk-factors for, and outcomes of children requiring ECMO within 24-hours of HTx. This study utilized a linked PHIS/SRTR database of pediatric HTx recipients (2002–2016). Post-HTx ECMO was identified using inpatient billing data. Logistic regression assessed risk-factors for post-HTx ECMO. Kaplan-Meier analyses assessed in-hospital mortality and post-discharge survival. A total of 2,820 patients were included with 224 (7.9%) requiring ECMO. Independent risk-factors for post-HTx ECMO include age

BACKGROUND: DiGeorge syndrome (DGS) is commonly associated with both congenital heart disease (CHD) and immunologic abnormalities. While CHD may prompt consideration for heart transplantation (HTx), little is known about HTx management or outcomes in this group. The aim of this study was to describe the spectrum of patients with DGS who undergo HTx and report post-HTx outcomes. METHODS: All pediatric HTx recipients (2002–2016) with DGS were identified using ICD codes from a linked billing and clinical registry database. Patient characteristics and outcomes were described and compared to non-DGS HTx recipients with CHD. Kaplan-Meier methods were used to assess overall survival, freedom from infection, and freedom from rejection. RESULTS: A total of 17 patients with DGS who underwent HTx at 12 different centers were included. Median age at HTx was 5yrs (IQR 0–13yrs). Steroids were used for induction in all patients in addition to thymoglobulin in 13/17 (76%) and IL2R antagonists in 3/17 (18%). Maintenance immunosuppression was a combination of tacrolimus or cyclosporine and mycophenolate or azathioprine in 16/17 (94%). Half received steroids at the time of discharge. There were 6 deaths (35%). The median post-HTx survival was 5.4yrs with no difference in freedom from rejection, infection, or overall survival between patients with and without DGS. CONCLUSIONS: Patients with DGS syndrome undergoing HTx receive standard immunosuppression. We found no difference in freedom from infection, rejection, or overall post-HTx survival compared to non-DGS patients, although the small size of our study resulted in limited statistical power. Given the potential for favorable outcomes, patients with DGS may be considered for HTx in the appropriate clinical setting.

Identify pediatric heart transplant (HT) recipients with heterotaxy and other complex arrangements of cardiac situs (heterotaxy/situs anomaly) and compare mortality, morbidities, length of stay (LOS), and costs to recipients with congenital heart disease without heterotaxy/situs anomaly.Using linked registry data (2001-2016), we identified 186 HT recipients with heterotaxy/situs anomaly and 1254 with congenital heart disease without heterotaxy/situs anomaly. We compared post-HT outcomes in univariable and multivariable time-to-event analyses. LOS and cost from HT to discharge were compared using Wilcoxon rank-sum tests. Sensitivity analyses were performed using stricter heterotaxy/situs anomaly group inclusion criteria and through propensity matching.HT recipients with heterotaxy/situs anomaly were older (median age, 5.1 vs 1.6 years; P .001) and more often black, Asian, Hispanic, or "other" nonwhite (54% vs 32%; P .001). Heterotaxy/situs anomaly was independently associated with increased mortality (hazard ratio, 1.58; 95% confidence interval, 1.19-2.09; P = .002), even among 6-month survivors (hazard ratio, 1.86; 95% confidence interval, 1.09-3.16; P = .021). Heterotaxy/situs anomaly recipients more commonly required dialysis (odds ratio, 2.58; 95% confidence interval, 1.51-4.42; P = .001) and cardiac reoperation (odds ratio, 1.91; 95% confidence interval, 1.17-3.11; P = .010) before discharge. They had longer ischemic times (19.2 additional minutes [range, 10.9-27.5 minutes]; P .001), post-HT intensive care unit LOS (16 vs 13 days; P = .012), and hospital LOS (26 vs 23 days; P = .005). Post-HT hospitalization costs were also greater ($447,604 vs $379,357; P = .001).Heterotaxy and other complex arrangements of cardiac situs are associated with increased mortality, postoperative complications, LOS, and costs after HT. Although increased surgical complexity can account for many of these differences, inferior late survival is not well explained and deserves further study.

Purpose Reduction in circulating alloantibodies is a common goal in treating antibody mediated rejection (AMR) and in desensitization of highly sensitized transplant recipients. There are limited data about safety and efficacy of these treatments in children. We report our experience using combined therapy with rituximab, plasmapheresis (PP), and bortezomib to reduce anti-HLA antibodies (Abs) in AMR and desensitization in pediatric heart transplantation (HT). Methods There were 16 treatment courses for desensitization or AMR at our institution from 5/2012-3/2018: 4 for desensitization and 12 for AMR. A typical cycle consists of PP followed by rituximab (375mg/m2) with 4 subsequent PP cycles, each followed by bortezomib (1.3mg/m2), over 21 days. Cycles may be repeated based on response. AlloAb burden was quantified using the OPTN cPRA calculator for Abs ≥4000 MFI to capture clinically relevant Abs. cPRA prior to treatment and at 3 and 12 months after therapy completion were analyzed. Results Median patient age was 12.6 (2.9-20.4) years. All 4 desensitized candidates achieved HT (3 with negative cytotoxicity crossmatch), with median wait time of 166 (68-412) days from therapy initiation. All are alive and free from >pAMR1 at 341.5 (119-904) days from HT. Of the 12 treated for AMR, 10 are alive and 4 had coronary allograft vasculopathy during median follow-up of 948.5 (40-1483) days from AMR diagnosis. Mean class I and II cPRAs were 28.5% and 51.4%, decreasing to 16.4% (p=0.29) and 20.1% (p bacteremia , 2 with peripheral neuropathy , and one with stroke. Conclusion Combined therapy with rituximab, PP, and bortezomib reduced circulating Abs, both in desensitization and treatment of AMR, in our small pediatric HT series. Survival to HT (for desensitization) and after HT (for AMR) also appear reassuring, with some risk of complications. More detailed and regimented multicenter studies are warranted.

