Steven Zangwill

The virtual crossmatch – A screening tool for sensitized pediatric heart transplant recipients

Abstract:  Heart transplantation in the setting of human leukocyte antigen (HLA) sensitization is challenging, as a time‐consuming prospective crossmatch (XM) may be required, severely limiting the number of potential donors. We evaluated a ‘virtual XM’, defining a positive virtual XM as the presence of recipient pre‐formed anti‐HLA antibodies to the prospective donor HLA type, and compared the virtual XM to a standard direct XM. Bead‐based flow cytometric analysis was used to identify anti‐HLA antibody (Ab) present in a child listed for heart transplantation. Using recipient serum, direct‐flow cytometric T‐ and B‐cell XM were run for potential donors against whose HLA type the recipient had specific antibodies (group 1, n = 7) and for potential donors with predicted compatible HLA types by virtual XM (group 2, n = 7). Results were expressed as median channel difference (MCD) between the control and recipient serum. A positive T‐cell XM was defined as MCD > 50, whereas MCD > 100 constituted a positive B‐cell result. The rate of T‐cell reactivity was significantly less in group 2 than in group 1 (29% vs. 100%, p = 0.02); similarly, B‐cell reactivity was also less for group 2 (14% vs. 100%, p = 0.005). The virtual XM was 100% sensitive in detecting positive flow cytometric XM results for T and B cells. Although only 72% specific in predicting a negative T‐cell XM, and 86% specific for negative B‐cell XM, the false negatives were weakly positive and would probably have been clinically acceptable. Currently, potentially suitable donor organs are often declined for lack of a prospective XM; these organs may ultimately be allocated to more distant recipients or perhaps not used at all. While further studies are needed, virtual XM has the potential to improve availability of organs for sensitized patients and improve the overall allocation process.

Practical application of the virtual crossmatch.

Abstract:  Background: HLA antibody sensitization is a risk factor for morbidity and mortality following heart transplantation. We previously reported the results of our in vitro study demonstrating the predictive value of the Virtual Crossmatch (VXM) and have since applied it clinically for sensitized children listed for heart transplant at our center. The VXM utilizes the results of specific antibody screening via flow cytometry to predict acute incompatibility. This review examines the effect of the VXM on wait times and outcomes. Methods: The study population included all patients listed for heart transplantation at Childrens Hospital of Wisconsin. Antibody sensitization was defined as PRA > 10% and/or by the identification of HLA specific antibody using AHG‐CDC or flow cytometry. Categorical data was analyzed via Fishers exact test while continuous variables were compared via an unpaired t test. Results: There were a total of 111 listed patients between 7/91 – 9/06. The sensitization rate was 23% (25/111). 19 patients who went on to transplant, deterioration or death were divided into 3 groups depending on listing strategy; Group 1 were listed with a prospective crossmatch requirement, Group 2 with a VXM, and Group 3 with a retrospective cross match. 7/8 patients in group 1 died prior to transplant with median wait time of 119 days. 9/10 patients in group 2 were transplanted with 100% survival and median wait time of 65 days, Group 3 included 1 patient who received a graft after 54 days and died 3 months post transplant with humoral rejection. The VXM was highly concordant with the retrospective crossmatch. Conclusions: Use of a VXM can lead to shorter wait times and better outcomes as a listing strategy for sensitized children requiring cardiac transplantation. The VXM allows transplant physicians to risk stratify patients and consider an anticipated positive crossmatch as one additional factor in the risk‐benefit analysis inherent to any donor offer. This experience supports use of the VXM as an alternative to prospective crossmatch requirements. One should recognize that other era dependent improvements such as updated criteria for patient and donor selection along with newer therapies and bridging options may have contributed to superior outcomes seen in the more recent cohort of patients treated with the VXM approach.

Outcomes of children with restrictive cardiomyopathy listed for heart transplant: a multi-institutional study.

