The Fontan immunophenotype and post-transplant outcomes in children: A multi-institutional study.

BACKGROUND: Patients after Fontan palliation represent a growing pediatric population requiring heart transplant (HTx) and often have lymphopenia (L) and/or hypogammaglobinemia that may be exacerbated by protein-losing enteropathy (PLE, P). The post-HTx effects of this altered immune phenotype are not well studied. METHODS: In this study of the Pediatric Heart Transplant Society Registry, 106 Fontan patients who underwent HTx between 2005 and 2018 were analyzed. The impact of lymphopenia and PLE on graft survival, infection, rejection, and malignancy was analyzed at 1 and 5 years post-HTx. RESULTS: The following combinations of lymphopenia and PLE were noted: +L+P, n = 37; +L-P, n = 23; -L+P, n = 10; and -L-P, n = 36. Graft survival between the groups was similar within the first year after transplant (+L+P: 86%, +L-P: 86%, -L+P: 87%, -L-P: 89%, p = .9). Freedom from first infection post-HTx was greatest among -L-P patients compared to patients with either PLE, lymphopenia, or both; with a 22.1% infection incidence in the -L-P group and 41.4% in all others. These patients had a significantly lower infection rate in the first year after HTx (+L+P: 1.03, +L-P: 1, -L+P: 1.3, -L-P: 0.3 infections/year, p < .001) and were similar to a non-single ventricle CHD control group (0.4 infections/year). Neither freedom from rejection nor freedom from malignancy 1 and 5 years post-HTx, differed among the groups. CONCLUSIONS: Fontan patients with altered immunophenotype, with lymphopenia and/or PLE, are at increased risk of infection post-HTx, although have similar early survival and freedom from rejection and malignancy. These data may encourage alternative immunosuppression strategies and enhanced monitoring for this growing subset of patients.

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.

Racial differences in attitudes to clinical pig organ Xenotransplantation.

INTRODUCTION: In addition to an organ donor shortage, racial disparities exist at different stages of the transplantation process. Xenotransplantation (XTx) could alleviate these issues. This study describes racial differences in attitudes to XTx among populations who may need a transplant or are transplant recipients. METHODS: A Likert-scale survey was distributed at outpatient clinics to parents of children with congenital heart disease (CHD) and kidney patients on their attitudes to pig organ XTx. Data from these two groups were stratified by race and compared. RESULTS: Ninety-seven parents of children with CHD (74.2% White and 25.8% Black) and 148 kidney patients (50% White and 50% Black) responded to our survey. Black kidney patients' acceptance of XTx although high (70%) was lower than White kidney patients (91%; P .003). White kidney patients were more likely to accept XTx if results are similar to allotransplantation (OR 4.14; 95% CI 4.51-11.41), and less likely to be concerned with psychosocial changes when compared to Black kidney patients (receiving a pig organ would change your personality OR 0.08; 95% CI 0.01-0.67 and would change social interaction OR 0.24; 95% CI 0.07-0.78). There were no racial differences in attitudes to XTx among parents of children with CHD. CONCLUSION: There are differences in attitudes to XTx particularly among Black kidney patients. Because kidneys may be the first organ for clinical trials of XTx, future studies that decrease scientific mistrust and XTx concerns among the Black community are needed to prevent disparities in uptake of possible future organ transplant alternatives.

Impact of induction strategy change on first-year rejection in pediatric heart transplantation at a single center-From postoperative basiliximab to either postoperative anti-thymocyte globulin or preoperative basiliximab.