Elevated serum soluble (s) suppressor of tumorigenicity-2 is observed during cardiovascular and inflammatory bowel diseases. To ascertain whether modulated ST2 levels signify heart (HTx) or small bowel transplant (SBTx) rejection, we quantified sST2 in serially obtained pediatric HTx (n = 41) and SBTx recipient (n = 18) sera. At times of biopsy-diagnosed HTx rejection (cellular and/or antibody-mediated), serum sST2 was elevated compared to rejection-free time points (1714 ± 329 vs. 546.5 ± 141.6 pg/mL; p = 0.0002). SBTx recipients also displayed increased serum sST2 during incidences of rejection (7536 ± 1561 vs. 2662 ± 543.8 pg/mL; p = 0.0347). Receiver operator characteristic (ROC) analysis showed that serum sST2 > 600 pg/mL could discriminate time points of HTx rejection and nonrejection (area under the curve [AUC] = 0.724 ± 0.053; p = 0.0003). ROC analysis of SBTx measures revealed a similar discriminative capacity (AUC = 0.6921 ± 0.0820; p = 0.0349). Quantitative evaluation of both HTx and SBTx biopsies revealed that rejection significantly increased allograft ST2 expression. Pathway and Network Analysis of biopsy data pinpointed ST2 in the dominant pathway modulated by rejection and predicted tumor necrosis factor-α and IL-1β as upstream activators. In total, our data indicate that alloimmune-associated pro-inflammatory cytokines increase ST2 during rejection. They also demonstrate that routine serum sST2 quantification, potentially combined with other biomarkers, should be investigated further to aid in the noninvasive diagnosis of rejection.

There are limited data available on the bioequivalence of generic and brand-name tacrolimus in pediatric and heart transplant patients. We characterized changes in 12-hour trough concentrations and clinical outcomes after transition from brand to generic tacrolimus in pediatric thoracic organ transplant recipients. Patients with a pharmacy-confirmed date of switch between generic and brand tacrolimus were identified, as well as a matched control group that did not switch for comparison. We identified 18 patients with a confirmed date of switch, and in 12 patients that remained on the same dose, trough concentrations were 14% less than when they were on brand (p = 0.037). The average change was -1.15 ± 1.76 ng/mL (p = 0.045). The control group did not experience a change in trough concentration and was different than the switched group (p = 0.005). There were no differences in dosage changes or kidney or liver function. In the year after switch, 24% of patients who were switched to generic experienced a rejection event vs. 18% in the patients on brand. We suggest a strategy of monitoring around the time of transition, and education of the patient/family to notify the care team when changes from brand to generic or between generics occur.

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Anti-HLA donor-specific antibodies are associated with worse outcomes after organ transplantation. Among sensitized pediatric heart candidates, requirement for negative donor-specific cytotoxicity crossmatch increases wait times and mortality. However, transplantation with positive crossmatch may increase posttransplantation morbidity and mortality. We address this clinical challenge in a prospective, multicenter, observational cohort study of children listed for heart transplantation (Clinical Trials in Organ Transplantation in Children-04 [CTOTC-04]). Outcomes were compared among sensitized recipients who underwent transplantation with positive crossmatch, nonsensitized recipients, and sensitized recipients without positive crossmatch. Positive crossmatch recipients received antibody removal and augmented immunosuppression, while other recipients received standard immunosuppression with corticosteroid avoidance. This first CTOTC-04 report summarizes study rationale and design and relates pretransplantation sensitization status using solid-phase technology. Risk factors for sensitization were explored. Of 317 screened patients, 290 were enrolled and 240 underwent transplantation. Core laboratory evaluation demonstrated that more than half of patients were anti-HLA sensitized. Greater than 80% of sensitized patients had class I (with or without class II) HLA antibodies, and one-third of sensitized patients had at least 1 HLA antibody with median fluorescence intensity of ≥8000. Logistic regression models demonstrated male sex, weight, congenital heart disease history, prior allograft, and ventricular assist device are independent risk factors for sensitization.

OBJECTIVES 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. METHODS 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. RESULTS 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. CONCLUSIONS 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.

