Brian Feingold

Persistent strong anti-HLA antibody at high titer is complement binding and associated with increased risk of antibody-mediated rejection in heart transplant recipients

BACKGROUND Sensitized heart transplant candidates are evaluated for donor-specific anti-HLA IgG antibody (DSA) by Luminex single-antigen bead (SAB) testing (SAB-IgG) to determine donor suitability and help predict a positive complement-dependent cytotoxicity crossmatch (CDC-XM) by virtual crossmatching (VXM). However, SAB testing used for VXM does not correlate perfectly with CDC-XM results and individual transplant programs have center-specific permissible thresholds to predict crossmatch positivity. A novel Luminex SAB-based assay detecting C1q-binding HLA antibodies (SAB-C1q) contributes functional information to SAB testing, but the relationship between SAB strength and complement-binding ability is unclear. METHODS In this retrospective study, we identified 15 pediatric and adult heart allograft candidates with calculated panel-reactive antibody (cPRA) >50% by SAB-IgG and compared conventional SAB-IgG results with SAB-C1q testing. RESULTS Pre- and post-transplant DSA by SAB-C1q correlated with DSA by SAB-IgG and also with CDC-XM results and early post-transplant endomyocardial biopsy findings. Individual HLA antibodies by SAB-IgG in undiluted sera correlated poorly with SAB-C1q; however, when sera were diluted 1:16, SAB-IgG results were well correlated with SAB-C1q. In some sera, HLA antibodies with low mean fluorescent intensity (MFI) by SAB-IgG exhibited high SAB-C1q MFIs for the same HLA antigens. Diluting or heat-treating these sera increased SAB-IgG MFI, consistent with SAB-C1q results. In 13 recipients, SAB-C1q-positive DSA was associated with positive CDC-XM and with early clinical post-transplant antibody-mediated rejection (cAMR). CONCLUSIONS Risk assessment for positive CDC-XM and early cAMR in sensitized heart allograft recipients are correlated with SAB-C1q reactivity.

Chronic High Epstein-Barr Viral Load State and Risk for Late-Onset Posttransplant Lymphoproliferative Disease/Lymphoma in Children

Increased use of serial EBV‐PCR monitoring after pediatric transplantation has led to the identification of asymptomatic patients who carry very high viral loads over prolonged periods. The significance of this high‐load state is unknown. We speculated that this state may identify patients at high risk for development of late PTLD/lymphoma. We reviewed data on 71 pediatric heart recipients who had serial viral load monitoring since 1997. Chronic high‐load state was defined as the presence of >16 000 genome copies/mL whole blood on ≥50% of samples over at least 6 months. Among 20 high‐load carriers (eight following prior PTLD, seven with prior symptomatic EBV infection, five without previous EBV disease), 9 (45%) developed late‐onset PTLD 2.5–8.4 years posttransplant (including with four Burkitts lymphoma). Among 51 controls with low (n = 39) or absent (n = 12) loads, only 2 (4%; p < 0.001 absent/low vs. high load) developed late PTLD/lymphoma. By multivariable analysis, high‐load carrier state (OR = 12.4, 95% CI 2.1–74.4) and prior history of PTLD (OR = 10.7, 95% CI 1.9–60.6) independently predicted late PTLD. A chronic high EBV‐load state is not benign and is a predictor of de novo or recurrent PTLD.

Outcomes of Children With Cardiomyopathy Listed for Transplant: A Multi-institutional Study