BACKGROUND: Our pediatric heart transplant center transitioned from post-bypass basiliximab (BAS) induction to either anti-thymocyte globulin (ATG) or pre-bypass BAS. The purpose of this study was to compare first-year rejection rates before and after this change. METHODS: A single-center retrospective analysis was conducted of pediatric heart transplant recipients from 2010 to 2019. Primary outcome was first-year rejection. Bivariate analysis, Kaplan-Meier curves, and multivariable regression were performed across eras. RESULTS: Forty-three early era patients (55%) received post-bypass BAS, and 35 late era patients (45%) received pre-bypass BAS (n = 17) or ATG (n = 18). First-year rejection decreased in the late era (31% vs 53%, p = .05). This finding was more pronounced after excluding infants (38% vs 73%, p = .006). Late era was associated with a decreased likelihood of rejection (all cohort OR 0.19, 95% CI 0.05-0.66; infants excluded OR 0.17, 95% CI 0.04-0.61). No differences in post-transplant lymphoproliferative disease, donor-specific antibody, or infection were observed. CONCLUSIONS: Fewer late era patients receiving ATG or pre-bypass BAS induction had first-year rejection compared to the early era patients receiving standard post-bypass BAS induction. This programmatic shift in induction strategy was readily achievable and potentially effective in reducing first-year rejection.

Examining racial and socioeconomic disparity in the pediatric heart transplant evaluation.

Racial disparities have been reported among pediatric patients waitlisted for and undergoing heart transplantation but have not been studied further upstream in the transplant candidate evaluation process. We retrospectively studied our single-center experience in order to investigate any potential biases in the evaluation process. Results of the heart transplant evaluation in children ≤18 years old at our institution were analyzed. Primary outcome was final disposition to waitlist or not. Race was defined by family self-identification. Descriptive and comparative statistical analyses were performed. From 2013 to 2019, 133 unique patients were referred for listing consideration. While Black patients comprised 44% of the referral population and had more markers of socioeconomic disadvantage, they comprised 43% of the patients who were listed for transplantation with no significant difference between these proportions (p = .96). Black and White patients made up a similar proportion of patients deemed too well or too ill for listing. Black patients had lower annual household income estimates and rates of household marriage. Despite identifying significant social challenges in 27 patients (18 of them Black), only five patients (3 Black and 2 White) were turned down for listing due to social barriers. While limited by the small number of patients turned down for social barriers, our transplant evaluation process does not appear to result in racial disparities in access to listing. Further studies are needed using national cohorts to explore possible racial disparities upstream from waitlisting and transplantation, such as during the referral and evaluation.

Attitudes toward xenotransplantation: A survey of parents and pediatric cardiac providers.

BACKGROUND: Scientific advancements are occurring in cardiac xenotransplantation (XTx). However, there have been religious and social concerns surrounding this allotransplantation alternative. The purpose of this study was to explore the acceptance of XTx among stakeholders of the congenital heart disease (CHD) community. METHODS: A Likert-scale anonymous survey was distributed to physicians and nurses who care for children with CHD and parents of children with CHD. Psychosocial and clinical attitudes were compared across all groups to identify differences, and regression analysis was performed to identify factors associated with XTx acceptance. RESULTS: A total of 297 responded to the survey: 134 physicians, 62 nurses, and 101 parents. Potential acceptance of XTx if outcomes were similar to allotransplantation was high overall (75.3%), but different between the groups (physicians 86%; nurses 71%, parents 64%; P < .0001). Regression analysis showed respondents who reported religion would influence medical decision making (OR 0.48; 95%CI 0.24-0.97) and those who would not use a pig heart transplant as a bridge until a human heart became available were less likely to accept XTx (OR 0.09; 95%CI 0.04-0.21). Psychosocial concerns to XTx were minimal but were also associated with XTx acceptance particularly among parents (OR 0.17; 95%CI 0.03-0.80). CONCLUSIONS: Potential acceptance of XTx is high, assuming results are similar to allotransplantation. Religious beliefs and attitudes toward the use of XTx as a bridge to allotransplant may present barriers to XTx acceptance. Future research is needed to assess potential attitude differences in light of ethical, psychosocial, and religious objections to XTx.

The immune system in infants: Relevance to xenotransplantation.

