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.

Prolonged hospital length of stay after pediatric heart transplantation: A machine learning and logistic regression predictive model from the Pediatric Heart Transplant Society.

BACKGROUND: Heart transplantation (HT) is the gold standard for managing end-stage heart failure. Multiple quality metrics, including length of stay (LOS), have been used in solid organ transplantation. However, limited data are available regarding trends and factors influencing LOS after pediatric HT. We hypothesized that various donor, peri-transplant and recipient factors affect LOS after pediatric HT. METHODS: We analyzed patients <18years at time of HT from January 2005 to December 2018 in the Pediatric Heart Transplant Society database, and examined LOS trends, defined prolonged LOS (PLOS = LOS>30days after HT), identified factors associated with PLOS and assessed outcomes. RESULTS: Of 4827 patients undergoing HT, 4414 patients were discharged and included for analysis. Overall median LOS was 19days[13,34]. Median LOS was longer in patients with congenital heart disease(CHD = 25days[15,43] than with cardiomyopathy(CM = 17days[12,27] across all ages. Median LOS in age <1year was 26-days[16,45.5] and in age >10year was 16days[11,26]. PLOS was seen in 1313 patients(30%). Patients with PLOS were younger, smaller and had longer CPB times. There was no difference in utilization of VAD at HT between groups, however, ECMO use at listing(8.45% vs 2.93%,p < 0.05) and HT was higher in the PLOS group(9.22% vs 1.58%,p < 0.05). PLOS was more common in patients with previous surgery, CHD, single ventricle physiology, recipient history of cardiac arrest or CPR, end organ dysfunction, lower GFR, use of mechanical ventilation at HT and Status 1A at HT. CONCLUSION: We present novel findings of LOS distribution and define PLOS after pediatric HT, providing a quality metric for individual programs to utilize and study in their practice.

Characteristics, risks, and outcomes of post-transplant lymphoproliferative disease >3 years after pediatric heart transplant: A multicenter analysis.

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.

Risk stratification to determine the impact of induction therapy on survival, rejection and adverse events after pediatric heart transplant: A multi-institutional study.

BACKGROUND: Induction therapy is increasingly being used in pediatric heart transplantation. General versus risk-adapted use remains controversial. We aimed to determine the impact of induction therapy on outcomes after stratifying patients by diagnosis and risk. METHODS: The Pediatric Heart Transplant Study (PHTS) database was used to identify patients (age ≤18 years) who underwent transplantation between January 1, 2001 and December 31, 2014. Patients were excluded if they survived <48 hours or received multiple induction agents. Patients were stratified using a multivariable model to predict 1-year mortality. Patients within the top 25% risk of predicted mortality were defined as high risk (HR) and the bottom 75% as low risk (LR). RESULTS: Of the 2,860 patients studied, 1,370 received anti-lymphocyte antibody (ALA), 707 received an interleukin-2 receptor antagonist (IL-2RA) and 783 received no induction (NI) therapy. Overall, patients with NI had lower survival (p < 0.01); however, multivariable analysis did not demonstrate an association with graft loss. Freedom from rejection was greater among LR congenital heart disease (CHD) and all cardiomyopathy (CMP) patients who received induction therapy (p < 0.01, for both), as confirmed in a multivariable analysis for CMP patients. Frequency of graft vasculopathy was higher in LR CMP patients who received NI. Freedom from infection was lower with IL-2RA in the LR groups. CONCLUSIONS: Pediatric heart transplant survival has improved in the recent era, in concert with increased use of induction therapy. Although induction therapy is associated with decreased rejection, it was not found to directly influence survival on multivariable analysis. Lower risk patients may benefit the most from induction therapy, particularly IL-2RA, which may be correlated with decreased infection and rejection in this cohort.

Heart transplantation in children with intellectual disability: An analysis of the UNOS database.

