External assessment and refinement of a population pharmacokinetic model to guide tacrolimus dosing in pediatric heart transplant.

STUDY OBJECTIVE: The immunosuppressant tacrolimus is a first-line agent to prevent graft rejection following pediatric heart transplant; however, it suffers from extensive inter-patient variability and a narrow therapeutic window. Personalized tacrolimus dosing may improve transplant outcomes by more efficiently achieving and maintaining therapeutic tacrolimus concentrations. We sought to externally validate a previously published population pharmacokinetic (PK) model that was constructed with data from a single site. DATA SOURCE: Data were collected from Seattle, Texas, and Boston Children's Hospitals, and assessed using standard population PK modeling techniques in NONMEMv7.2. MAIN RESULTS: While the model was not successfully validated for use with external data, further covariate searching identified weight (p < 0.0001 on both volume and elimination rate) as a model-significant covariate. This refined model acceptably predicted future tacrolimus concentrations when guided by as few as three concentrations (median prediction error = 7%; median absolute prediction error = 27%). CONCLUSION: These findings support the potential clinical utility of a population PK model to provide personalized tacrolimus dosing guidance.

Cardiac imaging and biomarkers for assessing myocardial fibrosis in children with hypertrophic cardiomyopathy.

BACKGROUND: Myocardial fibrosis, as diagnosed on cardiac magnetic resonance imaging (cMRI) by late gadolinium enhancement (LGE), is associated with adverse outcomes in adults with hypertrophic cardiomyopathy (HCM), but its prevalence and magnitude in children with HCM have not been established. We investigated: (1) the prevalence and extent of myocardial fibrosis as detected by LGE cMRI; (2) the agreement between echocardiographic and cMRI measurements of cardiac structure; and (3) whether serum concentrations of N-terminal pro hormone B-type natriuretic peptide (NT-proBNP) and cardiac troponin-T are associated with cMRI measurements. METHODS: A cross-section of children with HCM from 9 tertiary-care pediatric heart centers in the U.S. and Canada were enrolled in this prospective NHLBI study of cardiac biomarkers in pediatric cardiomyopathy (ClinicalTrials.gov Identifier: NCT01873976). The median age of the 67 participants was 13.8 years (range 1-18 years). Core laboratories analyzed echocardiographic and cMRI measurements, and serum biomarker concentrations. RESULTS: In 52 children with non-obstructive HCM undergoing cMRI, overall low levels of myocardial fibrosis with LGE >2% of left ventricular (LV) mass were detected in 37 (71%) (median %LGE, 9.0%; IQR: 6.0%, 13.0%; range, 0% to 57%). Echocardiographic and cMRI measurements of LV dimensions, LV mass, and interventricular septal thickness showed good agreement using the Bland-Altman method. NT-proBNP concentrations were strongly and positively associated with LV mass and interventricular septal thickness (P < .001), but not LGE. CONCLUSIONS: Low levels of myocardial fibrosis are common in pediatric patients with HCM seen at referral centers. Longitudinal studies of myocardial fibrosis and serum biomarkers are warranted to determine their predictive value for adverse outcomes in pediatric patients with HCM.

Fontan-associated liver disease after heart transplant.

