Evaluation and Management of Chronic Heart Failure in Children and Adolescents With Congenital Heart Disease: A Scientific Statement From the American Heart Association.

With continued medical and surgical advancements, most children and adolescents with congenital heart disease are expected to survive to adulthood. Chronic heart failure is increasingly being recognized as a major contributor to ongoing morbidity and mortality in this population as it ages, and treatment strategies to prevent and treat heart failure in the pediatric population are needed. In addition to primary myocardial dysfunction, anatomical and pathophysiological abnormalities specific to various congenital heart disease lesions contribute to the development of heart failure and affect potential strategies commonly used to treat adult patients with heart failure. This scientific statement highlights the significant knowledge gaps in understanding the epidemiology, pathophysiology, staging, and outcomes of chronic heart failure in children and adolescents with congenital heart disease not amenable to catheter-based or surgical interventions. Efforts to harmonize the definitions, staging, follow-up, and approach to heart failure in children with congenital heart disease are critical to enable the conduct of rigorous scientific studies to advance our understanding of the actual burden of heart failure in this population and to allow the development of evidence-based heart failure therapies that can improve outcomes for this high-risk cohort.

Review on clinician bias and its impact on racial and socioeconomic disparities in pediatric heart transplantation.

This expert review seeks to highlight implicit bias in health care, transplant medicine, and pediatric heart transplantation to focus attention on the role these biases may play in the racial/ethnic and socioeconomic disparities noted in pediatric heart transplantation. This review breaks down the transplant decision making process to highlight points at which implicit bias may affect outcomes and discuss how the science of human decision making may help understand these complex processes.

Three decades of collaboration through the Pediatric Heart Transplant Society Registry: A journey through registry data with a highlight on children with single ventricle anatomy.

BACKGROUND: The Pediatric Heart Transplant Society (PHTS) Registry was founded 30 years ago as a collaborative effort among like-minded providers of this novel life-saving technique for children with end-stage heart failure. In the intervening decades, the data from the Registry have provided invaluable knowledge to the field of pediatric heart transplantation. This report of the PHTS Registry provides a comprehensive look at the data, highlighting both the longevity of the registry and one unique aspect of the PHTS registry, allowing for exploration into children with single ventricle anatomy. METHODS: The PHTS database was queried from January 1, 1993 to December 31, 2019 to include pediatric (age < 18 years) patients listed for HT. For our analysis, we primarily analyzed patients by era. The early era was defined as children listed for HT from January 1, 1993 to December 31, 2004; middle era January 1, 2005 to December 31, 2009; and recent era January 1, 2010 to December 31, 2019. Outcomes after listing and transplant, including mortality and morbidities, are presented as unadjusted for risk, but compared across eras. RESULTS: Since 1993, 11 995 children were listed for heart transplant and entered into the PHTS Registry with 9755 listed during the study period. The majority of listings occurred within the most recent era. Waitlist survival improved over the decades as did posttransplant survival. Other notable changes over time include fewer patients experiencing allograft rejection or infection after transplant. Waitlist and posttransplant survival have changed dramatically in patients with single ventricle physiology and significantly differ by stage of single ventricle palliation. SUMMARY: Key points from this PHTS Registry summary and focus on patients with single ventricle congenital heart disease in particular, include the changing landscape of candidates and recipients awaiting heart transplant. There is clear improvement in waitlist and transplant outcomes for children with both cardiomyopathy and congenital heart disease alike.

Diagnostic and management roles of FDG PET/CT imaging in post-transplant lympho-proliferation in pediatric heart transplantation.