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

BACKGROUND: Pediatric mechanical circulatory support (MCS) has evolved considerably over the past decade. Though marked improvements in waitlist survival have been realized, costs have not been reassessed. This project aimed to assess contemporary MCS costs in children bridged to heart transplant (HT). METHODS: All pediatric HT recipients (2002–2016) were identified from a unique, linked PHIS/SRTR dataset. Costs were calculated from hospital charges, inflated to 2016 Dollars and adjusted for patient-specific characteristics using generalized linear mixed-effects models. Costs and length of stay (LOS) were compared across support strategies at the time of HT (no MCS, VAD, or ECMO) with select subgroup analyses. RESULTS: A total of 2873 pediatric HT recipients were included; no MCS: 2268 (78.9%), VAD: 470 (16.4%), and ECMO: 135 (4.7%). Both VAD and ECMO were associated with greater total hospitalization costs compared to no MCS ($755,345 and $808,771 vs. $457,086; p

Recent Organ Procurement and Transplantation Network bylaw revisions mandate that US transplant programs have an "approved pediatric component" in order to perform heart transplantation (HT) in patients18 years old. The impact of this change on adolescents, a group known to be at high risk for graft loss and nonadherence, is unknown. We studied all US primary pediatric (age18 years) HT from 2000 to 2015 to compare graft survival between centers organized mainly for adult versus pediatric care. Centers were designated as pediatric- or adult-specialty care according to the ratio of pediatric:adult HT performed and minimum age of HT (pediatric-specialty defined as ratio0.7; adult-specialty ratio0.05 and minimum age8 years). In propensity score-matched cohorts, we observed no difference in graft loss by center type (median survival: adult 12.4 years vs pediatric 9.2 years, P = .174). Compared to the matched pediatric cohort, adult-specialty center recipients lived closer to their transplant center (31 vs 45 miles, P = .012), and trended toward fewer out-of-state transplants (15 vs 25%, P = .082). Our data suggest that select adolescents can achieve similar midterm graft survival at centers organized primarily for adult HT care. Regardless of post-HT setting, the development of care models that demonstrably improve adherence may be of greatest benefit to improving survival of this high-risk population.

There is growing acceptance of transplantation across a positive crossmatch for highly allosensitized pediatric HT candidates. While survival may be similar to patients transplanted across a negative crossmatch, costs are unknown. Among 60 HT recipients at our center from 5/07 to 6/12, we analyzed hospital charges and length of stay from the day of HT to discharge and through the first year after transplant. Median age at HT was 6.2 years (15 days-20.5 years). Charges in the first year post-HT were greater for crossmatch-positive patients ($907 678 vs $549 754; P = .017), with a trend toward higher charges for the HT hospitalization ($537 640 vs $407 374; P = .07). Plasmapheresis was more common in crossmatch-positive patients during the HT hospitalization (80% vs 4%, P < .001). In the first year after HT, crossmatch-positive patients had a greater number of endomyocardial biopsies (10 vs 7.5, P = .03) and episodes of treated rejection (2 vs 0, P = .004). Pediatric HT across a positive crossmatch is associated with higher first-year costs, including increased use of plasmapheresis and care around an increased number of rejections. These novel data will help inform decision and policymaking regarding care practices for the growing population of highly sensitized pediatric HT candidates.

Destination ventricular assist device therapy (DT-VAD) is well accepted in select adults with medically refractory heart failure (HF) who are not transplant candidates; however, its use in younger patients with progressive diseases is unclear. We sought to evaluate the cost-effectiveness of DT-VAD in Duchenne muscular dystrophy (DMD) patients with advanced HF. We created a Markov-state transition model (5-year horizon) to compare survival, costs, and quality of life (QOL) between medical management and DT-VAD in DMD with advanced HF. Model input parameters were derived from the literature. We used sensitivity analyses to explore uncertainty around model assumptions. DT-VAD had higher costs ($435,602 vs. $125,696), survival (3.13 vs. 0.60 years), and quality-adjusted survival (1.99 vs. 0.26 years) than medical management. The incremental cost-effectiveness ratio (ICER) for DT-VAD was $179,086 per quality-adjusted life year (QALY). In sensitivity analyses that were widely varied to account for uncertainty in model assumptions, the DT-VAD strategy generally remained more costly and effective than medical management. Only when VAD implantation costs were

BACKGROUND: Turner syndrome (TS) patients with hypoplastic left heart syndrome (HLHS) have poor single ventricle palliation outcomes; therefore, consideration of other potential management strategies is important. Little is known about heart transplantation (HTx) in this group, as standard HTx databases do not allow for identification of TS. This study describes experiences and outcomes of HTx in TS using a unique linkage between the Scientific Registry of Transplant Recipients (SRTR) and the Pediatric Health Information System (PHIS) databases. METHODS: All pediatric HTx recipients (2002–2016) with TS were identified in the database using ICD-9 code 758.6 (gonadal dysgenesis) in conjunction with female sex. Patient characteristics and outcomes were described. RESULTS: Fourteen patients with TS were identified who underwent 16 HTx procedures at 8 centers. For initial HTx, HLHS was the most common indication (10/14) with a median age of 10 months (IQR 3–73 months). Median transplant-free survival following initial HTx was 4.1 years (IQR: 16 days–10.5 years), with all deaths occurring in the first year post-HTx. For patients that survived past 1 year (8/14), follow-up ranged from 4.1 to 10.9 years (median 8.0 years) with no deaths observed. CONCLUSIONS: Our cohort demonstrates that while there is a clear risk for early mortality, there is the potential for favorable outcomes following HTx in patients with TS. Therefore, TS should not be viewed as an absolute contraindication to HTx, but careful assessment of candidate risk is needed. Primary palliation with HTx for HLHS and TS may be a reasonable consideration given the poor outcomes of single ventricle palliation in this group. Further research is needed to fully delineate the outcomes and characteristics of this unique population.