BACKGROUND: Fontan associated liver disease (FALD) potentially impacts Fontan patients undergoing heart transplant. This multi-center study sought to identify pre-transplant risk factors and characterize any post-transplant liver recovery in those patients undergoing heart-alone transplant. METHODS: Review of Fontan patients at 12 pediatric institutions who underwent heart transplant between 2001-2019. Radiologists reviewed pre and post-transplant liver imaging for fibrosis. Laboratory, pathology and endoscopy studies were reviewed. RESULTS: 156 patients underwent transplant due to decreased ventricular function (49%), protein losing enteropathy (31%) or plastic bronchitis (10%); median age at transplant was 13.6 years (interquartile range IQR 7.8, 17.2) with a median of 9.3 years (IQR 3.2, 13.4) between the Fontan operation and transplant. Few patients had pre-transplant endoscopy (18%), and liver biopsy (19%). There were 31 deaths (20%). The median time from transplant to death was 0.5 years (95% Confidence Interval CI 0.0, 3.6). The five-year survival was 73% (95% CI 64%, 83%). Deaths were related to cardiac causes in 68% (21/31) and infection in 6 (19%). A pre-transplant elevation in bilirubin was a predictor of death. Higher platelet levels were protective. Immediate post-transplant elevations in creatinine, AST, ALT, and INR were predictive of death. Advanced liver fibrosis identified on ultrasound, computed tomography, or magnetic resonance imaging was not predictive of death. Liver imaging suggested some improvement in liver congestion post-transplant. CONCLUSIONS: Elevated bilirubin, but not fibrosis on liver imaging, was associated with post-heart transplant mortality in Fontan patients in this multicenter retrospective study. Additionally, heart transplant may alter the progression of FALD.

Attitudes & practices surrounding pregnancy post heart transplant among pediatric providers.

BACKGROUND: Many pediatric heart transplant (HT) recipients reach adulthood and may be interested in family planning; there is little data regarding safety of pregnancy post HT and clinicians' opinions differ. Pediatric HT clinicians are instrumental in early counseling. Thus, a better understanding of pediatric HT clinicians' practices regarding family planning and how well aligned these practices are with adult transplant centers is essential. METHODS: We conducted a confidential, web-based survey of pediatric HT clinicians in fall 2021. We summarized and compared answers using Fisher's exact test. RESULTS: The survey was sent to 53 United States-based HT directors and to the International Society for Heart and Lung Transplantation and Pediatric Heart Transplant Society list serves. There were 69 respondents. The majority (77%) of respondents felt pregnancy was feasible in selected or all female HT recipients. Ten respondents reported that their institution had an established policy regarding pregnancy post HT. A majority (77%) of HT clinicians would either use a shared care model or recommend transition to their adult institution if pregnancy occurred, though 74% of respondents were either unaware of their corresponding adult institution's policy (62%) or had a counterpart adult program with a policy against pregnancy post HT (12%). CONCLUSIONS: While many clinicians feel pregnancy is feasible in pediatric HT recipients, there remains significant practice variation. Few pediatric programs have a policy regarding pregnancy post HT. Future efforts to provide consistent messaging between adult and pediatric HT programs regarding the feasibility and care of post HT pregnancy are warranted.

Implications of Left Ventricular Dysfunction at Presentation for Infants with Coarctation of the Aorta.

Infants with aortic coarctation may present with left ventricular (LV) dysfunction which may complicate the postoperative course and lead to increased healthcare costs. We aimed to define the prevalence of moderate to severe left ventricular (LV) systolic dysfunction, evaluate time to recovery, and compare health care costs. Single-center retrospective cohort study at a tertiary care hospital was conducted. Infants < 6 months old at diagnosis with aortic coarctation were identified using surgical codes for coarctation repair between January 2010 and May 2018. Moderate to severe dysfunction was defined as ejection fraction (EF) < 40%. Of 160 infants studied, 18 (11%) had moderate to severe LV dysfunction at presentation. Compared to those with better LV function, infants with moderate to severe LV dysfunction were older at presentation (12 vs. 6 days, p = 0.004), had more postoperative cardiac intensive care unit (ICU) days (5 vs. 3, p < 0.001), and more ventilator days (3.5 vs. 1, p < 0.001). The median time to normal LV EF (≥ 55%) was 6 days postoperatively (range 1-230 days). Infants presenting with moderate to severe LV dysfunction had higher index hospitalization costs ($90,560 vs. $59,968, p = 0.02), but no difference in cost of medical follow-up for the first year following discharge ($3,078 vs. $2,568, p = 0.46). In the current era, > 10% of infants with coarctation present with moderate to severe LV dysfunction that typically recovers. Those with moderate to severe dysfunction had longer duration of mechanical ventilation and postoperative cardiac ICU stays, likely driving higher costs of index hospitalization.