Despite the improvement in surgical interventions in the treatment of congenital heart disease, many life-threatening lesions (eg, hypoplastic left heart syndrome) ultimately require transplantation. However, there is a great limitation in the availability of deceased human cardiac donors of a suitable size. Hearts from genetically engineered pigs may provide an alternative source. The relatively immature immune system in infants (eg, absence of anti-carbohydrate antibodies, reduced complement activation, reduced innate immune cell activity) should minimize the risk of early antibody-mediated rejection of a pig graft. Additionally, recipient thymectomy, performed almost routinely as a preliminary to orthotopic heart transplantation in this age-group, impairs the T-cell response. Because of the increasing availability of genetically engineered pigs (eg, triple-knockout pigs that do not express any of the three known carbohydrate antigens against which humans have natural antibodies) and the ability to diagnose congenital heart disease during fetal life, cardiac xenotransplantation could be preplanned to be carried out soon after birth. Because of these several advantages, prolonged graft survival and even the induction of tolerance, for example, following donor-specific pig thymus transplantation, are more likely to be achieved in infants than in adults. In this review, we summarize the factors in the infant immune system that would be advantageous in the success of cardiac xenotransplantation in this age-group.

Comparison of 10-year graft failure rates after induction with basiliximab or anti-thymocyte globulin in pediatric heart transplant recipients-The influence of race.

BACKGROUND/OBJECTIVE: The impact of induction therapy in pediatric heart transplantation has been uncertain. Given the risk of poor outcomes in black pediatric heart transplant recipients, we evaluated the effect on graft survival of ATG and BAS induction in black and non-black pediatric recipients. METHODS: This was a retrospective analysis of pediatric candidates (aged ≤18 years) who underwent heart transplantation from 2000 to 2016 identified from the UNOS database. Primary outcome was 10-year graft survival. RESULTS: This study included 654 patients receiving BAS, 2385 patients receiving ATG, and 2425 receiving no induction. Ten-year survival was similar for the following groups: non-black BAS (57%), non-black ATG (66%), and black ATG (51%). The black BAS group had a 10-year graft survival of 39% which was inferior on pairwise comparison to the other groups (all P values < 0.001). On multivariate analysis, ATG was associated with decreased risk of graft failure when compared to no induction (HR 0.86, 95% CI 0.76-0.97, P = 0.011) and had an association approaching statistical significance when compared to BAS induction (0.84, 0.7-1.01, P = 0.069). This association was seen in black recipients in whom ATG was strongly associated with decreased risk of graft failure when compared to either no induction (0.65, 0.5-0.83, P = 0.001) or BAS (0.64, 0.46-0.89, P = 0.008) but was not seen in non-black recipients. CONCLUSIONS: Black pediatric heart transplant recipients who received ATG induction had an improved long-term graft survival compared to those who received BAS induction or no induction.

The Case for Cardiac Xenotransplantation in Neonates: Is Now the Time to Reconsider Xenotransplantation for Hypoplastic Left Heart Syndrome?

Neonatal cardiac transplantation for hypoplastic left heart syndrome (HLHS) is associated with excellent long-term survival compared to older recipients. However, heart transplantation for neonates is greatly limited by the critical shortage of donor hearts, and by the associated mortality of the long pre-transplant waiting period. This led to the development of staged surgical palliation as the first-line surgical therapy for HLHS. Recent advances in genetic engineering and xenotransplantation have provided the potential to replicate the excellent results of neonatal cardiac allotransplantation while eliminating wait-list-associated mortality through genetically modified pig-to-human neonatal cardiac xenotransplantation. The elimination of the major pig antigens in addition to the immature B-cell response in neonates allows for the potential to induce B-cell tolerance. Additionally, the relatively mature neonatal T-cell response could be reduced by thymectomy at the time of operation combined with donor-specific pig thymus transplantation to "reprogram" the host's T-cells to recognize the xenograft as host tissue. In light of the recent significantly increased graft survival of genetically-engineered pig-to-baboon cardiac xenotransplantation, we propose that now is the time to consider devoting research to advance the potential clinical application of cardiac xenotransplantation as a treatment option for patients with HLHS. Employing cardiac xenotransplantation could revolutionize therapy for complex congenital heart defects and open a new chapter in the field of pediatric cardiac transplantation.

Ventricular assist device use in single ventricle congenital heart disease.