BACKGROUND Dilated (DCM), restrictive (RCM), and hypertrophic (HCM) cardiomyopathies (CM) in children have varying clinical courses and therapeutic options. Heart transplantation (HTx) offers a chance for long-term survival; but outcomes after listing have not been well defined. METHODS A multi-institutional registry of 3,147 patients listed for HTx (January 1993-December 2006) was used to compare outcomes of 1,320 children with CM (42%) and 1,827 with non-CM (58%) etiologies. Comparisons were made between sub-groups: 1,098 DCM (83%), 145 RCM (11%), and 77 HCM (6%). RESULTS CM patients had a waitlist mortality of 17% vs 32% for non-CM patients (p < 0.0001), with no difference between the CM sub-groups. Risk factors were younger age, black race (relative risk [RR], 1.65; p = 0.009), mechanical ventilation (RR, 3.17; p < 0.001), and extracorporeal membrane oxygenation (RR, 2.16; p < 0.001). Ten-year survival after listing was 66% for CM vs 53% for non-CM (p < 0.0001). HCM and RCM patients aged < 1 year at the time of listing had the highest waitlist mortality and the lowest overall survival. CM patients had a better 10-year survival after HTx (68% vs 61%, p < 0.0001). Risk factors for death early after HTx included mechanical ventilation at HTx (RR, 3.07; p < 0.001), longer ischemic time (RR, 1.27; p = 0.01), and earlier era (RR, 1.77; p = 0.002). Late risk factors included black race (RR, 3.01; p < 0.001), HCM or RCM (RR, 1.93; p = 0.007), and older age (RR, 1.9; p < 0.001). CONCLUSION Children with CM have a lower waitlist mortality and better survival post-HTx than children with a non-CM diagnosis. DCM patients have the best and HCM or RCM patients aged younger than 1 year have the worst overall outcomes.

Extubation after cardiothoracic surgery in neonates, children, and young adults: One year of institutional experience.

Objective: Describe risk factors associated with successful and early extubation in the pediatric cardiac intensive care unit. Design: Retrospective chart review. Setting: University hospital, cardiac intensive care unit. Measurements and Main Results: Review of 212 consecutive surgical admissions from January 2003 to January 2004, excluding deaths. Preoperative, intraoperative, and postoperative variables were studied. Successful extubation was defined as no reintubation at any time during the cardiac intensive care unit course and early extubation was defined as mechanical ventilation ≤24 hrs. Median subject age was 8 months (range, 1 day-25 yrs), with 57% <1 yr of age and 22% neonates. Fifty-eight (27%) were extubated in the operating room and 122 (58%) were extubated at <24 hrs (mean, 6.1 ± 7.7 hrs). Only seven patients failed extubation: three in the operating room because of upper airway obstruction and four in the cardiac intensive care unit for acute respiratory failure associated with atelectasis (n = 2), ventricular dysfunction (n = 1), and arrhythmia (n = 1). There were no extubation failures in patients extubated >24 hrs after surgery. A history of prematurity (odds ratio [OR], 5.84, 2.29–14.9; p < .001), base excess (OR, 1.47, 1.27–1.70; p < .001), cardiopulmonary bypass time (OR, 1.01, 1.01 to −1.2; p < .05), and the need for surgical reintervention (OR, 18.29, 2.78 to −120.07; p < .05) were associated with intubation for >24 hrs. Conclusion: Extubation without the need for reintubation can be achieved in nearly all children following cardiothoracic surgery. The majority of successful extubations can be achieved within 24 hrs of surgery.

Risk Factors for Late Renal Dysfunction after Pediatric Heart Transplantation: A Multi-institutional Study

Feingold B, Zheng J, Law YM, Morrow WR, Hoffman TM, Schechtman KB, Dipchand AI, Canter CE and the Pediatric Heart Transplant Study Investigators. Risk factors for late renal dysfunction after pediatric heart transplantation: A multi‐institutional study.
Pediatr Transplantation 2011: 15: 699–705.