BACKGROUND Restrictive cardiomyopathy (RCM) in children often has a progressive nature, with a high risk of clinical deterioration and death. Heart transplantation (HTx) is a widely accepted therapy that offers long-term survival, but criteria for and outcomes after listing have not been well defined. METHODS A multi-institutional, prospective, event-driven data registry of 3,147 patients aged < 18 years listed for HTx from January 1993 to December 2006 was used to assess risk factors and survival of 145 listed RCM patients. RESULTS Mean age at listing was 8.1 years, with 44% listed as United Network of Organ Sharing status 1, 33% on inotropic support, 10% on a ventilator, and 5% on mechanical support. At 1 year, 82% of these patients survived to HTx, whereas 9% died waiting. Univariate risk factors for death while waiting included younger age (p < 0.001), ventilator dependence (p < 0.001), status 1 (p < 0.001), and inotrope usage (p < 0.001). Use of multiple support devices at listing (ventilator, extracorporeal membrane oxygenation, ventricular assist device, intraaortic balloon pump) was also an important risk factor for early phase death while waiting (relative risk; 9.01, p < 0.0001). Survival after listing was 63% at 10 years and compared favorably with survival for non-cardiomyopathy patients (p = 0.01). CONCLUSIONS Children with RCM awaiting HTx have a generally low waitlist mortality and reasonable overall survival. Children requiring mechanical support and infants had a significantly higher risk of death while waiting. Further study is warranted to identify factors important in determining the optimal timing of listing in children with RCM before the need for inotropic or mechanical support.

Use of a HeartWare Ventricular Assist Device in a Patient With Failed Fontan Circulation

We present a successful case of the use of a HeartWare ventricular assist device as a bridge to transplantation in an 11-year-old with a hypoplastic left heart and failed Fontan circulation.

Comparison of risk factors and outcomes for pediatric patients listed for heart transplantation after bidirectional Glenn and after Fontan: an analysis from the Pediatric Heart Transplant Study.

BACKGROUND Patients listed for transplant after the bidirectional Glenn (BDG) may have better outcomes than patients listed after Fontan. This study examined and compared outcomes after listing for BDG and Fontan patients. METHODS All patients listed for transplant after the BDG in the Pediatric Heart Transplant Study between January 1993 and December 2008 were evaluated. Comparisons were made with Fontan patients and with a matched cohort of congenital heart disease patients. Competing outcomes analysis and actuarial survival were evaluated for the study populations, including an examination of various risk factors. RESULTS Competing outcomes analysis for BDG and Fontan patients after listing were similar. There was no difference in actuarial survival after listing or transplant among the 3 cohorts. Mechanical ventilation, United Network of Organ Sharing status, and age were risk factors for death after listing in BDG and Fontan patients, but ventilation at the time of transplant was significant only for the Fontan patients. Mortality was increased in Fontan patients listed < 6 months after surgery compared with patients listed > 6 months after surgery, but no difference was observed in BDG patients. There was a trend toward improved survival after listing for both populations across 3 eras of the study, but this did not reach statistical significance. CONCLUSION Outcomes after listing for BDG and Fontan patients are similar. Mechanical ventilation at the time of transplant remains a significant risk factor for death in the Fontan population, as does listing for transplant soon after the Fontan, suggesting that some patients may benefit from transplant instead of Fontan completion.

Mechanical Support as Failure Intervention in Patients with Cavopulmonary Shunts (MFICS): Rationale and Aims of a New Registry of Mechanical Circulatory Support in Single Ventricle Patients

It is now recognized that a majority of single ventricle patients, those with functionally univentricular hearts, who have survived palliative cavopulmonary connection will experience circulatory failure and end-organ dysfunction due to intrinsic inadequacies of a circulation supported by a single ventricle. Thus, there are an increasing number of patients with functional single ventricles presenting with failing circulations that may benefit from mechanical circulatory support (MCS). The paucity of experience with MCS in this population, even at high volume cardiac centers, contributes to limited available data to guide MCS device selection and management. Thus, a registry of MCS in this population would be beneficial to the field. A conference was convened in January 2012 of pediatric and adult cardiologists, pediatric cardiac intensivists, congenital heart surgeons, and adult cardiothoracic surgeons to discuss the current state of MCS, ventricular assist device, and total artificial heart therapy for patients who have undergone cavopulmonary connection, either superior cavopulmonary connection or total cavopulmonary connection. Specifically, individual experience and challenges with VAD therapy in this population was reviewed and creation of a multiinstitutional registry of MCS/ventricular assist device in this population was proposed. This document reflects the consensus from the meeting and provides a descriptive overview of the registry referred to as Mechanical Support as Failure Intervention in Patients with Cavopulmonary Shunts.