As VAD have become an effective therapy for end-stage heart failure, their application in congenital heart disease has increased. Single ventricle congenital heart disease introduces unique physiologic challenges for VAD use. However, with regard to the mixed clinical results presented within this review, we suggest that patient selection, timing of implant, and center experience are all important contributors to outcome. This review focuses on the published experience of VAD use in single ventricle patients and details physiologic challenges and novel approaches in this growing pediatric and adult population.

Aortic dilation in pediatric patients.

Aortic dilation at the level of the aortic root can be caused by a variety of congenital or acquired conditions that lead to weakening of the aortic wall. In this retrospective study, we sought to determine the frequency of different associated diagnoses from children with aortic dilation seen at a single institution. A total of 377 children (68 % male) met study inclusion criteria. Patients were classified based on the suspected or confirmed associated diagnosis in one of the following categories: congenital heart disease (241/377, 64 %), chromosomal (34/377, 9 %), Marfan syndrome (26/377, 7 %), other genetic and non-genetic (22/377, 6 %), Loeys-Dietz syndrome (6/377, 2 %), and unknown (48/377, 13 %). Bicuspid aortic valve was by far the most prevalent congenital heart defect (206/241, 85 %), while Turner syndrome was the most frequent chromosomal abnormality (12/34, 35 %). Patients with Marfan syndrome were more likely to have severe dilation of the ascending aorta (p = 0.002) and to require aortic root replacement surgery (p < 0.001) compared to those in other diagnosis categories. CONCLUSION: The differential diagnosis of aortic dilation is broad and requires a careful assessment of cardiac anatomy. Evaluation by a clinical geneticist in this setting should be strongly considered given the high frequency of associated genetic conditions. WHAT IS KNOWN: • Aortic dilation is frequent in bicuspid aortic valve and other congenital heart defects. • Aortic dilation can be seen in several connective tissue disorders. Limited information is available in regard to the differential diagnosis of aortic dilation in children. WHAT IS NEW: • In patients with aortic dilation concurrent congenital heart disease is frequently diagnosed. • Almost 18 % of cases in the present study had a defined presumptive or confirmed genetic diagnosis. We suggest considering a genetics evaluation in the setting of aortic dilation.

Mechanical circulatory support: strategies and outcomes in pediatric congenital heart disease.

Patients with acute or progressive heart failure in the setting of congenital heart disease may need mechanical circulatory support (MCS) to enhance survival while awaiting cardiac transplantation. Because the majority of MCS devices are implanted after prior cardiac operations, special precautions are necessary at the time of implant. MCS in single ventricle patients usually requires ventricular and aortic cannulation, with a systemic to pulmonary artery shunt for pulmonary blood flow. Limited outcomes data is available, with less than 15% of pediatric MCS patients having congenital heart disease. The Berlin EXCOR is the only durable device currently available for infants. Neurologic complications are the major cause of mortality, and survival during support is poor for infants <5 kg. Patients post-Fontan with acute cardiac failure and/or respiratory failure are at high risk for death before transplant and should be considered for MCS therapy. Several emerging miniature continuous flow devices will soon broaden the landscape of available pediatric devices.

Association Between Venous Homografts and Allosensitization After Norwood Procedure.

BACKGROUND: Right ventricle (RV) to pulmonary artery (PA) shunts have become the shunt of choice at many centers for use during the Norwood procedure for single ventricle palliation. Some centers have begun to use cryopreserved femoral or saphenous venous homografts as an alternative to polytetrafluoroethylene (PTFE) for shunt construction. The immunogenicity of these homografts is unknown, and potential allosensitization could have significant implications on transplant candidacy. METHODS: All patients undergoing Glenn procedure at our center between 2013 and 2020 were screened. Patients who initially underwent Norwood procedure with either PTFE or venous homograft RV-PA shunt and had available pre-Glenn serum were included in the study. The primary outcome of interest was panel reactive antibody (PRA) level at the time of Glenn surgery. RESULTS: Thirty-six patients met inclusion criteria (N = 28 PTFE, N = 8 homograft). Patients in the homograft group had significantly higher median PRA levels at the time of Glenn surgery (0% [IQR 0-18] PTFE vs 94% [IQR 74-100] homograft, P = .003). There were no other differences between the two groups. CONCLUSIONS: Despite potential improvements in PA architecture, the use of venous homografts for RV-PA shunt construction at the time of Norwood procedure is associated with significantly elevated PRA level at the time of Glenn surgery. Centers should carefully consider the use of currently available venous homografts given the high percentage of these patients who may require future transplantation.