Congenital extrahepatic portosystemic shunt associated with heterotaxy and polysplenia

BackgroundHeterotaxy with polysplenia is associated with many cardiovascular anomalies including the occasional occurrence of congenital extrahepatic portosystemic shunts (CEPS). Missing this anomaly can lead to inappropriate and ineffective therapy.ObjectiveTo emphasize the importance and associated anatomy of CEPS in conjunction with heterotaxy with polysplenia.Materials and methodsReview of three young children who presented with cyanosis and pulmonary hypertension without a cardiac etiology. They were known (1) or discovered (2) to have heterotaxy with polysplenia.ResultsThere was absence of the intrahepatic inferior vena cava (IVC) with azygos or hemiazygos continuation in all three cases. In spite of normal liver function, they were discovered to have large portosystemic shunts, splenorenal in location, along with diffuse peripheral pulmonary arterial dilatation suggestive of CEPS (Abernethy malformation) with hepatopulmonary or, more accurately, portopulmonary syndrome. All CEPS were ipsilateral to the spleens. Patency of the portal veins in these cases allowed for percutaneous shunt closure with resolution of cyanosis.ConclusionCEPS is associated with heterotaxy with polysplenia and can be symptomatic because of pulmonary arteriovenous (AV) shunting. Portal and hepatic vein patency are critical for determining feasibility of CEPS closure.

Human leukocyte antigen epitope analysis to assess complement- and non- complement-binding donor-specific antibody repertoire in a pediatric heart transplant recipient

This case report summarizes the spectrum of anti-human leukocyte antigen (HLA) antibody reactivity determined by single-allele Luminex immunoglobulin G and C1q binding assays before transplant, during an episode of antibody-mediated rejection (AMR), and following treatment in a sensitized pediatric heart transplant (Tx) recipient. We were able to discriminate between complement- and non-complement-binding epitope-specific antibodies present against a single donor antigen (HLA-A2) during the progression of AMR and its resolution. Our findings illustrate the usefulness of determining antibody specificities against epitopes using various Luminex-based assays.

Outcomes after listing with a requirement for a prospective crossmatch in pediatric heart transplantation

BACKGROUND Allosensitization is associated with inferior waitlist outcomes in pediatric heart transplant candidates, presumably because of the requirement for a negative prospective crossmatch. However, there are no reports of heart transplant candidate outcomes according to prospective crossmatch requirements. METHODS We analyzed data on all children listed for isolated heart transplantation from 1995 to 2009 in the USA according to prospective crossmatch requirement (PXMR). Primary objectives were to describe the prevalence of PXMR at and during listing and to compare waitlist and post-transplant survival for patients based on PXMR. Patients with a PXMR during listing include those with a PXMR at the time of listing as well as those who were designated by the listing center as needing a prospective crossmatch at some point after being placed onto the waitlist. RESULTS Among 6,343 listed children, 7.7% had a requirement for a prospective crossmatch at the time of listing and 11.8% had a requirement for a prospective crossmatch during listing. After controlling for risk factors associated with inferior survival, PXMR at listing was associated with increased waitlist mortality (HR 1.32, 95% CI 1.10 to 1.56; p = 0.003). Recipients with a PXMR during listing more commonly had a positive DSXM (22.1% vs 10.3%, p < 0.0001), as did recipients who carried a PXMR throughout listing (21.7% vs 11.3%, p = 0.004). However, there was no significant difference in post-transplant survival on the basis of a PXMR during listing (HR 1.04, 95% CI 0.87 to 1.25; p = 0.67). Nearly 30% of recipients with a PXMR during listing had a peak pre-transplant PRA ≤ 10%. CONCLUSIONS PXMR increases the likelihood of death while awaiting, but not after, pediatric heart transplantation. Further study is necessary to understand how PXMR is applied, and changes, after listing for pediatric heart transplantation.

Cost-Effectiveness of Implantable Cardioverter-Defibrillators in Children With Dilated Cardiomyopathy

BACKGROUND Implantable cardioverter-defibrillators (ICDs) improve survival and are cost-effective in adults with poor left ventricular function. Because of differences in heart failure etiology, sudden death rates, and ICD complication rates, these findings may not be applicable to children. METHODS AND RESULTS We developed a Markov model to compare typical management of childhood dilated cardiomyopathy with symptomatic heart failure to prophylactic ICD implantation plus typical management. Model costs included costs of outpatient care, medications, complications, and transplantation. Time horizon was up to 20 years from model entry. Total costs were

Expression of A and B Blood Group Antigens on Cryopreserved Homografts

433,000 (ICD strategy) and