Association of Race and Socioeconomic Position with Outcomes in Pediatric Heart Transplant Recipients

We assessed the association of socioeconomic (SE) position with graft loss in a multicenter cohort of pediatric heart transplant (HT) recipients. We extracted six SE variables from the US Census 2000 database for the neighborhood of residence of 490 children who underwent their primary HT at participating transplant centers. A composite SE score was derived for each child and four groups (quartiles) compared for graft loss (death or retransplant). Graft loss occurred in 152 children (122 deaths, 30 retransplant). In adjusted analysis, graft loss during the first posttransplant year had a borderline association with the highest SE quartile (HR 1.94, p = 0.05) but not with race. Among 1‐year survivors, both black race (HR 1.81, p = 0.02) and the lowest SE quartile (HR 1.77, p = 0.01) predicted subsequent graft loss in adjusted analysis. Among subgroups, the lowest SE quartile was associated with graft loss in white but not in black children. Thus, we found a complex relationship between SE position and graft loss in pediatric HT recipients. The finding of increased risk in the highest SE quartile children during the first year requires further confirmation. Black children and low SE position white children are at increased risk of graft loss after the first year.

Outcomes of Cardiac Transplantation in Single-Ventricle Patients With Plastic Bronchitis: A Multicenter Study

To the Editor: Plastic bronchitis (PB) is a rare condition characterized by formation of airway casts that obstruct the bronchial tree and cause respiratory failure. In the congenital cardiac population, PB occurs mostly in patients with single ventricle (SV) defects undergoing Fontan palliation.

A multi-institutional evaluation of antibody-mediated rejection utilizing the Pediatric Heart Transplant Study database: Incidence, therapies and outcomes

BACKGROUND Current knowledge of antibody-mediated rejection (AMR) after heart transplantation (HT) stems largely from adult data. Using the Pediatric Heart Transplant Study (PHTS) database, we report the incidence of AMR, describe treatment, and evaluate outcomes for treated AMR in children after HT. METHODS We queried the PHTS database for patients <18 years of age undergoing primary HT between January 2010 and December 2014. An AMR episode was defined as either a biopsy consistent with pathologic AMR or a rejection event based on immunotherapy augmentation directed against antibody production. Biopsy data, treatment strategies and survival were analyzed. RESULTS An episode of AMR was identified in 179 of 1,596 (11%) HT recipients and in 246 of 705 (35%) rejection episodes. AMR was diagnosed by biopsy in 182 of 246 episodes and by immunotherapy in 64 of 179 episodes. Mixed rejection was identified in 179. Freedom from AMR was 88% and 82% at 1 and 3 years, respectively. AMR therapies included intravenous immunoglobulin (IVIg) (58%), plasmapheresis (40%), rituximab (40%), bortezomib (11%) and eculizumab (0.4%). The most commonly used combination therapies included IVIg/plasmapheresis/rituximab (13%). Thirty-three patients (16%) died after developing AMR. Patient and graft survival were lower for the AMR+ group. One- and 3-year survival after initial AMR diagnosis was 88% and 77%, respectively. CONCLUSIONS In his study we report the largest experience of AMR in pediatric HT recipients. AMR was common and often occurred concurrently with acute cellular rejection. There is wide variability in the treatment of AMR. Short-term patient and graft outcomes were worse for those with treated AMR.

Ventricular Assist Device in Single-Ventricle Heart Disease and a Superior Cavopulmonary Anastomosis

Our objective is to describe the use of a ventricular assist device (VAD) in single-ventricle patients with circulatory failure following superior cavopulmonary anastomosis (SCPA). We performed a retrospective chart review of all single-ventricle patients supported with a VAD following SCPA. Implantation techniques, physiologic parameters while supported, medical and surgical interventions postimplant, and outcomes were reviewed. Four patients were supported with an EXCOR Pediatric (Berlin Heart Inc., The Woodlands, TX, USA) following SCPA for a median duration of 10.5 days (range 9-312 days). Selective excision of trabeculae and chords facilitated apical cannulation in all patients without inflow obstruction. There were two pump exchanges in the one patient supported for 312 days. Two patients were evaluated by cardiac catheterization while supported. Three of four patients were successfully bridged to transplantation. One patient died while supported. All patients had significant bleeding at the time of transplantation, and one required posttransplant extracorporeal membrane oxygenation with subsequent full recovery. VAD support can provide a successful bridge to transplantation in patients with single-ventricle circulation following SCPA. A thorough understanding of the challenges encountered during this support is necessary for successful outcomes.