BACKGROUND: Post-transplant lymphoproliferative disorder (PTLD) is a serious complication of pediatric heart transplant (PHTx). 18F-FDG PET/CT has been used to differentiate early lympho-proliferation from more advanced PTLD. We report our experience with PET/CT in the management of PTLD following PHTx. METHODS: This was a retrospective study of 100 consecutive PHTx recipients at our institution between 2004 and 2018. Patients who underwent PET/CT or conventional CT scans to evaluate for PTLD or high Epstein-Barr viral load were included. RESULTS: Males, eight females. Median age at transplant was 3.5 months (IQR = 1.5-27.5). Median age at PTLD diagnosis was 13.3 years (IQR = 9.2-16.1). Median time between transplant and PTLD diagnosis was 9.5 (IQR = 4.5-15) years. Induction agents were used in 12 patients (50%): Thymoglobulin (N = 9), anti-IL2 (N = 2), and Rituximab (N = 1). Eighteen patients (75%) had PET/CT, of whom 14 had 18FDG-avid PTLD. Six had conventional CT. Nineteen patients (79.2%) had diagnostic biopsy confirmation of PTLD, and 5 (20.8%) had excisional biopsies. Two patients had Hodgkin's lymphoma; nine had monomorphic PTLD; eight had polymorphic PTLD; five were classified as other. Nine patients had monomorphic PTLD, including seven with diffuse large cell lymphoma (DLBC) and one with T cell lymphoma. The majority (16/24) had multi-site involvement at PTLD diagnosis, and PET/CT showed that 31.3% (5/16) had easily accessible subcutaneous nodes. Seventeen patients (overall survival 71%) underwent successful treatment without recurrence of PTLD. Of seven deaths (7/24, 29%), five had DLBC lymphoma, one had polymorphic PTLD and one had T-cell lymphoma. CONCLUSION: PET-CT allowed simultaneous anatomical and functional assessment of PTLD lesions, while guiding biopsy. In patients with multiple lesions, PET/CT revealed the most prominent and active lesions, improving diagnostic accuracy.

Basiliximab therapy for immune-mediated bowel disease in a pediatric heart transplant patient.

In pediatric patients who undergo heart transplantation, severe immune-mediated bowel disease has been reported. Management is complex, and there are little data discussing the use of basiliximab for immune-mediated bowel disease. This case report discusses a pediatric patient who developed immune-mediated bowel disease following heart transplantation and was successfully managed with basiliximab.

Risk factors for 1-year allograft loss in pediatric heart transplant patients using machine learning: An analysis of the pediatric heart transplant society database.

BACKGROUND: Pediatric heart transplant patients are at greatest risk of allograft loss in the first year. We assessed whether machine learning could improve 1-year risk assessment using the Pediatric Heart Transplant Society database. METHODS: Patients transplanted from 2010 to 2019 were included. The primary outcome was 1-year graft loss free survival. We developed a prediction model using cross-validation, by comparing Cox regression, gradient boosting, and random forests. The modeling strategy with the best discrimination and calibration was applied to fit a final prediction model. We used Shapley additive explanation (SHAP) values to perform variable selection and to estimate effect sizes and importance of individual variables when interpreting the final prediction model. RESULTS: Cumulative incidence of graft loss or mortality was 7.6%. Random forests had favorable discrimination and calibration compared to Cox proportional hazards with a C-statistic (95% confidence interval [CI]) of 0.74 (0.72, 0.76) versus 0.71 (0.69, 0.73), and closer alignment between predicted and observed risk. SHAP values computed using the final prediction model indicated that the diagnosis of congenital heart disease (CHD) increased 1 year predicted risk of graft loss by 1.7 (i.e., from 7.6% to 9.3%), need for mechanical circulatory support increased predicted risk by 2, and single ventricle CHD increased predicted risk by 1.9. These three predictors, respectively, were also estimated to be the most important among the 15 predictors in the final model. CONCLUSIONS: Risk prediction models used to facilitate patient selection for pediatric heart transplant can be improved without loss of interpretability using machine learning.

Expanded utilization of rituximab in paediatric cardiac transplant patients.