Cardiac Biomarkers in Pediatric Cardiomyopathy: Study Design and Recruitment Results from the Pediatric Cardiomyopathy Registry.

BACKGROUND: Cardiomyopathies are a rare cause of pediatric heart disease, but they are one of the leading causes of heart failure admissions, sudden death, and need for heart transplant in childhood. Reports from the Pediatric Cardiomyopathy Registry (PCMR) have shown that almost 40% of children presenting with symptomatic cardiomyopathy either die or undergo heart transplant within 2 years of presentation. Little is known regarding circulating biomarkers as predictors of outcome in pediatric cardiomyopathy. STUDY DESIGN: The Cardiac Biomarkers in Pediatric Cardiomyopathy (PCM Biomarkers) study is a multi-center prospective study conducted by the PCMR investigators to identify serum biomarkers for predicting outcome in children with dilated cardiomyopathy (DCM) and hypertrophic cardiomyopathy (HCM). Patients less than 21 years of age with either DCM or HCM were eligible. Those with DCM were enrolled into cohorts based on time from cardiomyopathy diagnosis: categorized as new onset or chronic. Clinical endpoints included sudden death and progressive heart failure. RESULTS: There were 288 children diagnosed at a mean age of 7.2±6.3 years who enrolled in the PCM Biomarkers Study at a median time from diagnosis to enrollment of 1.9 years. There were 80 children enrolled in the new onset DCM cohort, defined as diagnosis at or 12 months prior to enrollment. The median age at diagnosis for the new onset DCM was 1.7 years and median time from diagnosis to enrollment was 0.1 years. There were 141 children enrolled with either chronic DCM or chronic HCM, defined as children ≥2 years from diagnosis to enrollment. Among children with chronic cardiomyopathy, median age at diagnosis was 3.4 years and median time from diagnosis to enrollment was 4.8 years. CONCLUSION: The PCM Biomarkers study is evaluating the predictive value of serum biomarkers to aid in the prognosis and management of children with DCM and HCM. The results will provide valuable information where data are lacking in children. CLINICAL TRIAL REGISTRATION NCT01873976: https://clinicaltrials.gov/ct2/show/NCT01873976?term=PCM+Biomarker&rank=1.

Predicting tacrolimus concentrations in children receiving a heart transplant using a population pharmacokinetic model.

OBJECTIVE: Immunosuppressant therapy plays a pivotal role in transplant success and longevity. Tacrolimus, a primary immunosuppressive agent, is well known to exhibit significant pharmacological interpatient and intrapatient variability. This variability necessitates the collection of serial trough concentrations to ensure that the drug remains within therapeutic range. The objective of this study was to build a population pharmacokinetic (PK) model and use it to determine the minimum number of trough samples needed to guide the prediction of an individual's future concentrations. DESIGN SETTING AND PATIENTS: Retrospective data from 48 children who received tacrolimus as inpatients at Primary Children's Hospital in Salt Lake City, Utah were included in the study. Data were collected within the first 6 weeks after heart transplant. OUTCOME MEASURES: Data analysis used population PK modelling techniques in NONMEM. Predictive ability of the model was determined using median prediction error (MPE, a measure of bias) and median absolute prediction error (MAPE, a measure of accuracy). Of the 48 children in the study, 30 were used in the model building dataset, and 18 in the model validation dataset. RESULTS: Concentrations ranged between 1.5 and 37.7 µg/L across all collected data, with only 40% of those concentrations falling within the targeted concentration range (12 to 16 µg/L). The final population PK model contained the impact of age (on volume), creatinine clearance (on elimination rate) and fluconazole use (on elimination rate) as covariates. Our analysis demonstrated that as few as three concentrations could be used to predict future concentrations, with negligible bias (MPE (95% CI)=0.10% (-2.9% to 3.7%)) and good accuracy (MAPE (95% CI)=24.1% (19.7% to 27.7%)). CONCLUSIONS: The use of PK in dose guidance has the potential to provide significant benefits to clinical care, including dose optimisation during the early stages of therapy, and the potential to limit the need for frequent drug monitoring.

