Impact of prolonged ischemic time on pediatric heart transplantation outcomes: Improved outcomes in the most recent era.

BACKGROUND: Impacts of ischemic time (IT) on pediatric heart transplant outcomes are multifactorial. We aimed to analyze the effect of prolonged IT on graft loss after pediatric heart transplantation. We hypothesized that graft survival with prolonged IT has improved across eras. METHODS: Patients <18 years old in the Pediatric Heart Transplant Society database were included (N=6,765) and stratified by diagnosis and era (1993-2004, 2005-2009, and 2010-2019). Severe graft failure (SGF) was defined as death, retransplant, or need for mechanical circulatory support in the first 7 days post-transplant. Descriptive statistical methods were used to compare differences between patient characteristics and IT. Kaplan-Meier survival analysis compared freedom from graft loss, rejection, and infection. Multivariable analysis was performed for graft loss and SGF (hazard and logistic regression modeling, respectively). RESULTS: Diagnoses were cardiomyopathy (N = 3,246) and congenital heart disease (CHD; N = 3,305). CHD were younger, more likely to have an IT ≥4.5 hours, and more likely to require extracorporeal membrane oxygenation or mechanical ventilation at transplant (all p < 0.001). Median IT was 3.6 hours (interquartile range 2.98-4.31; range 0-10.5). IT was associated with early graft loss (HR 1.012, 95% CI 1.005-1.019), but not when analyzed only in the most recent era. IT was associated with SGF (OR 1.016 95%CI 1.003-1.030). CONCLUSIONS: Donor IT was independently associated with an increased risk of graft loss, albeit with a small effect relative to other risk factors. Graft survival with prolonged IT has improved in the most recent era but the risk of SGF persists.

Role of HLA in cardiothoracic transplantation.

In current clinical practice, transplant clinicians create collaborative working relationships with histocompatibility laboratory scientists to identify the risk of long-term graft failure, which may assist in establishing strategies for treatment and surveillance. Transplant immunology research also focuses on optimizing human leukocyte antibody tissue typing and defines the most effective test for detecting the presence of donor-specific antibodies. Although several studies have been conducted, data on pediatric heart transplant recipients are limited. Epitope load information may be utilized to identify donors with permissible human leukocyte antibody mismatches to increase transplant success. Although current guidelines do not consider human leukocyte antibody epitope-based matching tools, these guidelines could be useful for identifying recipients at a high risk of donor-specific antibody production, which would be appropriate for routine donor-specific antibody screening to initiate early interventions to prevent antibody-mediated rejection. Human leukocyte antibody matching at the epitope level offers an effective approach for identifying acceptable mismatches in sensitized patients and provides information about epitope loads. In the future, eplet matching may be used to define the best immunosuppressive therapy protocol for cardiothoracic organ transplantation. This report provides an overview of the role of human leukocyte antibodies in heart and lung transplantation.

Successful implementation of telehealth visits in the paediatric heart failure and heart transplant population.

The Advanced Cardiac Therapies Improving Outcomes Network (ACTION) and Pediatric Heart Transplant Society (PHTS) convened a working group at the beginning of 2020 during the COVID-19 pandemic, with the aim of using telehealth as an alternative medium to provide quality care to a high-acuity paediatric population receiving advanced cardiac therapies. An algorithm was developed to determine appropriateness, educational handouts were developed for both patients and providers, and post-visit surveys were collected. Telehealth was found to be a viable modality for health care delivery in the paediatric heart failure and transplant population and has promising application in the continuity of follow-up, medication titration, and patient education/counselling domains.

Prevalence and clinical characteristics of oral lesions in heart transplant patients induced by sirolimus and everolimus: a systematic review and meta-analysis on a global scale.