WHAT IS KNOWN AND OBJECTIVE: Epstein-Barr virus (EBV) viraemia and autoimmune cytopenias (AICs) are significant complications that occur following paediatric solid organ transplantation. A variety of treatment methods have been investigated but limited research has focused on the utilization of rituximab in paediatric cardiac transplant recipients for these indications. Rituximab is a monoclonal antibody that binds the CD20 antigen on the surface of B-type lymphocytes resulting in B-cell cytotoxicity. It is considered a second-line therapy for treatment of autoimmune cytopenias and EBV viraemia following adult solid organ transplant (SOT) and haematopoietic stem cell transplant (HSCT). However, data for its use in the paediatric population for treatment of autoimmune cytopenias are lacking. Dosing is based on adult studies, and the frequency and length of therapy associated with resolution of EVB viraemia and AICs in paediatric cardiac transplant recipients is unknown. The objective of this retrospective study was to describe the dosing and length of therapy of expanded off-label use of rituximab for the management of refractory EBV viraemia and AICs, specifically in paediatric cardiac transplant patients. METHODS: A retrospective chart review was conducted evaluating children <18 years of age who underwent cardiac transplantation, were diagnosed with EBV viraemia or autoimmune cytopenia, and subsequently received treatment with rituximab between June 1995 and October 2018. Data were analysed descriptively. RESULTS AND DISCUSSION: Of all (n = 188) paediatric cardiac transplant recipients since 1995, 10 patients met the inclusion/exclusion criteria. Primary diagnoses were EBV viraemia (n = 6), immune haemolytic anaemia (n = 3) and immune thrombocytopenic purpura (n = 1). Complete responses were observed in 83.3% and 100% of patients with EVB viraemia and AICs treated with rituximab, respectively. All patients (n = 10) received rituximab 325 mg/m2 at weekly intervals. The number of total doses associated with complete resolution was 4-6 doses for EBV viraemia and 2-4 doses for AICs. The most common adverse events reported were neutropenia (n = 3), thrombocytopenia (n = 4), infusion reactions (n = 1) and significant anaemia (n = 2). WHAT IS NEW AND CONCLUSION: Although the efficacy of rituximab for treatment of EBV viraemia and autoimmune cytopenia in the paediatric cardiac transplant population remains unclear, our study supported the benefit of rituximab when added to therapy for treatment of EBV viraemia and ACIs.

Cardiomyopathy in Children: Classification and Diagnosis: A Scientific Statement From the American Heart Association.

In this scientific statement from the American Heart Association, experts in the field of cardiomyopathy (heart muscle disease) in children address 2 issues: the most current understanding of the causes of cardiomyopathy in children and the optimal approaches to diagnosis cardiomyopathy in children. Cardiomyopathies result in some of the worst pediatric cardiology outcomes; nearly 40% of children who present with symptomatic cardiomyopathy undergo a heart transplantation or die within the first 2 years after diagnosis. The percentage of children with cardiomyopathy who underwent a heart transplantation has not declined over the past 10 years, and cardiomyopathy remains the leading cause of transplantation for children >1 year of age. Studies from the National Heart, Lung, and Blood Institute-funded Pediatric Cardiomyopathy Registry have shown that causes are established in very few children with cardiomyopathy, yet genetic causes are likely to be present in most. The incidence of pediatric cardiomyopathy is ≈1 per 100 000 children. This is comparable to the incidence of such childhood cancers as lymphoma, Wilms tumor, and neuroblastoma. However, the published research and scientific conferences focused on pediatric cardiomyopathy are sparcer than for those cancers. The aim of the statement is to focus on the diagnosis and classification of cardiomyopathy. We anticipate that this report will help shape the future research priorities in this set of diseases to achieve earlier diagnosis, improved clinical outcomes, and better quality of life for these children and their families.

Resource utilization of cytomegalovirus immune globulin in prevention and treatment of cytomegalovirus infection in pediatric heart transplantation.

BACKGROUND: There is debate whether cytomegalovirus immunoglobulin (CMV-Ig) is also needed for CMV prevention in heart transplant recipients in the era of good anti-viral drugs. METHODS: We conducted a cost-savings quality initiative on CMV-Ig eventually leading to discontinuation of routine use of CMV-Ig for CMV prevention. Subsequently, a retrospective cohort study was conducted, comparing patients in cohort I (CMV-Ig plus anti-viral drugs, 2013-2015) to cohort II (anti-virals alone, 2015-2017). The medication acquisition costs and outcomes of CMV infection were assessed. RESULTS: There were 39 total patients: 22/39(56%) in cohort I, with mean follow-up of 35.14 ± 17.38 months and 17/39(44%) in cohort II, mean follow-up of 19.12 ± 7.08 months. In cohort I, 5/22(22.7%) patients died from causes unrelated to CMV and 0/17 in cohort II died. There were 5/22(22.7%) patients in cohort I, and 2/17(9%) patients in cohort II that developed CMV infection (P = .508). Freedom from rejection was 81.8% (18/22) in cohort I, and 71% (12/17) in cohort II (P = .46), and 100% for allograft vasculopathy. There was significant reduction in medication acquisition cost following the protocol change of $260 839 or $15 343 per patient. CONCLUSION: Our study demonstrated an acquisition cost savings with similar clinical outcomes utilizing anti-viral CMV prophylaxis alone vs anti-viral prophylaxis plus CMV-Ig.

