Epstein Barr virus-directed T-cell therapy for refractory EBV-PTLD in a toddler post Orthotopic heart transplantation.

Epstein-Barr Virus (EBV) is a ubiquitous herpes type virus that is associated with post-transplant lymphoproliferative disorder (PTLD). Usual management includes reduction or cessation of immunosuppression and in some cases chemotherapy including rituximab. However, limited therapies are available if PTLD is refractory to rituximab. Several clinical trials have investigated the use of EBV-directed T cells in rituximab-refractory patients; however, data regarding response is scarce and inconclusive. Herein, we describe a patient with EBV-PTLD refractory to rituximab after orthotopic heart transplantation (OHT) requiring EBV-directed T-cell therapy. This article aims to highlight the unique and aggressive clinical presentation and progression of PTLD with utilization of EBV-directed T-cell therapy for management and associated pitfalls.

Propranolol Therapy in Tetralogy of Fallot: Treating the Echocardiogram or Treating the Patient.

Hypercyanotic spells are one of the defining clinical features of Tetralogy of Fallot (TOF). Limited data exist on peak Doppler right ventricular outflow tract (RVOT) gradient as a risk factor for the development of hypercyanotic spells, frequency of prophylactic use of propranolol based on peak RVOT gradient, and its impact on preventing the occurrence of hypercyanotic spells. We aimed to quantify peak RVOT gradients as measured on transthoracic echocardiography in infants with unrepaired TOF and assess for correlation with clinical symptoms of hypercyanotic spells. We also assessed the frequency of pre-operative use of propranolol, indication for medication initiation, and occurrence of hypercyanotic spells with or without propranolol use. Retrospective analysis was performed on patients at our institution who were born between February 1, 2011 and May 31, 2023. Patients were excluded if they were maintained on prostaglandin infusion or underwent palliative shunt placement or balloon valvuloplasty prior to complete surgical repair. Demographics, occurrence of hypercyanotic spells, propranolol use, peripheral oxygen saturation, age at surgical repair, and peak RVOT gradient at the time of propranolol initiation were collected from the electronic medical record. If no propranolol use was recorded, the single highest maximum RVOT gradient prior to surgery was collected. 203 patients were identified, of which 92 patients were included in analysis. Thirty-six (39%) patients received propranolol and 19% of patients developed hypercyanotic spells prior to surgery. Patients with higher peak RVOT gradients were more likely to be started on propranolol even in the absence of overt symptoms, and they also demonstrated more systemic desaturation. Additionally, peak RVOT gradient was found to be a poor predictor for the development of hypercyanotic spells. Wide clinical variation exists in the prophylactic use of propranolol for prevention of hypercyanotic spells. Peak RVOT gradient is not a reliable tool for prophylactic propranolol initiation to prevent hypercyanotic spells.

A multi-centre randomised control trial of directly observed therapy to promote medication adherence in paediatric heart transplant recipients.

Medication non-adherence remains a significant challenge for adolescent heart transplant recipients. Building on the success of a pilot intervention study, herein we describe the protocol for a follow-up randomised control trial using mobile video directly observed therapy, featuring several innovations, to promote medication adherence in a multi-centre sample of adolescent heart transplant patients.

Elevated Aortic Stiffness after Pediatric Heart Transplantation.