OBJECTIVE: Sirolimus (SRL) and everolimus (EVL) are increasingly included in immunosuppressive protocols after heart transplantation. They present some side effects, including the appearance of painful lesions in the oral cavity. Therefore, this systematic review aimed to verify the global prevalence and clinical characteristics of oral lesions induced by SRL and EVL in heart transplant patients. STUDY DESIGN: A systematic review was performed using 5 main electronic databases (Medline/PubMed, SCOPUS, EMBASE, Web of Science, and LILACS), in addition to the gray literature. Studies were independently assessed by 2 reviewers based on established eligibility criteria. The risk of bias was assessed using the Joanna Briggs Institute appraisal tools, and the certainty of evidence was evaluated through GRADE assessment. RESULTS: Seventeen studies (860 patients) were included in the qualitative analysis. Of these, 11 studies were pooled in a meta-analysis of prevalence. The worldwide prevalence of oral lesions induced by SRL and EVL in heart transplant patients was 10.0%, and most lesions were described as ulcers >1.0 cm, related to significant pain. CONCLUSIONS: Oral lesions induced by SRL and/or EVL, although not very prevalent, have a relevant impact on patient's lives and the continuity of treatment.

Case Report: The Challenge for Diagnosis of Myocarditis and Transplant Rejection After COVID Infection in a Heart-Transplanted Adolescent.

Patients who have undergone organ transplantation are immunosuppressed hosts, leaving them at a higher risk of infections. SARS-COV-2 has been shown to affect heart-transplanted patients. In this case report, we present the case of a 14-year-old heart transplant recipient who developed signs and symptoms of heart failure, along with fatigue, after a COVID-19 infection. An endomyocardial biopsy was performed to diagnose rejection and to evaluate whether this was myocarditis due to SARS-COV-2. The biopsy showed intense acute cellular rejection (3R) and antibody rejection PAMR1 H+ but was negative for the SARS-CoV-2 virus. The patient received organ rejection therapy with high-dose methylprednisolone and human immunoglobulin. After treatment, her heart function recovered, with biopsy investigations showing a lower level of cellular rejection (1R).

Heart Transplantation in Children and Adults With Congenital Heart Disease: 3 Decades of Evolution.

Heart transplantation is the treatment of choice for children and adults with congenital heart disease. We report the heart transplant single-center experience. The number of transplantations has increased over the last 3 decades. The Kaplan-Meier survival curves in the first, second, and third decades at 5 and 10 years were 69% and 59%, 62% and 52%, and 66% and 60%, respectively.

Mechanical Circulatory Assistance in Children: Clinical Outcome.

BACKGROUND: In countries where organ donation is scarce, mortality in the pediatric heart transplant waiting list is high, and ventricular assist devices (VADs) are therapeutic alternatives in these situations. Berlin Heart EXCOR is currently 1 of the few VADs specific for children. METHODS: This retrospective study includes pediatric patients who underwent Berlin Heart EXCOR placement in a Brazilian hospital between 2012 and 2021. Clinical and laboratory data at the time of VAD implantation and the occurrence of complications and outcomes (success as a bridge to transplant or death) were analyzed. RESULTS: Eight patients, from 8 months to 15 years, were included: 6 with cardiomyopathy and 2 with congenital heart disease. Six were on Intermacs 1 and 2 on Intermacs 2. The most common complications observed were stroke and right ventricular dysfunction. Six were transplanted, and 2 died. Those submitted to transplant had a higher mean weight than those who died, with no statistically significant difference. The underlying disease had no impact on the outcome. The group undergoing transplant had lower brain natriuretic peptide and lactate values, but no laboratory variable showed a statistically significant difference in the outcome. CONCLUSION: A VAD is an invasive treatment with potentially serious adverse effects and is still poorly available in Brazil. However, as a bridge to transplant, it is a useful treatment for children in progressive clinical decline. In this study, we did not observe any clinical or laboratory factor at the time of VAD implantation that implied better outcomes.

Brain tuberculoma in pediatric heart transplant recipient.