Case report and review of the literature: the utilisation of a ventricular assist device as bridge to recovery for anthracycline-induced ventricular dysfunction.

Ventricular assist devices are used in children with heart failure as a bridge to myocardial recovery or cardiac transplantation. Anthracyclines cause cardiac toxicity and may result in acute or long-term cardiac failure. We describe the use of a ventricular assist device as a bridge to recovery in a child with severe acute anthracycline-induced cardiomyopathy, and we review the associated literature. A 6-year-old girl was treated for acute myeloblastic leukaemia with daunorubicin and mitoxantrone. After 2 weeks her final dose of chemotherapy, her Left Ventricular Ejection Fraction decreased to 21%. Despite initiation of medical therapy, she had continued deterioration of left ventricular function and developed evidence of poor end-organ perfusion. She was not a candidate for cardiac transplantation, as the post-transplant immune suppression therapy would put her at risk for recurrence of her malignancy. We placed her on a short-term ventricular assist device as a bridge to ultimately placing her on a long-term ventricular assist device versus continuing medical therapy. Her left ventricular ejection fraction improved to 55% 24 days after ventricular assist device insertion. She was separated from the ventricular assist device 26 days after its insertion. She was discharged home 29 days later and is now 28 months after ventricular assist device implantation with stable ventricular function, as documented by a left ventricular ejection fraction of 55%, and normal end organ function. This case is one of the only reports known describing successful use of a short-term ventricular assist device as a bridge to recovery in a child with severe acute anthracycline-induced cardiotoxicity.

Eighteen years of paediatric extracorporeal membrane oxygenation and ventricular assist devices: insight regarding late outcomes.

BACKGROUND: We reviewed all patients who were supported with extracorporeal membrane oxygenation and/or ventricular assist device at our institution in order to describe diagnostic characteristics and assess mortality. METHODS: A retrospective cohort study was performed including all patients supported with extracorporeal membrane oxygenation and/or ventricular assist device from our first case (8 October, 1998) through 25 July, 2016. The primary outcome of interest was mortality, which was modelled by the Kaplan-Meier method. RESULTS: A total of 223 patients underwent 241 extracorporeal membrane oxygenation runs. Median support time was 4.0 days, ranging from 0.04 to 55.8 days, with a mean of 6.4±7.0 days. Mean (±SD) age at initiation was 727.4 days (±146.9 days). Indications for extracorporeal membrane oxygenation were stratified by primary indication: cardiac extracorporeal membrane oxygenation (n=175; 72.6%) or respiratory extracorporeal membrane oxygenation (n=66; 27.4%). The most frequent diagnosis for cardiac extracorporeal membrane oxygenation patients was hypoplastic left heart syndrome or hypoplastic left heart syndrome-related malformation (n=55 patients with HLHS who underwent 64 extracorporeal membrane oxygenation runs). For respiratory extracorporeal membrane oxygenation, the most frequent diagnosis was congenital diaphragmatic hernia (n=22). A total of 24 patients underwent 26 ventricular assist device runs. Median support time was 7 days, ranging from 0 to 75 days, with a mean of 15.3±18.8 days. Mean age at initiation of ventricular assist device was 2530.8±660.2 days (6.93±1.81 years). Cardiomyopathy/myocarditis was the most frequent indication for ventricular assist device placement (n=14; 53.8%). Survival to discharge was 42.2% for extracorporeal membrane oxygenation patients and 54.2% for ventricular assist device patients. Kaplan-Meier 1-year survival was as follows: all patients, 41.0%; extracorporeal membrane oxygenation patients, 41.0%; and ventricular assist device patients, 43.2%. Kaplan-Meier 5-year survival was as follows: all patients, 39.7%; extracorporeal membrane oxygenation patients, 39.7%; and ventricular assist device patients, 43.2%. CONCLUSIONS: This single-institutional 18-year review documents the differential probability of survival for various sub-groups of patients who require support with extracorporeal membrane oxygenation or ventricular assist device. The indication for mechanical circulatory support, underlying diagnosis, age, and setting in which cannulation occurs may affect survival after extracorporeal membrane oxygenation and ventricular assist device. The Kaplan-Meier analyses in this study demonstrate that patients who survive to hospital discharge have an excellent chance of longer-term survival.