In adults, arterial stiffness has been linked to the development of target end-organ damage, thought to be related to abnormal transmission of pulse pressure. Increased arterial stiffness and endothelial dysfunction have been hypothesized to contribute to the development of microvascular dysfunction and coronary allograft vasculopathy (CAV), an important comorbidity after heart transplantation. However, little data exists regarding arterial stiffness in pediatric heart transplantation and its influence on development of coronary allograft vasculopathy is not well understood. We sought to assess aortic stiffness and distensibility in pediatric post-heart transplant patients. A prospective, observational study analyzing the ascending (donor tissue) and descending aorta (recipient tissue) using transthoracic echocardiographic M-mode measurements in patients aged < 21 years was conducted. Descending and ascending aorta M-modes were obtained from the subcostal long axis view, and the parasternal long axis view 3-5mm above the sinotubular junction, respectively. Two independent reviewers averaged measurements over 2-3 cardiac cycles, and Aortic Distensibility (AD) and Aortic Stiffness Index (ASI) were calculated using previously validated methods. We recruited 39 heart transplant (HT) patients and 47 healthy controls. Median end diastolic dimension of the ascending aorta (donor tissue) was significantly larger in the transplant group than the control group (1.92 cm vs. 1.74 cm, p = 0.01). Ascending aortic distensibility in post-transplant patients was significantly lower than in the control group (4.87 vs. 10.53, p < 0.001). Ascending aortic stiffness index was higher in the transplant patients compared to the controls (4.63 vs. 2.21, p < 0.001). There is evidence of altered ascending aortic distensibility and stiffness parameters in post-heart transplant patients. Further studies are required to assess its influence on complications like development of coronary artery vasculopathy.

Use of REGEN-COV in children after heart transplantation for treatment and post-exposure prophylaxis of COVID-19.

COVID-19 pandemic continues to evolve and new variants like Delta and Omicron have been discovered. REGEN-COV is a recombinant human monoclonal antibody to the spike protein of SARS-CoV-2 which received emergency use authorisation for treatment and post-exposure prophylaxis in patients with high risk of progression to severe disease. We review our experience with use of REGEN-COV in paediatric heart transplant patients.

Directly observed therapy to promote medication adherence in adolescent heart transplant recipients.

PURPOSE: HT recipients experience high levels of medication non-adherence during adolescence. This pilot study examined the acceptability and feasibility of an asynchronous DOT mHealth application among adolescent HT recipients. The app facilitates tracking of patients' dose-by-dose adherence and enables transplant team members to engage patients. The DOT application allows patients to self-record videos while taking their medication and submit for review. Transplant staff review the videos and communicate with patients to engage and encourage medication adherence. METHODS: Ten adolescent HT recipients with poor adherence were enrolled into a single-group, 12-week pilot study examining the impact of DOT on adherence. Secondary outcomes included self-report measures from patients and parents concerning HRQOL and adherence barriers. Long-term health outcomes assessed included AR and hospitalization 6 months following DOT. FINDINGS: Among 14 adolescent HT patients approached, 10 initiated the DOT intervention. Of these, 8 completed the 12-week intervention. Patients and caregivers reported high perceptions of acceptability and accessibility. Patients submitted 90.1% of possible videos demonstrating medication doses taken. MLVI values for the 10 patients initiating DOT decreased from 6 months prior to the intervention (2.86 ± 1.83) to 6 months following their involvement (2.08 ± 0.87) representing a 21.7% decrease in non-adherence, though not statistically significant given the small sample size. CONCLUSIONS: Result of this pilot study provides promising insights regarding the feasibility, acceptability, and potential impact of DOT for adolescent HT recipients. Further randomized studies are required to confirm these observations.

Lodewyk H.S. van Mierop (March 31, 1927-October 17, 2021): a true giant.

We honour a great man and a true giant. Lodewyk H.S. van Mierop (March 31, 1927 - October 17, 2021), known as Bob, was not only a Paediatric Cardiologist but also a dedicated Scientist. He made many significant and ground-breaking contributions to the fields of cardiac anatomy and embryology. He was devoted as a teacher, spending many hours with medical students, Residents, and Fellows, all of whom appreciated his regularly scheduled educational sessions. Those of us who were fortunate to know and spend time with him will always remember his great mind, his willingness to share his knowledge, and his ability to encourage spirited and fruitful discussions. His life was most productive, and he will long be remembered by many through his awesome and exemplary scientific contributions.His legacy continues to influence the current and future generations of surgeons and all providers of paediatric and congenital cardiac care through the invaluable archive he established at University of Florida in Gainesville: The University of Florida van Mierop Heart Archive. Undoubtedly, with these extraordinary contributions to the fields of cardiac anatomy and embryology, which were way ahead of his time, Professor van Mierop was a true giant in Paediatric Cardiology. The invaluable archive he established at University of Florida in Gainesville, The University of Florida van Mierop Heart Archive, has been instrumental in teaching medical students, Residents, Medical Fellows, and Surgical Fellows. Only a handful of similar archives exist across the globe, and these archives are the true legacy of giants such as Dr. van Mierop. We have an important obligation to leave no stone unturned to continue to preserve these archives for the future generations of surgeons, physicians, all providers of paediatric and congenital cardiac care, and, most importantly, our patients.