INTRODUCTION: Heart transplantation is the standard treatment for end-stage heart disease. Despite advances in the field, patients remain under risk of developing complications, including opportunistic infections, such as tuberculosis. We present the unprecedented case of cerebral tuberculoma in a 9-year-old heart transplant recipient. CASE SCENARIO: A 9-year-old female child, who underwent heart transplantation in December 2020, was admitted to the emergency department in September 2021 due to headache and vomiting. She had normal vital signs and a mild left hemiparesis. Laboratory findings included lymphopenia and a low C Reactive Protein and brain images showed expansive lesions. A biopsy of the intracranial lesion was performed and anatomopathological analysis was compatible with tuberculoma. After the diagnosis was established, treatment protocol for neurotuberculosis was initiated, the patient had a satisfactory clinical evolution and was discharged 22 days after admission. DISCUSSION: Clinical manifestation of tuberculosis usually occurs up to 6 months after transplantation, the findings are commonly atypical and symptoms may be mild. We could not find in medical literature any description of the disease in a heart transplant recipient as young as the one presented in this case report. We documented great response to treatment, even though conventional antituberculosis therapy may interfere with immunosuppression. CONCLUSION: Patients in the postoperative period following heart transplantation are at high risk for developing opportunistic infections such as tuberculosis, which may present with atypical symptoms. Therefore the clinician must have a high index of suspicion in order to make the correct diagnosis and promptly start treatment.

The Fontan immunophenotype and post-transplant outcomes in children: A multi-institutional study.

BACKGROUND: Patients after Fontan palliation represent a growing pediatric population requiring heart transplant (HTx) and often have lymphopenia (L) and/or hypogammaglobinemia that may be exacerbated by protein-losing enteropathy (PLE, P). The post-HTx effects of this altered immune phenotype are not well studied. METHODS: In this study of the Pediatric Heart Transplant Society Registry, 106 Fontan patients who underwent HTx between 2005 and 2018 were analyzed. The impact of lymphopenia and PLE on graft survival, infection, rejection, and malignancy was analyzed at 1 and 5 years post-HTx. RESULTS: The following combinations of lymphopenia and PLE were noted: +L+P, n = 37; +L-P, n = 23; -L+P, n = 10; and -L-P, n = 36. Graft survival between the groups was similar within the first year after transplant (+L+P: 86%, +L-P: 86%, -L+P: 87%, -L-P: 89%, p = .9). Freedom from first infection post-HTx was greatest among -L-P patients compared to patients with either PLE, lymphopenia, or both; with a 22.1% infection incidence in the -L-P group and 41.4% in all others. These patients had a significantly lower infection rate in the first year after HTx (+L+P: 1.03, +L-P: 1, -L+P: 1.3, -L-P: 0.3 infections/year, p < .001) and were similar to a non-single ventricle CHD control group (0.4 infections/year). Neither freedom from rejection nor freedom from malignancy 1 and 5 years post-HTx, differed among the groups. CONCLUSIONS: Fontan patients with altered immunophenotype, with lymphopenia and/or PLE, are at increased risk of infection post-HTx, although have similar early survival and freedom from rejection and malignancy. These data may encourage alternative immunosuppression strategies and enhanced monitoring for this growing subset of patients.

Waitlist and post-transplant outcomes for children with myocarditis listed for heart transplantation over 3 decades.