Conversion from calcineurin inhibitors to mTOR inhibitors as primary immunosuppressive drugs in pediatric heart transplantation.

There are only a few reports of successful use of mammalian target of rapamycin (mTORI) as primary immunosuppression in pediatric heart transplantation. Compared to calcineurin inhibitors, mTORI have less side effects, especially nephrotoxicity, infections, and malignancies. A retrospective study was conducted at our institution of all 170 heart transplants from 1995 to 2015. Nineteen patients were switched from tacrolimus (n=15) or cyclosporin (n=4) to everolimus (n=4) or sirolimus (n=15) due to nephrotoxicity (n=5), malignancy (n=8), EBV viremia/reactive plasmacytic changes (n=5), and immune hemolytic anemia (n=1). We monitored for rejection, infection, BUN, creatinine, hyperlipidemia, EBV and CMV copies, CBC, cardiac allograft vasculopathy (CAV), and death. Target trough levels of sirolimus and everolimus were 4-10. Four treatment failures included debilitating rash, bone marrow suppression, recurrent rejection, and renal transplantation. There were no deaths. One patient had recurrent rejection episodes, and tacrolimus was reinitiated. One patient with preexisting CAV underwent heart retransplantation. One patient, who was treated for PTLD, transformed to CD30+ Hodgkins disease, and was treated with brentuximab. There were three acute rejection episodes. Median creatinine preswitch was higher 0.82 than postswitch 0.78 (P=.016). Median eGFR was lower preswitch, 75.6, than postswitch, 91.2 (P=.0004). These results indicate that conversion to mTORI as primary immunosuppression may be safely accomplished in some pediatric heart transplant patients.

Big Data and paediatric cardiovascular disease in the era of transparency in healthcare.

The objectives of this review were to discuss the potential impact of Big Data analytics in paediatric cardiovascular disease and its potential to address the challenges of transparency in delivery of care to this unique population.

Trametinib-induced Left Ventricular Dysfunction in a Child With Relapsed Neuroblastoma.

The MEK inhibitor trametinib is globally approved for metastatic melanoma harboring BRAF mutations. There are no reports thus far on its use in children. Exome sequencing on a relapsed tumor sample from an 11-year-old male with progressive, multiply relapsed stage 4 neuroblastoma revealed NRASQ61K mutation. After demonstration of normal cardiac function, he was started on oral trametinib. On day 13 of treatment, echocardiogram showed moderate left ventricular dysfunction. Trametinib was discontinued on day 15 and oral lisinopril was started. Left ventricular function recovered to baseline 37 days after discontinuing trametinib. However, neuroblastoma showed further progression.

Summary of the 2015 International Paediatric Heart Failure Summit of Johns Hopkins All Children's Heart Institute.

In the United States alone, ∼14,000 children are hospitalised annually with acute heart failure. The science and art of caring for these patients continues to evolve. The International Pediatric Heart Failure Summit of Johns Hopkins All Children's Heart Institute was held on February 4 and 5, 2015. The 2015 International Pediatric Heart Failure Summit of Johns Hopkins All Children's Heart Institute was funded through the Andrews/Daicoff Cardiovascular Program Endowment, a philanthropic collaboration between All Children's Hospital and the Morsani College of Medicine at the University of South Florida (USF). Sponsored by All Children's Hospital Andrews/Daicoff Cardiovascular Program, the International Pediatric Heart Failure Summit assembled leaders in clinical and scientific disciplines related to paediatric heart failure and created a multi-disciplinary "think-tank". The purpose of this manuscript is to summarise the lessons from the 2015 International Pediatric Heart Failure Summit of Johns Hopkins All Children's Heart Institute, to describe the "state of the art" of the treatment of paediatric cardiac failure, and to discuss future directions for research in the domain of paediatric cardiac failure.