Single-drug immunosuppression is associated with noninferior medium-term survival in pediatric heart transplant recipients.

BACKGROUND: Patients are usually maintained on at least 2 immunosuppressive drugs (ISDs) after the first year post heart transplant. Anecdotally, some children are switched to single-drug monotherapy (a single ISD) for various reasons and varying durations. Outcomes associated with differences in immunosuppression after heart transplantation are unknown for children. OBJECTIVES: A priori we defined a noninferiority hypothesis for monotherapy compared to ≥2 ISDs. The primary outcome was graft failure, a composite of death and retransplantation. Secondary outcomes included rejection, infection, malignancy, cardiac allograft vasculopathy and dialysis. METHODS: This international, multicenter, retrospective, observational cohort study used data from the Pediatric Heart Transplant Society. We included patients who underwent first-time heart transplant <18 years of age between 1999 and 2020 with ≥1 year of follow-up data available. RESULTS: Our analysis included 3493 patients with a median time post-transplant of 6.7 years. There were 893 patients (25.6%) switched to monotherapy at least once with the remaining 2600 patients always on ≥2 ISDs. The median time on monotherapy after the first year post-transplant was 2.8 years (range 1.1-5.9 years). We found an adjusted hazard ratio (HR) of 0.65 (95%CI: 0.47-0.88) favoring monotherapy compared to ≥2 ISDs (p = 0.002). There were no meaningful differences in the incidence of secondary outcomes between groups, except for a lower rate of cardiac allograft vasculopathy in patients on monotherapy (HR 0.58, 95%CI: 0.45-0.74). CONCLUSIONS: For pediatric heart transplant recipients placed on monotherapy, immunosuppression with a single ISD after the first year post-transplant was noninferior to standard therapy with ≥2 ISDs in the medium term. CONDENSED ABSTRACT: Some children are switched to a single immunosuppressive drug (ISD) for various reasons after heart transplant, but outcomes associated with differences in immunosuppression are unknown for children. We assessed graft failure in children on a single ISD (monotherapy) compared to ≥2 ISDs in a cohort of 3493 children with a first heart transplant. We found an adjusted hazard ratio of 0.65 (95%CI: 0.47-0.88) favoring monotherapy. We concluded that for pediatric heart transplant recipients placed on monotherapy, immunosuppression with a single ISD after the first year post-transplant was non-inferior to standard therapy with ≥2 ISDs in the medium term.

Racial and socioeconomic disparities in pediatric heart transplant outcomes in the era of anti-thymocyte globulin induction.

BACKGROUND: Black race is associated with worse outcomes across solid organ transplantation. Augmenting immunosuppression through antithymocyte globulin (ATG) induction may mitigate organ rejection and graft loss. We investigated whether racial and socioeconomic outcome disparities persist in children receiving ATG induction. METHODS: Using the Pediatric Heart Transplant Society registry, we compared outcomes in Black and White children who underwent heart transplant with ATG induction between 2000 and 2020. The primary outcomes of treated rejection, rejection with hemodynamic compromise (HC), and graft loss (death or re-transplant). We explored the association of these outcomes with race and socioeconomic disparity, assessed using a neighborhood deprivation index [NDI] score at 1-year post-transplant (high NDI score implies more socioeconomic disadvantage). RESULTS: The study cohort included 1,719 ATG-induced pediatric heart transplant recipients (22% Black, 78% White). There was no difference in first year treated rejection (Black 24.5%, White 28.1%, p = 0.2). During 10 year follow up, the risk of treated rejection was similar; however, Black recipients were at higher risk of HC rejection (p = 0.009) and graft loss (p = 0.02). Black recipients had a higher mean NDI score (p < 0.001). Graft loss conditional on 1-year survival was associated with high NDI score in both White and Black recipients (p < 0.0001). In a multivariable Cox model, both high NDI score (HR 1.97, 95% CI 1.23-3.17) and Black race (HR 2.22, 95% CI 1.40-3.53) were associated with graft loss. CONCLUSION: Black race and socioeconomic disadvantage remain associated with late HC rejection and graft loss in children with ATG induction. These disparities represent important opportunities to improve long term transplant outcomes.