BACKGROUND: There is limited and conflicting information on waitlist and transplant outcomes for children with myocarditis. METHODS: Retrospective review included children with myocarditis and dilated cardiomyopathy (DCM) listed for HT from January 01, 1993 to December 31, 2019 in the Pediatric Heart Transplant Society database. Clinical characteristics, waitlist and post-HT outcomes (graft loss, rejection, cardiac allograft vasculopathy, infection and malignancy) for children listed from early (1993-2008) and current era (2009-2019) with myocarditis were evaluated and compared to those with DCM. RESULTS: Of 9755 children listed, 322 (3.3%) had myocarditis and 3178 (32.6%) DCM. Compared to DCM, children with myocarditis in the early and the current era were significantly more likely to be listed at higher urgency; be in intensive care unit; on mechanical ventilation; extracorporeal membrane oxygenation and ventricular assist device (p < 0.05 for all). While unadjusted analysis revealed lower transplant rates and higher waitlist mortality for children with myocarditis, in multivariable analysis, myocarditis was not a risk factor for waitlist mortality. Myocarditis, however, was a significant risk factor for early phase post-HT graft loss (HR 2.46; p = 0.003). Waitlist and post-HT survival for children with myocarditis were similar for those listed and transplanted in the early era to those listed and transplanted in the current era (p > 0.05 for both). CONCLUSIONS: Children with myocarditis have a higher acuity of illness at listing and at HT and have inferior post-HT survival compared to children with DCM. Outcomes for children with myocarditis have not improved over the 3 decades and efforts are needed to improve outcomes for this cohort.

Desmoid tumour of the chest wall in paediatric post-operatory of heart transplant.

We will report a case of a desmoid tumour (DT), which developed at the surgical site of the pacemaker after a late childhood heart transplant. Patients with idiopathic dilated cardiomyopathy followed up in the paediatric cardiology service. It evolved with the dissociation of ventricular rhythm caused by severe heart failure, which led to the implantation of a cardiac resynchronization device prior to heart transplantation. The progression to end-stage heart disease culminated in a heart transplant at 12 years old. One year after the transplant, at the age of 13 years, he presented a progressively growing mass on the generator site of the resynchronization device. The initial decision was to remove the device. During the removal surgery, there was no haematoma or fluid collection. However, there was a progression of the lesion. The lesion was biopsied with the anatomopathological diagnosis of a DT. Resection surgery happened 4 months after the start of the mass growth. At that time, the tumour reached 20 cm in diameter. The lesion infiltrated the pectoralis major muscle and this muscle was resected partially en bloc with the lesion. The defect had primary closure. The patient evolved without postoperative complications and was discharged on the 14th postoperative day. The surgical specimen came with negative circumferential margins. However, the deep margin was microscopically positive. Due to deep involvement, the patient underwent adjuvant radiotherapy. Currently, the patient is under clinical follow-up and has no evidence of tumour recurrence. DT is a rare tumour, with unpredictable courses. Surgery can be considered in the progression of lesions. Treatment is justified by long survival after a heart transplant and in DT patients. DT is a differential diagnosis to be considered in progressive growth lesions.

Clinical approach to antibody-mediated rejection from the pediatric heart transplant society.

OBJECTIVE: This document is designed to outline the definition, pathogenesis, diagnostic modalities and therapeutic measures to treat antibody-mediated rejection in children postheart transplant METHODS: Literature review was conducted by a Pediatric Heart Transplant Society (PHTS) working group to identify existing pediatric and adult studies on antibody-mediated rejection (AMR). In addition, the centers participating in PHTS were asked to submit their approach to diagnosis and management of pediatric AMR. This document synthesizes information gathered from both these sources to highlight a practical approach to diagnosing and managing a child with AMR postheart transplant. This document may not represent the practice at all centers in the PHTS and serves as a starting point to understand an approach to this clinical scenario.

Clinical approach to mechanical circulatory support in the transplant patient from the Pediatric Heart Transplant Society.

The use of mechanical circulatory support (MCS) for pediatric patients who have undergone heart transplant has grown rapidly in the past decade. This includes support in the immediate post-transplant period and "rescue" therapy for patient later in their transplant course. Extracorporeal membrane oxygenation (ECMO) remains a standard modality of support for intraoperative concerns and for acute decompensation in the immediate post-transplant period. However, both pulsatile and continuous flow ventricular assist devices (VADs) have been used with increasing success in transplant patients for longer durations of support. Centers participating in the Pediatric Heart Transplant Society (PHTS) were queried to provide their internal protocols and rationale for mechanical circulatory support following heart transplant. These protocols coupled with evidence-based literature were used to provide the following description of clinical approaches to MCS in the transplant patient highlighting areas of both broad consensus and significant practice variation.