ISHLT pathology antibody mediated rejection score correlates with increased risk of cardiovascular mortality: A retrospective validation analysis.

BACKGROUND: Antibody-mediated rejection (AMR) in cardiac transplant recipients is a serious form of rejection with adverse patient outcomes. The International Society of Heart and Lung Transplantation (ISHLT) has published a consensus schema for the pathologic diagnosis of various grades of antibody-mediated rejection (pathology antibody-mediated rejection [pAMR]). We sought to determine whether the ISHLT pAMR grading schema correlates with patient outcomes. METHODS: Using our database, which contains a semi-quantitative scoring of all pathologic descriptors of pAMR, we retrospectively used these descriptors to convert the previous AMR categories to the current ISHLT pAMR categories. Cox proportional hazard models were fit with cardiovascular (CV) death or retransplant as the outcome. The pAMR value was included as a categorical variable, and cellular rejection (CR) values were included in a separate model. RESULTS: There were 13,812 biopsies from 1,014 patients analyzed. The pAMR grades of pAMR1h, pAMR1i, and pAMR2 conferred comparable increased risk for CV mortality. Significantly increased risk of CV mortality was conferred by biopsies graded as severe AMR (pAMR3). CONCLUSIONS: The new ISHLT pAMR grading schema identifies patients at increased risk of CV mortality, consistent with risks published from several programs before 2011. The current schema is validated by this analysis in a large biopsy database. Because pAMR1h, pAMR1i, and pAMR2 have similar CV risks associated with them, the threshold for a positive diagnosis of pAMR should be re-evaluated in future iterations of the ISHLT schema.

Systolic-diastolic functional coupling in healthy children and in those with dilated cardiomyopathy.

Systolic and diastolic function affect dilated cardiomyopathy (DCM) outcomes. However, systolic-diastolic coupling, as a distinct characteristic, may itself affect function but is poorly characterized. We hypothesized that echocardiographic left ventricular (LV) longitudinal systolic tissue velocities (S') correlate with diastolic longitudinal velocities (E') and that their relationship is associated with ventricular function and that this relationship is impaired in pediatric DCM. We analyzed data from the Pediatric Heart Network Ventricular Volume Variability study, using linear regression and generalized additive modeling to assess relationships between S' and E' at the lateral and septal mitral annulus. We explored relationships between the systolic:diastolic (S:D) coupling ratio (S':E' relative to age) and ventricular function. Up to 4 echocardiograms from 130 DCM patients (mean age: 9.3 ± 6.1 yr) and 1 echocardiogram from each of 591 healthy controls were analyzed. S' and E' were linearly related in controls (r = 0.64, P < 0.001) and DCM (r = 0.83, P < 0.001). In DCM, the magnitude of association between S' and E' was reduced with progressive ventricular remodeling. The S:D ratio was more strongly associated with LV function in controls vs. DCM. The septal S:D ratio was higher (presumed worse) in DCM vs. controls (0.69 ± 0.13 vs. 0.62 ± 0.12, P = 0.001). A higher septal S:D ratio was associated with worse LV dimensions (parameter estimate: 0.0061, P = 0.004), mass (parameter estimate: 0.0074, P = 0.002), ejection fraction (parameter estimate: -0.0303, P = 0.024), and inflow propagation (parameter estimate: -0.3538, P < .001). S:D coupling becomes weaker in DCM with LV remodeling and dysfunction. The S:D coupling ratio may be useful to assess coupling, warranting study in relation to patient outcomes.

Mixed cellular and antibody-mediated rejection in heart transplantation: In-depth pathologic and clinical observations.