Renin angiotensin aldosterone system in pulmonary fibrosis: Pathogenesis to therapeutic possibilities.

Pulmonary fibrosis is a devastating lung disease with multifactorial etiology characterized by alveolar injury, fibroblast proliferation and excessive deposition of extracellular matrix proteins, which progressively results in respiratory failure and death. Accumulating evidence from experimental and clinical studies supports a central role of the renin angiotensin aldosterone system (RAAS) in the pathogenesis and progression of idiopathic pulmonary fibrosis. Angiotensin II (Ang II), a key vasoactive peptide of the RAAS mediates pro-inflammatory and pro-fibrotic effects on the lungs, adversely affecting organ function. Recent years have witnessed seminal discoveries in the field of RAAS. Identification of new enzymes, peptides and receptors has led to the development of several novel concepts. Of particular interest is the establishment of a protective axis of the RAAS comprising of Angiotensin converting enzyme 2 (ACE2), Angiotensin-(1-7) [Ang-(1-7)], and the Mas receptor (the ACE2/Ang-(1-7)/Mas axis), and the discovery of a functional role for the Angiotensin type 2 (AT2) receptor. Herein, we will review our current understanding of the role of RAAS in lung fibrogenesis, provide evidence on the anti-fibrotic actions of the newly recognized RAAS components (the ACE2/Ang-(1-7)/Mas axis and AT2 receptor), discuss potential strategies and translational efforts to convert this new knowledge into effective therapeutics for PF.

Directly observed therapy to promote medication adherence in paediatric heart transplant recipients.

Medication non-adherence causes poor outcomes in paediatric organ transplantation. COVID-19 pandemic has led to an exponential use of mobile health approaches for patient care. Herein, we describe a pilot intervention study using mobile video directly observed therapy building on emerging trends in research and clinical practice pertaining to medication adherence in paediatric organ transplantation.

Electrocardiographic interference: know your patient well.

Two cases of paediatric patients with gastric pacemakers causing distinct electrocardiographic artefact. Recognition of extracardiac artefact is essential for proper ECG interpretation in patients.

Family functioning in the families of paediatric heart transplant recipients prior to outpatient visits and procedures.

In a cross-sectional study, we assessed family functioning prior to outpatient visits and routine heart catheterisations in the families of paediatric heart transplant recipients. Caregivers rated higher short-term family functioning prior to outpatient visits, but not prior to catheterisations. This finding may indicate that family functioning benefits from the support provided during outpatient visits.

Takayasu's arteritis presenting as acute myocardial infarction: case series and review of literature.

This series describes three adolescent females who presented with chest pain and ventricular dysfunction related to acute coronary ischemia secondary to Takayasu's arteritis with varied courses of disease progression leading to a diverse range of therapies including cardiac transplantation. While Takayasu's arteritis is rare in childhood, it should be strongly considered in any adolescent female presenting with systemic inflammation and chest pain consistent with myocardial infarction. A high index of suspicion can lead to early detection and aggressive management of the underlying vasculitis reducing associated morbidity and mortality. The purpose of this report is to describe the challenges in the clinical diagnosis and management of Takayasu's arteritis with myocardial infarction. We also seek to enhance awareness about unique presentations of Takayasu's arteritis within the paediatric community.

Risk factors associated with post-transplant superior caval vein stenosis in paediatric heart transplantation.