Early report from the Pediatric Heart Transplant Society on COVID-19 infections in pediatric heart transplant candidates and recipients.

BACKGROUND: Reports focused on adult heart transplant (HTx) recipients with COVID-19 suggest an increased risk of severe disease, however; it is unclear if this holds true for pediatric HTx patients, given the typically 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 HTx candidates and recipients, with the aim of describing the patient population and infection related outcomes. METHODS: The Pediatric Heart Transplant Society (PHTS) is a multi-center collaboration that seeks to improve the outcomes of children who are listed and undergo HTx. The society consists of pediatric HTx 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 on pediatric HTx candidates and recipients. Non-PHTS centers were also invited to submit data. Data fields included pre-and post-HTx patient characteristics, presumed versus documented infection, need for hospitalization (including ICU and ventilator use), treatments administered, and 30-day outcome (resolution, death, sequelae, and or unresolved) RESULTS: Data collection was initiated on 4/30/20. As of 03/15/21 there were 225 patients [19 pre-HTx and 206 post-HTx, median age 14 years (IQR 7, 18)] reported from 41 centers. Hospitalization occurred in 42% (n = 8) of the pre-HTx and 21% (n=43) of the post-HTx patients. Among the patients listed for HTx, 21% (n = 4) required ICU and 10.5% (n = 2) were mechanically ventilated. Among post-HTx patients, 7% (n = 14) required ICU and 1% (n = 3) were mechanically ventilated. At 30 days, the majority of patients had resolution of symptoms (94.7% pre-HTx, 95.6% post-HTx). One death was reported in a post-HTx patient prior to 30 days from onset of COVID-19 illness. CONCLUSIONS: These data demonstrate the ability to rapidly adapt the PHTS data collection infrastructure in response to a novel infection and represent the first known multi-center report of characteristics and early outcomes for patients listed and following pediatric HTx with COVID-19. Hospitalization appears to be more common for both candidates and recipients due to COVID-19 than for the general pediatric population though stays were short and mortality minimal.

Case Report: Dilated Cardiomyopathy in a Newborn, a Potential Association With SARS-COV-2.

Objective: The objective of this study was to describe the clinical course of a newborn who developed dilated cardiomyopathy (DCM) after COVID-19 infection. Methods: We retrospectively assessed the clinical notes of a pediatric patient with decompensated heart failure and who was previously positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Results: A 23-day-old newborn presented with diarrhea, hypoactivity, tachypnea, and lethargy. The infant progressed to develop respiratory failure and required orotracheal intubation due to apnea. A nasopharyngeal swab tested positive for SARS-COV-2. An echocardiogram (ECHO) demonstrated severe left ventricular dysfunction. The patient was discharged after 18 days with furosemide and angiotensin-converting enzyme inhibitors. During the follow-up period, the infant had two episodes of decompensated heart failure, with evidence of DCM. Investigations for known causes of secondary DCM were negative. The infant was promptly referred for heart transplantation. Conclusion: Although rare, we have observed a case of DCM in a newborn following COVID-19 disease. DCM may be a complication following COVID-19 disease in newborns.

Improved heart transplant survival for children with congenital heart disease and heterotaxy syndrome in the current era: An analysis from the pediatric heart transplant society.