BACKGROUND: Little is known about mixed cellular and antibody-mediated rejection (MR) in heart transplantation. It remains unclear whether cardiac MR has distinctive pathologic and clinical features beyond those of simultaneous cellular rejection (CR) and antibody-mediated rejection (AMR). In this study we systematically explore the pathologic and clinical characteristics of MR in heart transplantation. METHODS: The UTAH Cardiac Transplant Program database was queried for transplant recipients who survived long enough to have at least one endomyocardial biopsy (EMB) between 1985 and 2014. Only EMBs with both CR and AMR scores documented were included. In addition to detailed pathologic analyses, we also examined the incidence and prevalence of MR, the likelihood to transition from and to MR, and mortality associated with MR. RESULTS: Patients (n = 1,207) with a total of 28,484 EMBs met the study inclusion criteria. The overall prevalence of MR was 7.8% and it was nearly twice as frequent within the first year post-transplant. Mild MR was by far the most common occurrence and was typically preceded by an immune active state. When CR increased in severity, AMR tended to follow, but the reverse was not true. On pathology, individual features of CR and AMR were more easily separated in cases of mild MR, whereas they substantially overlapped in more severe cases. MR was associated with a significant cardiovascular death risk that was incremental with severity. CONCLUSIONS: MR is not common, usually occurs early after transplant, and is associated with worse outcomes. MR reflects a complex interplay between cellular and humoral processes, which varies with rejection severity.

Impact of initial Norwood shunt type on young hypoplastic left heart syndrome patients listed for heart transplant: A multi-institutional study.

BACKGROUND: Pulmonary blood flow during Stage 1 (Norwood) palliation for hypoplastic left heart syndrome (HLHS) is achieved via modified Blalock-Taussig shunt (MBT) or right ventricle to pulmonary artery conduit (RVPA). Controversy exists regarding the differential impact of shunt type on outcome among those who require transplantation early in life. In this study we explored waitlist and post-transplant outcomes within this sub-population stratified by shunt type. METHODS: Eligible patients were enrolled through the Pediatric Heart Transplant Study (PHTS) database. Patients included those listed for heart transplantation at 1 of 35 participating centers, all of whom were <6 years of age and with a diagnosis of HLHS (and variants) status post Stage 1 palliation with MBT or RVPA. Standard risk factors for death were analyzed using multivariable hazards modeling. RESULTS: Between 2010 and 2013, 190 patients were identified. Compared with the RVPA group (n = 111), the MBT group (n = 79) was less likely to have undergone a Glenn palliation (41% vs 73%, p < 0.001), were younger at listing (median age 1.3 vs 1.8 years, p = 0.05), had lower median weight (7.9 vs 9.4 kg, p = 0.02), and were more likely to be mechanically ventilated at listing (35% vs 22%, p = 0.04). There were no significant differences in median waitlist time (1.7 vs 2.6 months, p = 0.2) or rate of transplantation (61% vs 60%, p = 1.0). Among waitlisted patients, 3-month survival was less for MBT compared with RVPA patients (74% vs 91%, p = 0.02). Patients who had not yet achieved Glenn palliation before listing had lower waitlist 3-month survival (76% vs 90%, p = 0.02). In MBT infants <1 year old, there was a trend toward improved survival in those with Glenn palliation compared to those without (100% vs 68%, p = 0.08). Early post-transplant mortality rates were similar between the RVPA and MBT groups (p = 0.4) with overall survival 84% at 1 year. CONCLUSIONS: Among HLHS patients, the need for transplant before Glenn palliation is associated with poorer waitlist survival. Waitlist survival is poorer in the MBT group, with this difference driven by pre-Glenn MBT infants. Post-transplant outcomes were unaffected by shunt type.

Yield of cardiac magnetic resonance imaging as an adjunct to echocardiography in young infants with congenital heart disease.