Heart transplantation in children with intellectual disability (ID) is an issue of debate due to the shortage of available donor organs. We sought to perform the first large-scale retrospective cohort study describing the prevalence and outcomes of heart transplantation in this population. The United Network of Organ Sharing database was queried from 2008 to 2015 for pediatric patients (age <19 years) receiving first, isolated heart transplant. Recipients were divided into three subgroups: definite ID, probable ID, and no ID. The chi-square test was used to compare patients' baseline characteristics. Kaplan-Meier and Cox proportional hazard regression analyses were used to estimate the association between ID and death-censored graft failure and patient survival. Over the study period, 565 pediatric patients with definite (131) or probable (434) ID received first heart transplant, accounting for 22.4% of all first pediatric heart transplants (n=2524). Recipients with definite ID did not significantly differ from those without ID in terms of gender, ethnicity, ischemia time, severity of pretransplant condition (waitlist status, mechanical ventilation, inotrope dependence, ECMO, VAD, PVRI, infection prior to transplant), or incidents of acute rejection within the first year. ID was associated with prolonged waitlist time (P<.001). Graft and patient survival at 3 years was equivalent between children with and without ID (P=.811 and .578, respectively). We conclude that intellectual disability is prevalent in children receiving heart transplants, with 22.4% of recipients over the study period having definite or probable ID. ID does not appear to negatively affect transplantation outcomes. Future studies are needed to assess long-term outcomes of transplantation in this population.

Post-transplant lymphoproliferative disease and other malignancies after pediatric cardiac transplantation: an evolving landscape.

PURPOSE OF REVIEW: Post-transplant lymphoproliferative disorders (PTLDs) remain a significant cause of morbidity and mortality after pediatric solid organ transplantation (SOT). PTLD treatment outcomes have improved steadily over the past decade, in large part due to an enhanced understanding of the disease process, newer immunosuppression regimens, and implementation of evolving chemotherapeutic treatment protocols. RECENT FINDINGS: New therapies continue to be employed to treat PTLDs while maintaining normal allograft function in SOT recipients. These include use of immunosuppressant medications with antitumor activity (mammalian target of rapamycin inhibitors), monoclonal antibody therapies, and the advent of cytotoxic T-cell therapy. Treatment methods to render latent Epstein-Barr virus (EBV)-infected tumor cells more susceptible to antiviral agents continue to be investigated. SUMMARY: PTLD remains a significant potential complication after SOT, particularly in pediatric patients who are more likely to be EBV-negative at the time of transplant and subsequently undergo EBV seroconversion. Risk for PTLD may be reduced by employing strategies such as EBV prophylaxis in seronegative patients, minimizing overall intensity of immunosuppression, and utilizing newer agents that have both immunosuppressive and antiproliferative properties. Treatment outcomes for PTLD have steadily improved over the past decade, related in part to the availability of monoclonal antibody therapies and refined chemotherapeutic regimens.

Bacterial pancarditis with myocardial abscess: successful surgical intervention in a 14-month-old boy.

A 14-month-old boy with a structurally normal heart presented with signs of cardiac tamponade caused by purulent pericarditis. During his hospital stay, mitral and tricuspid valve endocarditis developed, and a ventricular septal abscess expanded despite appropriate, prolonged antibiotic therapy for methicillin-resistant Staphylococcus aureus. The day before scheduled surgical correction, the abscess ruptured, creating a septal aneurysm. Surgical intervention resulted in an excellent outcome. Throughout the patient's 67-day hospitalization, the use of echocardiography was crucial in monitoring and diagnosis. In addition to reporting this case, we discuss our diagnostic and treatment considerations. To our knowledge, this is only the 4th report of S. aureus bacterial pancarditis with myocardial abscess.

Hypoalbuminemia and poor growth predict worse outcomes in pediatric heart transplant recipients.

Children with end-stage cardiac failure are at risk of HA and PG. The effects of these factors on post-transplant outcome are not well defined. Using the PHTS database, albumin and growth data from pediatric heart transplant patients from 12/1999 to 12/2009 were analyzed for effect on mortality. Covariables were examined to determine whether HA and PG were risk factors for mortality at listing and transplant. HA patients had higher waitlist mortality (15.81% vs. 10.59%, p = 0.015) with an OR of 1.59 (95% CI 1.09-2.30). Survival was worse for patients with HA at listing and transplant (p ≤ 0.01 and p = 0.026). Infants and patients with congenital heart disease did worse if they were HA at time of transplant (p = 0.020 and p = 0.028). Growth was poor while waiting with PG as risk factor for mortality in multivariate analysis (p = 0.008). HA and PG are risk factors for mortality. Survival was worse in infants and patients with congenital heart disease. PG was a risk factor for mortality in multivariate analysis. These results suggest that an opportunity may exist to improve outcomes for these patients by employing strategies to mitigate these risk factors.

Partial anomalous pulmonary venous return: transcatheter repair.

This report describes a case of partial anomalous pulmonary venous return in a young white girl for whom transcatheter intervention successfully replaced surgical correction. This intervention was feasible because the left lung had dual pulmonary venous drainage.