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

For many neuromuscular diseases (NMDs), cardiac disease represents a major cause of morbidity and mortality. The management of cardiac disease in NMDs is made challenging by the broad clinical heterogeneity that exists among many NMDs and by limited knowledge about disease-specific cardiovascular pathogenesis and course-modifying interventions. The overlay of compromise in peripheral muscle function and other organ systems, such as the lungs, also makes the simple application of endorsed adult or pediatric heart failure guidelines to the NMD population problematic. In this statement, we provide background on several NMDs in which there is cardiac involvement, highlighting unique features of NMD-associated myocardial disease that require clinicians to tailor their approach to prevention and treatment of heart failure. Undoubtedly, further investigations are required to best inform future guidelines on NMD-specific cardiovascular health risks, treatments, and outcomes.

Background Histopathologic features of late graft dysfunction (LGD) in endomyocardial biopsies (EMBs) after pediatric heart transplantation (HT) have been incompletely described and rarely quantified. We employed automated, morphometric analysis of whole-slide EMB images to objectively quantify fibrosis and microvasculopathy after pediatric HT. Methods Nine recipients with clinical LGD were matched with controls on age, listing diagnosis, crossmatch and time since HT. Fibrosis was quantified as percent tissue area with fibrosis and capillary density as capillaries per unit area, number of capillary “neighbors” within 30 μm of each myocyte and myocyte-to-nearest-capillary diffusion distance. Clinical data, including all EMB reports, were also reviewed. Results The groups were well matched for age at HT (median 4.0 vs 3.1 years), listing diagnosis (50% congenital heart disease for each), positive crossmatch (11% each) and days post-HT (2,628 vs 2,894, p = 0.69). Despite a similar number of previous EMBs (median 23 each, p = 0.43), areas occupied by fibrosis were greater in LGD cases (44.5% vs 23.2%, p = 0.012). Capillary number/area data were not statistically different between LGD cases and controls (378/mm 2 vs 559/mm 2 , p = 0.57), but LGD cases more commonly had zero capillary neighbors (35% vs 20%, p = 0.02) and greater myocyte-to-nearest-capillary distances (27.1 μm vs 18.7 μm, p = 0.005). Cumulative rejection history correlated with fibrosis ( r = 0.49, p = 0.039) and myocyte-to-nearest-capillary distance ( r = 0.5, p = 0.036). Conclusions LGD after pediatric HT is associated with previous rejection and characterized histologically by fibrosis and microvasculopathy, which are not readily appreciated by traditional semi-quantitative EMB analysis. Software-assisted EMB analysis may enable greater pathophysiologic understanding of LGD and identification of targets for future study and intervention.

Fibrosis is commonly described in heart allografts lost late after transplantation. CMR-derived ECV is a validated measure of DMF in native adult hearts that may predict heart failure and mortality. We explored associations of ECV with histologic myocardial fibrosis and clinical features after pediatric heart transplantation. Twenty-five recipients (7.0±6.3 years at transplant and 10.7±6.5 years post-transplant) were prospectively recruited for CMR and BNP measurement at the time of surveillance biopsy. All had normal ejection fractions and lacked heart failure symptoms. Fibrosis was quantified on biopsy after picrosirius red staining as CVF. ECV was quantified using contemporaneous hematocrit on basal and mid-short-axis slices. ECV was moderately correlated with CVF (r=.47; P=.019). We found no associations of ECV with hemodynamics, ischemic time, time since transplantation, or number of prior biopsies or acute rejections. Compared to healthy non-transplant controls, there was no significant difference in ECV (25.1±3.0 vs 23.7±2.0%, P=.09). Log-transformed BNP was correlated with ECV (recipients: r=.46, P=.02; recipients and controls: r=.45, P=.006). These findings suggest ECV quantifies DMF and relates to biological indicators of cardiac function after pediatric heart transplantation.

Objective We sought to assess the relationship between serious infections and fever, white blood cell count (WBC), and C-reactive protein (CRP) levels in children on ventricular assist device (VAD). Methods We retrospectively reviewed all children who underwent VAD placement from 2006 to 2014 at Children's Hospital of Pittsburgh. Daily maximum temperature, maximum WBC, CRP levels, microbiologic data and antibiotic use were abstracted from the electronic health record. Serious infection was defined as bacteremia, mediastinitis and/or driveline infection. Results Thirty-six consecutive patients underwent VAD placement with mean age of 7.1 years ±6.3 years (range 9 days −18.1 years). The median duration of VAD support was 24 days (1–102 days). Patients were on antibiotics for 58% of total VAD days. We found no drive line infections or mediastinitis and only 5 episodes of blood stream infections in 4 patients (11%) during 1167 total days. Fever was present on 23% of total VAD days and nearly all (35/36) patients had at least one day of fever. CRP was elevated in 298 of 318 (94%) of all samples tested. 53% (448/851) of the total WBC assessments were elevated. On detailed analysis of confirmed bloodstream infection, only 2 of the 5 episodes were associated with fever within 24 h of the positive culture. WBC and CRP levels (drawn within 24 h of positive culture) were normal in 2/5 (40%). Conclusions Despite a low prevalence of serious infection in our pediatric VAD cohort, we found that fever, elevated WBC and CRP were common. This suggests that traditional markers of infection are unreliable. Fever, elevated WBC count and elevated CRP were poorly predictive of serious bacterial infection in our pediatric VAD cohort. Their presence alone should not be an indication for long-term antibiotics.