Echocardiography provides adequate preoperative imaging for most young infants with congenital heart disease (CHD). When anatomic details require further clarification, cardiac magnetic resonance imaging (CMRI) may be useful but adds the risks of sedation or general anesthesia for a vulnerable population. This study aimed to determine the safety of CMRI and its yield of additional significant information for this population. The study identified all infants age 90 days or younger with preoperative echocardiography and a CMRI from the period 2002-2012. Indications, complications, and imaging results were collected. The additional CMRI information was defined as "significant" if it altered surgical management or "not significant" if it did not. Associations between indications for CMRI and the likelihood of new significant findings were sought. For 137 infants (58% male), CMRI was performed at a median age of 5 days (range, 0-89 days). The CMRI yielded additional information for 76% (104/137) of the patients. The additional findings were significant for 69% (72/104) of these patients. The incidence of significant new findings was similar among indication categories. All the infants were intubated. Complications occurred for 5% of the patients, including one subject with a bradycardic event that prevented completion of the exam and six patients with transient vital sign changes that allowed exam completion. More than 50% of young infants with CHD who underwent preoperative CMRI had new findings affecting surgical management. Among these patients, CMRI-associated complications were few and predominantly minor for intubated infants. Further studies to determine standard preoperative criteria for the use of CMRI for infants with CHD may help to define appropriate cost-effective use of this diagnostic method.

Pulmonary artery resuscitation for isolated ductal origin of a pulmonary artery.

OBJECTIVE: Ductal origin of a pulmonary artery (DOPA) is commonly misdiagnosed as agenesis of a pulmonary artery (PA), which may result in inadequate treatment. The objective is to describe the results of resuscitation of unilateral DOPA. METHODS: This study is a retrospective review of all patients with unilateral DOPA who underwent PA resuscitation at Texas Children's Hospital from 1993 to 2012. Patients with other cardiac or contralateral lung anomalies were excluded. RESULTS: Ten patients, median age 2 years (range, 3 days to 9 years), with unilateral DOPA were included. Symptoms were present in 6 patients. Cardiac catheterization was performed in all and showed a patent duct or a ductal stump in most patients and a small PA on wedge angiography of the pulmonary veins. Two patients underwent single-stage centralization. The other 8 underwent ductal stenting (n=2) or a systemic-to-PA shunt (n=6) as the first stage before centralization. The 2 patients with ductal stenting developed pulmonary edema. The 2 patients with a cryopreserved vein shunt developed early thrombosis requiring reintervention. Nine patients have undergone centralization. Six patients have required further interventional procedures. There have been no deaths. Symptoms and lung hypoplasia have improved in all patients. Median relative lung perfusion at follow-up was 26% (range, 12%-46%) with significant improvement in the size of the affected PA. CONCLUSIONS: PA resuscitation is effective at restoring flow to the affected lung resulting in improved diameter of the PA, lung growth, and resolution of symptoms. PA resuscitation should be considered in all children with DOPA, including those beyond infancy.

Predictors of disease progression in pediatric dilated cardiomyopathy.

BACKGROUND: Despite medical advances, children with dilated cardiomyopathy (DCM) remain at high risk of death or need for cardiac transplantation. We sought to identify predictors of disease progression in pediatric DCM. METHODS AND RESULTS: The Pediatric Heart Network evaluated chronic DCM patients with prospective echocardiographic and clinical data collection during an 18-month follow-up. Inclusion criteria were age <22 years and DCM disease duration >2 months. Patients requiring intravenous inotropic/mechanical support or listed status 1A/1B for transplant were excluded. Disease progression was defined as an increase in transplant listing status, hospitalization for heart failure, intravenous inotropes, mechanical support, or death. Predictors of disease progression were identified using Cox proportional hazards modeling and classification and regression tree analysis. Of the 127 patients, 28 (22%) had disease progression during the 18-month follow-up. Multivariable analysis identified older age at diagnosis (hazard ratio=1.14 per year; P<0.001), larger left ventricular (LV) end-diastolic M-mode dimension z-score (hazard ratio=1.49; P<0.001), and lower septal peak systolic tissue Doppler velocity z-score (hazard ratio=0.81; P=0.01) as independent predictors of disease progression. Classification and regression tree analysis stratified patients at risk of disease progression with 89% sensitivity and 94% specificity based on LV end-diastolic M-mode dimension z-score ≥7.7, LV ejection fraction <39%, LV inflow propagation velocity (color M-mode) z-score <-0.28, and age at diagnosis ≥8.5 months. CONCLUSIONS: In children with chronic stable DCM, a combination of diagnosis after late infancy and echocardiographic parameters of larger LV size and systolic and diastolic function predicted disease progression. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00123071.