Superior caval vein stenosis is a known complication following paediatric heart transplantation. Herein, we sought to assess the incidence of superior caval vein stenosis and need for intervention in a single centre paediatric heart transplantation programme. A retrospective review was performed to identify variables associated with superior caval vein stenosis and need for intervention. Patients were identified based on angiographic and echocardiographic signs of superior caval vein stenosis. Of 204 paediatric heart transplantation recipients, 49 (24.0%) had evidence of superior caval vein stenosis with no need for catheter intervention and 12 (5.9%) had superior caval vein stenosis requiring catheter intervention. Overall, patients with superior caval vein stenosis with and without intervention had more cavopulmonary anastomosis (41.7%; 20.4%), pre-transplant superior caval vein procedures (41.7%; 28.6%), and bicaval approach (100.0%; 98.0%), compared to the group with no stenosis (11.9% and p = 0.015, 12.6% and p = 0.004, 73.4% and p < 0.001, respectively). Smaller recipients and donors were more likely to need intervention. Intervention was also seen more frequently in recipients who were younger at diagnosis (4.7 years) compared to non-intervention (13.3 years; p = 0.040). Re-intervention was required in 16.7% patients (n = 2) and was not associated with any complications.

Postoperative vasoactive inotropic score is predictive of outcomes in pediatric heart transplantation.

Vasoactive inotrope score (VIS) is scarcely studied in pediatric orthotopic heart transplantation (pOHT). We conducted a retrospective review of pOHT (<21 years) recipients. Max VIS and mean VIS were calculated at 0-24 and 24-48 hours post-pOHT. Patients were divided into groups based on ISHLT guidelines: high (>10) and low (≤10). In our group (n = 104), patients with high max and mean VIS groups at 0-24 and 24-48 hours had longer bypass times (high: >130 minutes; low: <108 minutes; P < .05) and high max and mean VIS groups at 0-24 hours had longer ischemic times (high: >215 minutes; low: <192 minutes; P < .05). Patients with high max and mean VIS at 0-24 and 24-48 hours had longer hospital stay, ventilation, inotrope duration, more cardiac events, and acute kidney injury postoperatively (P < .05). High max VIS at 24-48 hours and high mean VIS at 24-48 hours had higher 3-year mortality (P = .04; P = .02). Multivariate analysis confirmed the association of VIS with short-term outcomes. However, VIS was not identified as an independent predictor of mortality. The ROC curve exhibits 10 as the ideal cutoff with area under the curve >0.8 for primary graft dysfunction (PGD).

Family functioning in pediatric heart transplantation: Variables associated with poor outcomes.

Family functioning is integral in a child's life and is linked to quality of life in health as well as disease. This has been scarcely studied in pediatric orthotopic heart transplantation (pOHT). In this study, we evaluate demographic and clinical factors associated with family functioning in this patient population. Pediatric post-transplant families were recruited in an outpatient setting (n = 71). The PedsQL Family Impact Module was administered, along with the Parent and Adolescent Medication Barriers Scales (PMBS; AMBS) and the McArthur socioeconomic scale. Associations between clinical and demographic variables and scaled scores were evaluated. In our sample, patients with congenital heart disease, developmental delay, and enteral feeding had lower total impact (P = .026; P = .011; P = .008) and parent self-reported HRQL scores (P = .018; P = .012; P = .005). Patients with developmental delay and enteral feeding also had lower family functioning summary scores (P = .025; P = .031). Higher parent educational status was associated with lower total impact scores (P = .043). Higher PMBS scores demonstrated negative correlation with total impact (P < .001), parent self-reported HRQL (P < .001), and family functioning summary scores (P = .003). Multiple linear regression analysis identified developmental delay, parental education, and PMBS as independent variables associated with family functioning. Our study highlights important factors impacting family functioning in pOHT. Developmental delay, higher parental education, and PMBS were associated with poorer family functioning. Our findings emphasize the need for a multi-disciplinary approach including serial psychological assessment and interventions in the management of pOHT patients in order to optimize family functioning.

Review of the discard and/or refusal rate of offered donor hearts to pediatric waitlisted candidates.