A comparison of the modified Blalock-Taussig shunt with the right ventricle-to-pulmonary artery conduit.

BACKGROUND: This study compared the modified Blalock-Taussig (MBT) shunt with the right ventricle-to-pulmonary artery (RVPA) conduit with respect to outcome and PA growth. METHODS: PA growth was assessed in 19 MBT patients and in 15 RVPA patients before stage 2 palliation for hypoplastic left heart syndrome. The RVPA was done with a ringed Gore-Tex tube (W. L. Gore and Assoc, Flagstaff, AZ) at each anastomosis. RESULTS: The two cohorts had similar pre-Glenn demographic and hemodynamic data. No patient required transcatheter or surgical intervention on the shunt or PAs after stage 1 palliation. The branch PA growth was better in RVPA (McGoon ratio: MBT, 1.5±0.2 vs RVPA, 2.0±0.6; p<0.003) and was significantly more balanced (right-to-left PA area ratio: MBT, 1.5±0.5 vs RVPA, 0.9±0.6; p=0.002). The Nakata index trended higher in RVPA (MBT, 242A±90 mm2/m2 vs RVPA, 267±95 mm2/m2, p=0.2). After stage 2 palliation, oxygen saturation trended higher in the RVPA (81%±5%) vs MBT cohort (77%±8%, p<0.08). CONCLUSIONS: The Norwood operation using a RVPA nonvalved conduit is associated with improved branch PA growth.

Hybrid procedure for obstructive neonatal left ventricular tumors.

We report the use of the hybrid procedure (bilateral pulmonary artery banding, ductal stenting followed by balloon atrial septostomy) in the first week of life for the treatment of two neonates with large left ventricular fibromas resulting in univentricular physiology. At 6 months of age, second-stage palliation was accomplished and the 2 patients are growing well with normal developmental milestones and no atrial or ventricular ectopy at 30 months. Hybrid strategy offers a less invasive, initial intervention and the options of typical second-stage univentricular palliation, conversion to biventricular physiology in cases of tumor regression, planned surgical resection, or transplantation.

Prenatal diagnosis of congenital heart disease.

This article presents advancements in the field of fetal echocardiography and the significant impact of these within the fields of pediatric cardiology, perinatology, and neonatology. A prenatal diagnosis of congenital heart disease allows for improved counseling of the parents, guides the timing and optimal location of delivery, and allows appropriate planning and consultation between the cardiologist and neonatologist. It also facilitates accurate diagnosis and management of fetal arrhythmias, identifies potential candidates for in utero cardiac intervention, and serves as the imaging guidance technique for these procedures. The goals, indications, advantages, limitations, and spectrum of congenital heart disease that can be diagnosed are reviewed.

Hyperlipidemia in children after heart transplantation.

BACKGROUND: Long-term outcome after cardiac transplantation is limited by graft coronary vasculopathy (GCV). Hyperlipidemia may contribute to the development and progression of GCV. The purpose of this study was to determine the distribution of lipid levels in children after heart transplantation and to determine the incidence and risk factors for hyperlipidemia. METHODS: We compared the distribution of lipid values 1 year after heart transplantation in children participating in Pediatric Heart Transplant Study to those of normal U.S. children and then performed a multivariable analysis to identify risk factors for hyperlipidemia. RESULTS: The median values of total and LDL-cholesterol in heart transplant patients were similar to those of normal U.S. pediatric population. However, total cholesterol level was >200 mg/dl in 14% and >170 mg/dl in 33% of transplant patients. LDL-cholesterol was >130 mg/dl in 12%, >110 mg/dl in 27% and >100 mg/dl (greater than "optimal" levels) in 39% of transplant patients. The distribution curve for serum triglycerides was shifted to the right and that for HDL-cholesterol levels was shifted to the left of the normal U.S. pediatric curve. As a result, triglyceride levels were >75th centile of U.S. normal distribution in 59% of the transplant patients. HDL-cholesterol level was <25th centile of U.S. normal distribution in 61% of the transplant patients. Independent risk factors for elevated levels of total and LDL-cholesterol were patient age and use of cyclosporine and prednisone. CONCLUSIONS: Lipid levels considered to be in the intervention range in adults at high risk of coronary artery disease are a common finding after cardiac transplantation in children.

Advances in pediatric heart transplantation.