Parvovirus B19 myocarditis causes significant morbidity and mortality in children.

Although parvovirus B19 (PVB19) currently is the most common cause of viral myocarditis, limited pediatric data exist. Whereas other viruses infect cardiomyocytes, PVB19 targets coronary endothelium, leading to myocardial ischemia and dysfunction. A retrospective review investigated patients with polymerase chain reaction (PCR)-verified PVB19 myocarditis at Texas Children's Hospital and Arkansas Children's Hospital (January 2005 to August 2008). The primary end points of the study were transplant-free survival and circulatory collapse (death, mechanical support, or transplantation). For the 19 patients identified (age, 6 months to 15 years), the most common presenting symptoms were respiratory and gastrointestinal. At admission, all the patients demonstrated ventricular dysfunction requiring inotropic support (median ejection fraction, 24 %; median left ventricle end-diastolic diameter [LVEDD] z-score, 4.6). Whereas T-wave abnormalities were common, ST elevation was evident in five patients (two died and three required transplantation). Serum B-type natrietic peptide was elevated in all 12 patients tested (range, 348-8,058 pg/ml), and troponin I was high in 7 of 9 patients (range, 0.04-14.5 ng/ml). Of the 15 patients with circulatory collapse, nine received mechanical support, eight underwent successful transplantation, and five died. Only six patients (32 %) experienced transplant-free survival, and five patients had full recovery of function at discharge. In the transplant-free survival group, ST changes on presenting electrocardiography were less likely (p = 0.03), and the admission LVEDD z-score tended to be lower (3.3 vs 5.6; p = 0.08). In children, PVB19 myocarditis causes significant mortality and morbidity. Although mechanical intervention can support patients in the initial stage of decompensated heart failure, patients with PVB19 myocarditis often demonstrate persistent dysfunction requiring medical therapy and transplantation.

Biopsy-diagnosed antibody-mediated rejection based on the proposed International Society for Heart and Lung Transplantation working formulation is associated with adverse cardiovascular outcomes after pediatric heart transplant.

BACKGROUND: There is greater awareness of the pathologic features and clinical implications of antibody-mediated rejection (AMR) after heart transplantation (HT). Yet, compared with adults, the lack of routine surveillance for AMR has limited the growth of evidence in the pediatric population. Herein, we compared outcomes of pediatric HT recipients with and without AMR. METHODS: All recipients ≤18 years of age with at least 1 endomyocardial biopsy (EMB) between 1988 and 2009 were included in this study. Assessment for AMR was routine. AMR severity was assigned retrospectively using the proposed 2011 ISHLT grading schema for pathologic AMR (pAMR). Outcome comparisons were made between patients with histologic and immunopathologic evidence for AMR (pAMR 2), those with severe AMR (pAMR 3), and those without evidence of AMR (pAMR 0) or without both histologic and immunopathologic findings (pAMR 1). RESULTS: Among 1,406 EMBs, pAMR 2 or higher was present in 258 (18%), occurring in 45 of 76 (59%) patients. Of the 17 episodes of pAMR 3 in 9 patients, 6 (35%) were sub-clinical. Mortality was not different between groups. Patients with at least 1 pAMR 3 episode had lower freedom from cardiovascular (CV) mortality or cardiac allograft vasculopathy within 5 years of HT than those without pAMR 3 (45% vs 91%, p < 0.001). CONCLUSIONS: Biopsy findings of AMR (pAMR 2 or higher) are common after pediatric HT. Like cellular rejection, biopsy grading of AMR seems important to delineate those at risk of adverse events. Our results suggest that pAMR 3 is associated with worse CV outcomes. Widespread surveillance for pAMR with a uniform grading system is an important next step to further validate these findings in the pediatric HT population.