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

Sub-acute neonatal hemochromatosis in an infant with hypoplastic left heart syndrome on ventricular assist device awaiting transplantation.

Single-ventricle pediatric patients, amongst other children waiting for OHT, are a vulnerable population, especially if candidacy is established before any palliation. NH is a rare disease with poor prognosis in the post-natal period. We present a case of sub-acute NH diagnosed in an infant with HLHS who was listed for OHT while bridged with a pulsatile paracorporeal VAD, with an emphasis on the evolution of the condition throughout the patient's clinical course and the ultimate decision for compassionate deactivation of VAD.

Thenar Muscle Oxygen Saturation Using Vascular Occlusion Test: A Novel Technique to Study Microcirculatory Abnormalities in Pediatric Heart Failure Patients.

Heart failure (HF) is associated with microcirculatory changes secondary to neuro-humoral imbalance, vascular stiffness and increased sympathetic tone. Near Infra-Red Spectroscopy (NIRS) derived Thenar muscle tissue oxygenation levels (StO2) can provide an estimate of the functional status of microcirculation. There is a paucity of literature regarding evaluation of microcirculation in pediatric subjects with HF. We hypothesized that microcirculation and oxygen saturation dynamics as assessed by Thenar StO2 levels using vascular occlusion test (VOT) would be altered in HF subjects and that these changes may correlate with the severity of heart failure. We prospectively enrolled 60 pediatric subjects (29 healthy control, 31 HF). Baseline StO2 levels were measured using InSpectra™ StO2 probe placed over the Thenar eminence of right hand, followed by a VOT for 3 min, during which the changes in StO2 levels during the occlusion phase and post occlusion phase were recorded. Baseline Thenar StO2 levels (72 ± 8 vs 76 ± 5, p = 0.02) and time to baseline StO2 in seconds (150 ± 70 vs 200 ± 70, p = 0.007) were significantly lower in HF group compared to healthy control (HC). In addition, HF patients had a significantly lower trough StO2 (37 ± 9 vs 42 ± 11%, p = 0.04) and peak StO2 compared to HC (87 ± 8 vs 91 ± 5%, p = 0.01). However, there was no difference in the rate of desaturation, rate of resaturation or time to peak StO2 levels in between the 2 groups. Significant correlation was present between baseline Thenar StO2 levels and NYU Pediatric Heart Failure Index Score (NYU-PHFI) (p = 0.003). This study is the first to report an objective assessment of microcirculation and Thenar tissue oxygen dynamics in pediatric subjects with HF in comparison with HC. Our study suggests altered microcirculation and oxygenation patterns in these subjects as well as correlation with a validated pediatric heart failure clinical score. Large-scale prospective studies are needed to further study the utility of this novel technology in HF subjects.

Effect of prenatal diagnosis on hospital costs in complete transposition of the great arteries.

OBJECTIVE: Prenatal diagnosis of congenital heart disease (CHD) is associated with improved clinical outcomes, yet its impact on the cost of hospitalization is not well described. We hypothesized that prenatal diagnosis of complete transposition of the great arteries (d-TGA) results in lower total hospital costs compared with postnatal diagnosis. METHODS: Retrospective analysis of infants with d-TGA repaired at our center from July 2006 to 2014. Total charges from initial hospitalization until discharge were converted to costs using the cost-to-charge ratio and then converted into 2016 dollars using the consumer price index. A direct cost comparison from the hospital perspective was performed between groups. A secondary analysis included the cost of prenatal diagnosis. RESULTS: Thirty-three infants with d-TGA were identified; 8 with and 25 without prenatal diagnosis. There was no difference in baseline characteristics. Mean direct cost of hospitalization was higher in infants without prenatal diagnosis ($108 014 ± $51 305 vs $88 305 ± $22 896, P = .31). On secondary analysis, the cost of prenatal diagnosis was negligible compared with total hospital cost. CONCLUSIONS: Total cost of initial hospitalization was higher for infants without prenatal diagnosis of d-TGA. Prenatal diagnosis not only improves clinical outcomes but may also be cost saving in the current era of increasing health care costs.