PURPOSE OF REVIEW: Heart transplantation has become a reasonable treatment option for pediatric patients with end-stage heart failure or complex congenital cardiac defects not amenable to conventional surgical intervention. This review will summarize the current state of pediatric cardiac transplantation and review recent advances leading to new therapies. RECENT FINDINGS: Improvements in early mortality after cardiac transplantation have occurred consistently over time since the 1980s, short-term survival rates are high, and most patients enjoy an excellent quality of life with minimal restrictions. The reduction of late mortality is still a major challenge, however, largely as a result of transplant-related coronary artery disease causing chronic graft failure and arrhythmogenic sudden death. Additional causes of morbidity and mortality occurring late after transplantation include renal dysfunction related to chronic immunosuppressive therapy with calcineurin inhibitors (tacrolimus or cyclosporine) and posttransplant lymphoproliferative disorders related to chronic immunosuppression. Newer agents (sirolimus, everolimus) have shown promise in immunosuppressive regimens that may alter the development or progression of long-term complications. SUMMARY: New immunosuppressive agents allow alterations in drug regimens to minimize renal complications, and may influence the incidence and progression of transplant vasculopathy. Recent studies on posttransplant lymphoproliferative disorders should result in earlier diagnosis and therapy.

Increased myocardial performance index correlates with biopsy-proven rejection in pediatric heart transplant recipients.

BACKGROUND: To date, cardiac catheterization and endomyocardial biopsy have been considered the "gold standard" for rejection surveillance after heart transplantation. Factors such as patient size (i.e., infant transplantation), loss of vascular access after repeated catheterizations, and anesthesia requirements all present unique problems and risks related to pediatric rejection surveillance. Therefore, additional methods to monitor for rejection in a non-invasive, reliable and frequent manner have been sought. We studied the utility of echocardiographic measurement of the left ventricular myocardial performance index (LVMPI), a reproducible measure of combined systolic and diastolic performance, in pediatric heart transplant recipients as a method of identifying acute rejection. METHODS: Two-dimensional/Doppler echocardiographic studies (n = 36) were performed on 21 cardiac transplant patients (ages 6.2 to 21.9 years) at the time of endomyocardial biopsy. The LVMPI, the sum of the isovolumic contraction time and isovolumic relaxation time divided by aortic ejection time, was determined at each study, as well as other echocardiographic measures of systolic and diastolic function. Patients were grouped by concurrent histologic rejection grade and the results compared between groups. RESULTS: Significant differences in LVMPI (p < 0.001) were noted between patients with no rejection (Grade 0; n = 23) and those with moderate to severe rejection (Grade 3; n = 5), as well as between those with no rejection and those with focal moderate (Grade 2; n = 8) rejection (p < 0.05). The LVMPI was 0.42 +/- 0.03 (mean +/- SEM) for the group without rejection, 0.57 +/- 0.06 for those with Grade 2 rejection and 0.73 +/- 0.05 for those with Grade 3 rejection. Although 9 of the 23 studies in the non-rejection group had LVMPI values exceeding 0.44 (upper threshold value), 12 of 13 patients in the rejection groups exceeded this threshold. LVMPI >or= 0.64 was associated with significant rejection in all cases in this study (n = 7). No significant differences were noted between groups for left ventricular ejection fraction or shortening fraction, percent septal or posterior wall thickening, left ventricular mass index or mitral valve deceleration time. In addition, for those individual patients with multiple studies, the LVMPI consistently increased with higher rejection grades and decreased after therapy. CONCLUSIONS: In this series, increased LVMPI correlated with biopsy-proven rejection, and frequent serial assessments using this technique may provide a relatively sensitive non-invasive means of rejection surveillance after pediatric cardiac transplantation. False positive results may be encountered, likely due to alterations in diastolic function that have been previously observed in transplant recipients.

Tacrolimus: in vitro effects on myelopoiesis, apoptosis, and CD11b expression.