Cardiac and Pulmonary Histopathology in Baboons Following Genetically-Engineered Pig Orthotopic Heart Transplantation.

BACKGROUND Although improving, survival after pig orthotopic heart transplantation (OHTx) in baboons has been mixed and largely poor. The causes for the high incidence of early failure remain uncertain. MATERIAL AND METHODS We have carried out pig OHTx in 4 baboons. Two died or were euthanized within hours, and 2 survived for 3 and 8 months, respectively. There was evidence of a significant 'cytokine storm' in the immediate post-OHTx period with the elevations in IL-6 correlating closely with the final outcome. RESULTS All 4 baboons demonstrated features suggestive of respiratory dysfunction, including increased airway resistance, hypoxia, and tachypnea. Histopathological observations of pulmonary infiltration by neutrophils and, notably, eosinophils within vessels and in the perivascular and peribronchiolar space, with minimal cardiac pathology, suggested a role for early lung acute inflammation. In one, features suggestive of transfusion-related acute lung injury were present. The 2 longer-term survivors died of (i) a cardiac dysrhythmia with cellular infiltration around the conducting tissue (at 3 months), and (ii) mixed cellular and antibody-mediated rejection (at 8 months). CONCLUSIONS These initial findings indicate a potential role of acute lung injury early after OHTx. If this response can be prevented, increased survival may result, providing an opportunity to evaluate the factors affecting long-term survival.

The Genetically Engineered Heart as a Bridge to Allotransplantation in Infants Just Around the Corner?

BACKGROUND: Mortality for infants on the heart transplant waitlist remains unacceptably high, and available mechanical circulatory support is suboptimal. Our goal is to demonstrate the feasibility of utilizing genetically engineered pig (GEP) heart as a bridge to allotransplantation by transplantation of a GEP heart in a baboon. METHODS: Four baboons underwent orthotopic cardiac transplantation from GEP donors. All donor pigs had galactosyl-1,3-galactose knocked out. Two donor pigs had human complement regulatory CD55 transgene and the other 2 had human complement regulatory CD46 and thrombomodulin. Induction immunosuppression included thymoglobulin, and anti-CD20. Maintenance immunosuppression was rapamycin, anti-CD-40, and methylprednisolone. One donor heart was preserved with University of Wisconsin solution and the other three with del Nido solution. RESULTS: All baboons weaned from cardiopulmonary bypass. B217 received a donor heart preserved with University of Wisconsin solution. Ventricular arrhythmias and depressed cardiac function resulted in early death. All recipients of del Nido preserved hearts easily weaned from cardiopulmonary bypass with minimal inotropic support. B15416 and B1917 survived for 90 days and 241 days, respectively. Histopathology in B15416 revealed no significant myocardial rejection but cellular infiltrate around Purkinje fibers. Histopathology in B1917 was consistent with severe rejection. B37367 had uneventful transplant but developed significant respiratory distress with cardiac arrest. CONCLUSIONS: Survival of B15416 and B1917 demonstrates the feasibility of pursuing additional research to document the ability to bridge an infant to cardiac allotransplant with a GEP heart.

Inhaled nitric oxide improves oxygen saturation in children with pulmonary arteriovenous malformations after the Fontan procedure.