To compare the outcomes and comorbidities of children with mitochondrial disease undergoing heart transplantation with children without mitochondrial disease.Using a unique linkage between the Pediatric Health Information System and Scientific Registry of Transplant Recipients databases, pediatric heart transplantation recipients from 2002 to 2016 with a diagnosis of cardiomyopathy were included. Post heart transplantation survival and morbidities were compared between patients with and without mitochondrial disease.A total of 1330 patients were included, including 47 (3.5%) with mitochondrial disease. Survival after heart transplantation was similar between patients with and without mitochondrial disease over a median follow-up of 4 years. Patients with mitochondrial disease were more likely to have a stroke after heart transplantation (11% vs 3%; P = .009), require a longer duration of mechanical ventilation after heart transplantation (3 days vs 1 day; P .001), and have a longer intensive care unit stay after heart transplantation (10 vs 6 days; P = .007). The absence of a hospital readmission within the first post-transplant year was similar among patients with and without mitochondrial disease (61.7% vs 51%; P = .14). However, patients with mitochondrial disease who were readmitted demonstrated a longer length of stay compared with those without (median, 14 days vs 8 days; P = .03).Patients with mitochondrial disease can successfully undergo heart transplantation with survival comparable with patients without mitochondrial disease. Patients with mitochondrial disease have greater risk for post-heart transplantation morbidities including stroke, prolonged mechanical ventilation, and longer intensive care unit and readmission length of stay. These results suggest that the presence of mitochondrial disease should not be an absolute contraindication to heart transplantation in the appropriate clinical setting.

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.

Purpose Recent reports indicate that >50% of pediatric heart transplant (HT) candidates are HLA-sensitized at time of HT. Clinicians have a difficult choice: wait for an ideal organ offer without HLA antibody (Ab) or take the first acceptable offer. Desensitization can be useful to facilitate HT by decreasing or abrogating HLA Ab. We have evolved to use desensitization to evaluate which HLA Ab may be safely crossed and which to avoid. To illustrate our approach, we present: a non-responder, a partial-responder, and a total-responder. Methods HLA Ab analysis was done by Luminex® single antigen bead assay (SAB), with serial dilutions and C1q-fixing assay. Ab ≥2000 MFI by IgG-SAB and ≥500 MFI by C1q-SAB were used to determine the calculated PRA (cPRA). One desensitization cycle consisted of rituximab (x1), bortezomib (BTZ) (x4), and plasmapheresis (x5). Cycles are repeated leaving 2 weeks between last and first doses of each cycle. Results Non-responder (Fig 1A): Bw4/Aw4 sensitized patient did not respond to desensitization. Ab reassessment showed rebound, and after the 3rdcycle the titer increased and Ab was C1q+. The patient received HT with a Bw6/Bw6 donor without Aw4 antigens; no donor specific Ab (DSA) is detected 1 year post-HT. Partial-responder (Fig 1B): selective response for 1 HLA Ab group. Both anti-DR53 and DQ7/DQ8/DQ9 Abs were C1q+. However, DQ7/DQ8/DQ9 Ab had lower baseline titer. After 2 cycles, DR53 Ab did not change while DQ7/DQ8/DQ9 Ab was reduced in titer and became C1q-. HT proceeded with a DQ7+ donor and DSA remains negative 2.5 years post-HT. Total responder (Fig 1C): Ab to all but self HLA. A complete response was seen; by the end of 3rdcycle, most Ab was reduced to low titer and C1q-. HT was done crossing 2 C1q- Abs. No DSA detected 118 days post-HT. Conclusion Multi-dimensional testing of HLA Ab titer and C1q binding and serial monitoring pre- and post-desensitization helps to determine if more treatment is needed and allows for safe HT risk assessment when crossing HLA Abs.

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 Primary graft dysfunction following heart transplantation (HT) is associated with significant morbidity and mortality. The aim of this study was to assess the incidence, risk factors, and outcomes of pediatric patients requiring extracorporeal membrane oxygenation (ECMO) support post-HT. Methods This study utilized an existing data linkage between the PHIS and SRTR databases from which pediatric HT recipients were identified (2002-2016). Post-HT ECMO support was identified by billing codes within one day of HT. Logistic regression was performed to assess risk factors for ECMO post-HT. Kaplan-Meier analyses assessed in-hospital mortality and post-discharge survival. Results A total of 2,820 patients were included with 224 (7.9%) requiring ECMO post-HT. Risk factors independently associated with the need for ECMO included age Conclusion There are identifiable risk factors associated with the need for ECMO in the post-HT period. Length of time on ECMO post-HT is strongly associated with the risk of in-hospital mortality. While patients who require ECMO post-HT demonstrate worse overall survival, those who survive to discharge have comparable outcomes to patients who did not require ECMO.