Using machine learning to predict five-year transplant-free survival among infants with hypoplastic left heart syndrome.

Hypoplastic left heart syndrome (HLHS) is a congenital malformation commonly treated with palliative surgery and is associated with significant morbidity and mortality. Risk stratification models have often relied upon traditional survival analyses or outcomes data failing to extend beyond infancy. Individualized prediction of transplant-free survival (TFS) employing machine learning (ML) based analyses of outcomes beyond infancy may provide further valuable insight for families and healthcare providers along the course of a staged palliation. Data from both the Pediatric Heart Network (PHN) Single Ventricle Reconstruction (SVR) trial and Extension study (SVR II), which extended cohort follow up for five years was used to develop ML-driven models predicting TFS. Models incrementally incorporated features corresponding to successive phases of care, from pre-Stage 1 palliation (S1P) through the stage 2 palliation (S2P) hospitalization. Models trained with features from Pre-S1P, S1P operation, and S1P hospitalization all demonstrated time-dependent area under the curves (td-AUC) beyond 0.70 through 5 years following S1P, with a model incorporating features through S1P hospitalization demonstrating particularly robust performance (td-AUC 0.838 (95% CI 0.836-0.840)). Machine learning may offer a clinically useful alternative means of providing individualized survival probability predictions, years following the staged surgical palliation of hypoplastic left heart syndrome.

Lymphatic Leakage in Pediatric Heart Transplantation: Early Recognition and Timely Management with Interventional Radiologic and Endoscopic Therapy.

Protein-losing enteropathy (PLE) is a severe complication of the Fontan procedure that leads to systemic complications owing to enteric protein loss. Hepatoduodenal lymphatic leakage resulting from increased lymphatic pressure is one such complication. We present the case of a pediatric heart transplant patient who experienced refractory PLE symptoms requiring serial albumin infusions and exhibited lymphatic leakage into the duodenum. Using diagnostic lymphangiography and endoscopy, we identified the affected area and treated it successfully with endoscopic sclerotherapy using ethanolamine injection. This treatment allowed for the cessation of lymphatic fluid and may serve as a potential intervention for PLE-associated hepatoduodenal lymphatic leakage. The present case highlights the importance of early recognition and timely intervention with radiology and endoscopic therapy to manage PLE and its associated complications.

Race and Socioeconomic Bias in Pediatric Cardiac Transplantation.

BACKGROUND: To date, no studies evaluated implicit bias among clinicians caring for children with advanced heart failure. OBJECTIVES: This study aims to evaluate implicit racial and socioeconomic bias among pediatric heart transplant clinicians. METHODS: A cross-sectional survey of transplant clinicians from the Pediatric Heart Transplant Society was conducted between June and August 2021. The survey consisted of demographic questions along with explicit and validated race and socioeconomic status (SES) implicit association tests (IATs). Implicit and explicit biases among survey group members were studied and associations were tested between implicit and explicit measures. RESULTS: Of 500 members, 91 (18.2%) individuals completed the race IAT and 70 (14%) completed the SES IAT. Race IAT scores indicated moderate levels of implicit bias (mean = 0.33, d = 0.76; P < 0.001; ie, preference for White individuals). SES IAT scores indicated strong implicit bias (mean = 0.52, d = 1.53; P < 0.001; ie, preference for people from upper SES). There were weak levels of explicit race and wealth bias. There was a strong level of explicit education bias (mean = 5.22, d = 1.19; P < 0.001; ie, preference for educated people). There were nonsignificant correlations between the race and the SES IAT and explicit measures (P > 0.05 for all). CONCLUSIONS: As observed across other health care disciplines, among a group of pediatric heart transplant clinicians, there is an implicit preference for individuals who are White and from higher SES, and an explicit preference for educated people. Future studies should evaluate how implicit biases affect clinician behavior and assess the impact of efforts to reduce such biases.