BACKGROUND: Challenges exist with heterotaxy due to the complexity of heart disease, abnormal venous connections, and infection risks. This study aims to understand heart transplant outcomes for children with heterotaxy. METHODS: All children with congenital heart disease listed for transplant from 1993 to 2018 were included. Those with and without heterotaxy were compared. Waitlist outcomes and survival post-listing and transplant were analyzed. Post-transplant risk factors were identified using multiphase parametric hazard modeling. RESULTS: There were 4814 children listed, of whom 196 (4%) had heterotaxy. Heterotaxy candidates were older (5.8 ± 5.7 vs 4.2 ± 5.5 years, p < 0.01), listed at a lower urgency status (29.8% vs 18.4%, p < 0.01), more commonly single ventricle physiology (71.3% vs 59.2%, p < 0.01), and less often supported by mechanical ventilation (22% vs 29.1%, p < 0.05) or extracorporeal membrane oxygenation (3.6% vs 7.5%, p < 0.05). There were no differences in waitlist outcomes of transplant, death, or removal. Overall, post-transplant survival was worse for children with heterotaxy: one-year survival 77.2% vs 85.1%, with and without heterotaxy, respectively. Heterotaxy was an independent predictor for early mortality in the earliest era (1993-2004), HR 2.09, CI 1.16-3.75, p = 0.014. When stratified by era, survival improved with time. Heterotaxy patients had a lower freedom from infection and from severe rejection, but no difference in vasculopathy or malignancy. CONCLUSIONS: Mortality risk associated with heterotaxy is mitigated in the recent transplant era. Early referral may improve waitlist outcomes for heterotaxy patients who otherwise have a lower status at listing. Lower freedom from both infection and severe rejection after transplant in heterotaxy highlights the challenges of balancing immune suppression.

Multisystem Inflammatory Syndrome Associated with COVID-19 Anti-thrombosis Guideline of Care for Children by Action.

With growing number of pediatric cases of COVID-19, a unique hyper-inflammatory syndrome, linked to SARS-CoV-2 infection, has emerged in children referred to as multisystem inflammatory syndrome in children (MIS-C). This Kawasaki Disease (KD)-like illness has been described across the world. This syndrome shares features of KD, toxic shock syndrome, and macrophage activation syndrome and is associated with significantly elevated inflammatory markers. Everyday there are new data emerging improving the care of these patients. The Advanced Cardiac Therapies Improving Outcomes Network (ACTION) is a collaborative network designed to improve the outcomes of pediatric patients with end-stage heart failure and involves centers from across North America. The committee gathered information concerning COVID-19 anticoagulation practices at various centers and harmonized the data to formulate a set of recommendations.

A Comprehensive and Contemporary Review on Immunosuppression Therapy for Heart Transplantation.

Heart transplantation is the standard of therapy for patients with end-stage heart disease. Since the first human-to-human heart transplantation, performed in 1967, advances in organ donation, surgical techniques, organ preservation, perioperative care, immunologic risk assessment, immunosuppression agents, monitoring of graft function and surveillance of long-term complications have drastically increased recipient survival. However, there are yet many challenges in the modern era of heart transplantation in which immunosuppression may play a key role in further advances in the field. A fine-tuning of immune modulation to prevent graft rejection while avoiding side effects from over immunosuppression has been the vital goal of basic and clinical research. Individualization of drug choices and strategies, taking into account the recipient's clinical characteristics, underlying heart failure diagnosis, immunologic risk and comorbidities seem to be the ideal approaches to improve post-transplant morbidity and survival while preventing both rejection and complications of immunosuppression. The aim of the present review is to provide a practical, comprehensive overview of contemporary immunosuppression in heart transplantation. Clinical evidence for immunosuppressive drugs is reviewed and practical approaches are provided. Cardiac allograft rejection classification and up-to-date management are summarized. Expanding therapies, such as photophoresis, are outlined. Drug-to-drug interactions of immunosuppressive agents focused on cardiovascular medications are summarized. Special situations involving heart transplantation such as sarcoidosis, Chagas diseases and pediatric immunosuppression are also reviewed. The evolution of phamacogenomics to individualize immunosuppressive therapy is described. Finally, future perspectives in the field of immunosuppression in heart transplantation are highlighted.