BACKGROUND: Tacrolimus is a common component of multi-drug immunosuppressive regimens that are used for the prevention of rejection in transplant recipients. Tacrolimus therapy has been associated with anemia after transplantation, and recent clinical evidence in children suggests its association with the development of neutropenia for which an alternative etiology is not apparent. Mechanisms of suspected tacrolimus-related neutropenia have not been previously elucidated. We hypothesized that this variety of neutropenia might be due to a negative effect of tacrolimus on neutrophil production and/or survival. METHODS: We designed in vitro studies to determine the dose-dependent effect of tacrolimus on myeloid cell production and/or apoptosis. CD34+ cells and neutrophils isolated from umbilical cord blood of term gestations were cultured with tacrolimus (0-1,000 ng/ml). To evaluate apoptosis, cells cultured for 24 hours were stained with annexin V-fluorescein isothiocyanate (V-FITC) and 7-amino-actinomycin D (7-AAD) and analyzed by flow cytometry. For clonal analysis, CD34+ cells cultured in cytokine-enhanced semi-solid media were scored for their myeloid/erythroid mix colony forming units (CFU-Mix) and myeloid (CFU-GM) progenitor cell contents. RESULTS: Tacrolimus induced a dose-dependent enhancement of clonogenesis and survival of CD34+ cells at clinically relevant doses. Conversely, tacrolimus had no effect on the survival of mature neutrophils or on the upregulation of CD11b in response to chemotactic stimulation. CONCLUSION: In contrast to our initial hypothesis, we observed that tacrolimus at clinically relevant concentrations enhanced clonogenesis of neutrophil progenitors and promoted their survival. Our in vitro studies suggest that tacrolimus alone is unlikely to be a significant factor in the neutropenia observed during immunosuppressive therapy.

An institutional review of the value of computed tomographic angiography in the diagnosis of congenital cardiac malformations.

The ultra-fast, thin-cut computerised tomographic angiogram is an efficient method to diagnose extracardiac lesions associated with congenital cardiac disease. For the purposes of this review, we evaluated various facets of the technique as used in 30 patients who were referred for diagnosis of congenital cardiac disease. The technique had high diagnostic accuracy, with a sensitivity of 93 percent in 15 of these patients referred for either interventional catheterisation or surgery. There were no immediate side-effects associated with the scanning procedure. The scan was also found to be more cost-effective as compared to an alternative noninvasive modality for imaging modality, namely magnetic resonance imaging. The angiographic technique, however, does expose the child to between 2 and 2.5 rems of radiation, despite the short period of scanning, of 10 plus or minus 2 seconds.

Toxic serum trough concentrations after administration of nebulized tobramycin.

The goal of administering nebulized antibiotics is to provide patients with a high concentration of drug at the infection site with minimal systemic effects. In two studies in which nebulized tobramycin 300 mg twice/day was administered, systemic peak concentrations were below 0.2 and 3.62 microg/ml, and trough concentrations were undetectable, making toxicity from this route of administration negligible. A 19-year-old woman who received a heart transplant was administered tobramycin inhalation solution for Acinetobacter baumanii pneumonia; her serum trough concentrations were found to be toxic (> 2.0 microg/ml). Her risk factors for experiencing these toxic concentrations were renal failure and administration of the drug by positive pressure ventilation. Although nebulized tobramycin is safe under routine circumstances, clinicians must be aware of its potential for toxicity in patients with renal dysfunction or in those receiving positive pressure ventilation.

Decreased functional caspase-3 expression in umbilical cord blood neutrophils is linked to delayed apoptosis.

Resolution of inflammatory processes depends on the efficient removal of aging neutrophils by the reticuloendothelial system. Neutrophil apoptosis is key to this process, and its impairment may contribute to the pathogenesis of chronic inflammation. We recently discovered that Fas-mediated apoptosis in umbilical cord blood neutrophils was significantly delayed as compared with those of adults. Because execution of apoptosis relies on caspases, we used reverse transcription PCR, immunoblots, and enzymatic assays to study the integrity of several members of those proteases known to mediate Fas-induced apoptosis in neutrophils. Our results indicate that diminished expression of caspase-3 mRNA and the precursor form of the protein, as well as a lower functional enzymatic activity of caspase-3, correlates with delayed apoptosis in umbilical cord blood neutrophils. Our data suggest that functional expression of caspase-3 in neutrophils may be regulated during ontogeny.

Catecholaminergic polymorphic ventricular tachycardia in a 3-year-old with occult myocarditis.

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a rare clinical entity in children. Occult myocarditis has not been previously implicated as an etiologic agent. A 3-year-old female presents with a presumed breath-holding spell and is found to have ventricular fibrillation requiring DC cardioversion. An invasive electrophysiological study was performed demonstrating the absence of inducible ventricular arrhythmias. Low dose epinephrine confirmed the presence CPVT. Right ventricular endomyocardial biopsies sent for polymerase chain reaction (PCR) analysis demonstrated the presence of adenoviral DNA. The authors hypothesize that occult myocarditis may be the inciting agent for CPVT in children.