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

As methods for human leukocyte antigens (HLA) antibody detection have evolved and newer solid phase assays are much more sensitive, the last 15 years has seen a renewed focus on the importance of HLA antibodies in solid organ transplant rejection. However, there is still much controversy regarding the clinical significance of antibody level as depicted by the mean fluorescence intensity of a patient’s neat serum. Emerging techniques, including those that identify antibody level and function, show promise for the detection of individuals at risk of allograft rejection, determination of the effectiveness of desensitization prior to transplant, and for monitoring treatment of rejection. Here, we review current publications regarding the relevance of donor-specific HLA antibodies (DSA) in adult and pediatric heart transplantation (HT) with graft survival, development of antibody-mediated rejection and cardiac allograft vasculopathy (CAV). The negative impact of DSA on patient and allograft survival is evident in adult and pediatric HT recipients. Many questions remain regarding the most appropriate frequency of assessment of pre- and posttransplant DSA as well as the phenotype of DSA memory vs. true de novo antibody using large multicenter adult and pediatric cohorts and state-of-the-art methodologies for DSA detection and characterization.

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.

Background C4d assessment of endomyocardial biopsies (EMBs) after heart transplantation (HTx) has been widely adopted to aid in the diagnosis of antibody-mediated rejection (AMR), yet it remains unclear whether or not to assess all patients routinely and with what frequency/duration. In this study we sought to evaluate the utility of routine C4d immunostaining in the first year after pediatric and young adult HTx. Methods We reviewed pre-transplant alloantibody and clinical data, including serial EMB reports, on all 51 patients who received HTx at our center since we instituted routine C4d staining of all first-year EMBs. C4d was considered positive if diffuse capillary staining (≥2 + ) was present. Rare/focal capillary staining or absence of staining was considered negative. Results Twenty-six of 406 first-year EMBs (6%) were C4d + in 6 (12%) patients. Sixty-five percent of all C4d + EMBs occurred by 30 days post-transplant. Five of 6 patients had pre-transplant donor-specific antibody (DSA)≥4,000 MFI. The sixth patient had neither pre-transplant anti-HLA antibodies nor a positive donor-specific cytotoxicity crossmatch (DSXM), but there was clinical concern for AMR. Among the entire cohort, 5 of 10 patients with pre-transplant DSA≥4,000 MFI and/or a positive DSXM were C4d + compared with only 1 of 41 without (50% vs 2%; p = 0.001). Conclusions In the first year after HTx, C4d + occurred early and only in children and young adults with pre-transplant DSA or with clinical suspicion of AMR. Although our data suggest that assessment limited to the first 90 days post-transplant in patients with pre-transplant DSA≥4,000 MFI may be appropriate in the absence of clinical concern for AMR, further research is needed to determine the optimum strategy for post-transplant surveillance.

Renal dysfunction is a major determinant of outcome after HTx. Using a large, multi-institutional database, we sought to identify factors associated with late renal dysfunction after pediatric HTx. All patients in the PHTS database with eGFR ≥60 mL/min/1.73 m(2) at one yr post-HTx (n = 812) were analyzed by Cox regression for association with risk factors for eGFR 1 yr after HTx. Freedom from late renal dysfunction was 71% and 57% at five and 10 yr. Multivariate risk factors for late renal dysfunction were earlier era of HTx (HR 1.84; p < 0.001), black race (HR 1.42; p = 0.048), rejection with hemodynamic compromise in the first year after HTx (HR 1.74; p = 0.038), and lowest quartile eGFR at one yr post-HTx (HR 1.83; p < 0.001). Renal function at HTx was not associated with onset of late renal dysfunction. Eleven patients (1.4%) required chronic dialysis and/or renal transplant during median follow-up of 4.1 yr (1.5-12.6). Late renal dysfunction is common after pediatric HTx, with blacks at increased risk. Decreased eGFR at one yr post-HTx, but not at HTx, predicts onset of late renal dysfunction. Future research on strategies to minimize late renal dysfunction after pediatric HTx may be of greatest benefit if focused on these subgroups.

The 2005 ISHLT rejection grading system merged grades 1A, 1B and 2 into a single grade (1R), assuming equivalent prognostic significance. We hypothesized that recurrent 1B acute cellular rejection (ACR) is associated with adverse outcomes. Data on all heart transplant recipients at our center from 1990–2007 were reviewed. Patients were excluded if they had more than one grade ≥3A/2R biopsy in the first 6 weeks or any grade ≥3A/2R biopsies during the first year thereafter. Patients with ≥2 grade 1B biopsies from 6 weeks-1 year were classified as “recurrent 1B.” Outcomes were freedom from late (>1 year) ACR (grade ≥3A/2R), coronary artery disease (CAD), re-transplantation/death, and a composite end-point. Sixty-two patients (53 non-recurrent 1B, 9 recurrent 1B) met inclusion criteria. In univariate analyses, recurrent 1B status was associated with decreased freedom from late ACR (p