OBJECTIVE: To report the utility of inhaled nitric oxide to ameliorate excessive hypoxemia in children with pulmonary arteriovenous malformations after the Fontan procedure. DESIGN: Case series. SETTING: A tertiary pediatric cardiac intensive care unit in a freestanding children's hospital. PATIENTS: Three children with complex congenital heart disease and pulmonary arteriovenous malformations who underwent the Fontan procedure. INTERVENTIONS: The 3 patients all exhibited moderate-to-severe hypoxemia in the immediate postoperative period. The hypoxemia persisted despite mechanical ventilation and oxygen at an Fio2 of 1.0. Inhaled nitric oxide was initiated with immediate and dramatic improvements in oxygen saturation in all patients. All patients were eventually weaned off inhaled nitric oxide. CONCLUSIONS: The use of inhaled nitric oxide in patients with pulmonary arteriovenous malformations after having the Fontan procedure improves hypoxemia and may potentially reduce postoperative morbidity, unnecessary testing, and duration of hospital stay.

Late Heart Transplantation in Hypoplastic Left Heart Syndrome With Intact Atrial Septum.

This case report describes 2 patients born with hypoplastic left heart syndrome and an intact atrial septum who underwent a strategy of immediate extracorporeal membrane oxygenation and left atrial decompression followed by hybrid Norwood palliation as a bridge to further palliation. Heart transplantation was ultimately performed in these 2 patients with persisting pulmonary vascular resistance abnormalities.

Clinical outcomes of children receiving ABO-incompatible versus ABO-compatible heart transplantation: a multicentre cohort study.

BACKGROUND: ABO-incompatible heart transplantation increases donor availability in young children and is evolving into standard of care in children younger than 2 years. Previous smaller studies suggest similar outcomes to ABO-compatible heart transplantation, but persisting alterations of the immune system in ABO-incompatible recipients might increase the risk of some infections or benefit the graft owing to reduced HLA reactivity. We aimed to assess long-term outcomes in young children after they received ABO-incompatible or ABO-compatible heart transplantation. METHODS: In this multicentre, prospective cohort study, we analysed data from the Pediatric Heart Transplant Society registry to compare children who received ABO-incompatible or ABO-compatible heart transplantation before age 2 years between Jan 1, 1999, and June 30, 2018. Given significantly different clinical demographics between the two groups, we also matched each ABO-incompatible recipient to two ABO-compatible recipients using propensity score matching. We assessed patient and graft survival, coronary allograft vasculopathy, malignancy, acute rejection (any episode resulting in augmentation of immunosuppression), and infections (requiring intravenous antibiotic or antiviral therapy or life-threatening infections treated with oral therapy). FINDINGS: We included 2206 children who received a heart transplant before age 2 years, with 11 332·6 patient-years of cumulative observation time. Children who received an ABO-incompatible transplant (n=364) were younger and a larger proportion had congenital heart disease and ventilator and mechanical circulatory support than the ABO-compatible recipients (n=1842). After matching, only differences in blood group (more O in ABO-incompatible and more AB in ABO-compatible groups) and use of polyclonal induction therapy with anti-thymocyte globulins persisted. The two matched groups had similar post-transplantation graft survival (p=0·74), freedom from coronary allograft vasculopathy (p=0·75), and malignancy (p=0·51). ABO-incompatible recipients showed longer freedom from rejection (p=0·0021) in the overall cohort, but not after matching (p=0·48). Severe infections (p=0·0007), bacterial infections (p=0·0005), and infections with polysaccharide encapsulated bacteria (p=0·0005) that share immunological properties with blood group antigens occurred less frequently after ABO-incompatible heart transplantation. INTERPRETATION: ABO-incompatible heart transplantation for children younger than 2 years is a clinically safe approach, with similar survival and incidences of rejection, coronary allograft vasculopathy, and malignancy to ABO-compatible recipients, despite higher-risk pre-transplant profiles. ABO-incompatible transplantation was associated with less bacterial infection, particularly encapsulated bacteria, suggesting that the acquired immunological changes accompanying ABO tolerance might benefit rather than jeopardise transplanted children. FUNDING: Pediatric Heart Transplant Society.