Implantable cardioverter-defibrillators (ICDs) improve survival and are cost-effective in adults with poor left ventricular function. Because of differences in heart failure etiology, sudden death rates, and ICD complication rates, these findings may not be applicable to children.We developed a Markov model to compare typical management of childhood dilated cardiomyopathy with symptomatic heart failure to prophylactic ICD implantation plus typical management. Model costs included costs of outpatient care, medications, complications, and transplantation. Time horizon was up to 20 years from model entry. Total costs were $433,000 (ICD strategy) and $355,000 (typical management). Although quality adjusted survival was greater in the ICD group (6.78 versus 6.43 quality adjusted life-years [QALY]), the incremental cost-utility ratio was $281,622/QALY saved with the ICD strategy. In sensitivity analyses, the ICD strategy cost less than the $100,000/QALY benchmark for cost-effectiveness only when the annual probability of sudden death exceeded 13% or when strong, sustained benefits in quality of life from the ICD were assumed.Prophylactic ICD use in children with dilated cardiomyopathy, poor ventricular function, and symptomatic heart failure does not appear to be cost-effective. This is likely due to lower sudden death rates in this population.

Late-onset paroxysmal AVB has been described as a rare complication after HT and has been associated with AR or CAV. We describe 4 pediatric HT recipients who developed paroxysmal AVB hours after routine cardiac catheterization in the absence of AR, CAV, or underlying conduction system disease. Four pediatric HT recipients who were >1 year post-transplant had episodes of paroxysmal AVB hours after surveillance cardiac catheterization with EMB. Telemetry demonstrated high-grade block, ranging from 2:1 AVB to complete AVB without ventricular escape for several seconds. None of the patients had significant AR or rapidly progressive CAV. Supplemental testing did not reveal underlying conduction system disease. Three of the 4 patients received permanent pacemakers, although subsequent interrogations showed minimal ventricular pacing. These pediatric HT recipients had paroxysmal AVB hours after cardiac catheterization in the absence of significant AR, CAV, or underlying conduction system disease. Subsequent pacemaker interrogations showed minimal ventricular pacing, suggesting these were isolated episodes. These cases suggest that mechanisms in addition to AR and CAV may cause paroxysmal AVB in pediatric HT recipients, warranting further investigation.

Dilated (DCM), restrictive (RCM), and hypertrophic (HCM) cardiomyopathies (CM) in children have varying clinical courses and therapeutic options. Heart transplantation (HTx) offers a chance for long-term survival; but outcomes after listing have not been well defined.A multi-institutional registry of 3,147 patients listed for HTx (January 1993-December 2006) was used to compare outcomes of 1,320 children with CM (42%) and 1,827 with non-CM (58%) etiologies. Comparisons were made between sub-groups: 1,098 DCM (83%), 145 RCM (11%), and 77 HCM (6%).CM patients had a waitlist mortality of 17% vs 32% for non-CM patients (p0.0001), with no difference between the CM sub-groups. Risk factors were younger age, black race (relative risk [RR], 1.65; p = 0.009), mechanical ventilation (RR, 3.17; p0.001), and extracorporeal membrane oxygenation (RR, 2.16; p0.001). Ten-year survival after listing was 66% for CM vs 53% for non-CM (p0.0001). HCM and RCM patients aged1 year at the time of listing had the highest waitlist mortality and the lowest overall survival. CM patients had a better 10-year survival after HTx (68% vs 61%, p0.0001). Risk factors for death early after HTx included mechanical ventilation at HTx (RR, 3.07; p0.001), longer ischemic time (RR, 1.27; p = 0.01), and earlier era (RR, 1.77; p = 0.002). Late risk factors included black race (RR, 3.01; p0.001), HCM or RCM (RR, 1.93; p = 0.007), and older age (RR, 1.9; p0.001).Children with CM have a lower waitlist mortality and better survival post-HTx than children with a non-CM diagnosis. DCM patients have the best and HCM or RCM patients aged younger than 1 year have the worst overall outcomes.

Background The contribution of ABO blood group mismatching on the rate of cardiac homograft failure is uncertain. It has been shown that there is lack of expression of A and B blood group antigens on fresh and cryopreserved homograft valves. However, expression of these antigens on the homograft vessel conduit has not been reported. Methods Unused portions of cryopreserved pulmonary artery homografts (n = 16) were immunohistochemically stained and examined for expression of endothelial cell marker CD31 and A and B blood group antigens. The staining pattern for each antigen was described. Comparison of homograft donor blood group (as determined by immunostaining) to the blood group reported by the homograft supplier was made. Results Staining of CD31 and A and B blood group antigens was poor on the luminal surface (tunica intima) of the homograft conduit but strong in the vaso vasorum of the tunica media and adventitia. Homograft donor blood group was consistent with the reported donor blood group in 15 of 16 specimens (4 group A, 3 group B, 8 group O). In one specimen (reported as group O), we detected strong expression of CD31 and A antigen on the endothelium of the vaso vasorum. Conclusions Cryopreserved homografts strongly express A and B blood group antigens on well-preserved endothelial surfaces of the medial and adventitial vaso vasorum. The significance of this finding with regard to the immunologic response to mismatched ABO blood group antigens and homograft longevity is uncertain.

Immunoperoxidase techniques for demonstration of complement split product C4d on paraffin-embedded endomyocardial biopsy samples have been used for the evaluation of humoral rejection mainly in adult heart transplantation. Interpretation of suspected humoral rejection in children requires knowledge of the pattern and frequency of C4d deposition in nonpresensitized pediatric heart transplantation patients. Paraffin-embedded endomyocardial biopsy samples of 65 patients with no rejection, acute cellular rejection (ACR), or early ischemic/reperfusion injury were studied. Six biopsies within each grade of ACR both early (6 months) after heart transplantation were reviewed, as were 5 biopsies of ischemic/reperfusion injury. None of the subjects was sensitized prior to transplant. All slides were blindly evaluated for histologic features traditionally associated with humoral rejection. C4d staining was quantified by counting the number of positive capillaries in 10 random high-power fields (hpf). C4d positivity (C4d+) was defined as >10 capillaries/10 hpf. C4d+ was observed in 6 (9%) endomyocardial biopsy samples; 2 in the early and 4 in the late ACR groups. Four had ACR grades 1A/B, and 2 had grade 3B/4. Thirteen (20%) endomyocardial biopsy samples had histologic features suggestive of humoral rejection. Of these, only 2 were C4d+ and both had ACR grade 3B/4. No C4d+ staining was found in the ischemic/reperfusion injury group. C4d immunostaining was negative in endomyocardial biopsy samples of the majority of our patients (91%). Endomyocardial biopsy samples with C4d+ did not show consistent ACR grade or time specificity. Contrary to previously reported data, none of the ischemic/reperfusion injury endomyocardial biopsy samples was C4d+, and histologic features alone were poor predictors of C4d+.

Increased use of serial EBV-PCR monitoring after pediatric transplantation has led to the identification of asymptomatic patients who carry very high viral loads over prolonged periods. The significance of this high-load state is unknown. We speculated that this state may identify patients at high risk for development of late PTLD/lymphoma. We reviewed data on 71 pediatric heart recipients who had serial viral load monitoring since 1997. Chronic high-load state was defined as the presence of >16,000 genome copies/mL whole blood on > or =50% of samples over at least 6 months. Among 20 high-load carriers (eight following prior PTLD, seven with prior symptomatic EBV infection, five without previous EBV disease), 9 (45%) developed late-onset PTLD 2.5-8.4 years posttransplant (including with four Burkitt's lymphoma). Among 51 controls with low (n = 39) or absent (n = 12) loads, only 2 (4%; p < 0.001 absent/low vs. high load) developed late PTLD/lymphoma. By multivariable analysis, high-load carrier state (OR = 12.4, 95% CI 2.1-74.4) and prior history of PTLD (OR = 10.7, 95% CI 1.9-60.6) independently predicted late PTLD. A chronic high EBV-load state is not benign and is a predictor of de novo or recurrent PTLD.

Background Little is known about the effect of pre-transplant alloantibody in the pediatric cardiac transplant population. Methods All cardiac listings ( n = 298) at Children's Hospital of Pittsburgh from January 1990 through February 2006 were reviewed to determine the impact of allosensitization on transplantation outcomes. Analysis focused on: (1) wait list outcomes; (2) survival from the time of listing, regardless of subsequent transplantation; (3) post-transplant graft and patient survival; and (4) post-transplant freedom from graft vasculopathy. Institutional policy required a negative, prospective crossmatch for candidates with panel-reactive antibody >20%. Results Alloantibody data were available for 252 (85%) listings. Median time to transplantation was greater for sensitized vs non-sensitized subjects (2.7 months vs 1.3 months; p = 0.02). At 1 year after listing, sensitized subjects had a higher incidence of death (22% vs 8.4%; p = 0.055). Survival at all time-points after listing (regardless of transplantation) was worse for sensitized subjects ( p = 0.04). Although no statistically significant differences in post-transplant graft or patient survival were noted, pre-transplant allosensitization was associated with decreased freedom from graft vasculopathy (hazard ratio [HR] 2.76, 95% confidence interval [CI] 1.18 to 6.45; p = 0.019). Conclusions A policy requiring a negative, prospective crossmatch for highly sensitized candidates is associated with longer wait list time and higher mortality after listing. The development of graft vasculopathy appears to be influenced by the presence of pre-transplant alloantibody.

Nesiritide (B-type natriuretic peptide) is one of the newest therapies available in the treatment of adults with decompensated congestive heart failure (CHF). It rapidly improves hemodynamics and induces diuresis in adult patients with moderate to severe CHF. This report details our experience with nesiritide in 4 pediatric cases in 3 subjects with chronic CHF of various causes. As described in adults, our patients generally diuresed and had symptomatic improvement in response to the infusion with only dose-related hypotension and asymptomatic hyponatremia as recognized side effects. Given the number of pediatric patients who progress to CHF as a result of myocarditis, cardiomyopathy, or failed palliation for complex congenital heart disease, we believe nesiritide has a role in managing acutely decompensated CHF in the pediatric population.