Impact of a positive crossmatch on pediatric heart transplant outcomes.

BACKGROUND: Pediatric heart transplant (HT) candidates experience high waitlist mortality due to a limited donor pool that is constrained in part by anti-HLA sensitization. We evaluated the impact of CDC and Flow donor-specific crossmatch (XM) results on pediatric HT outcomes. METHODS: All pediatric HTs between 1999 and 2019 in the OPTN database were included. Donor-specific XM results were sub-categorized based on CDC and Flow results. Primary outcomes were treated rejection in the first year and time to death or allograft loss. Propensity scores were utilized to adjust for differences in baseline characteristics. RESULTS: A total of 4,695 pediatric HT patients with T-cell XM data were included. After propensity score adjustment, a positive T-cell CDC-XM was associated with 2 times higher odds of treated rejection (OR 2.29 (1.56, 3.37)) and shorter time to death/allograft loss (HR 1.50 (1.19, 1.88)) compared to a negative Flow-XM. HT recipients who were Flow-XM positive with negative/unknown CDC-XM did not have higher odds of rejection or shorter time to death/allograft loss. An isolated positive B-cell XM was also not associated with worse outcomes. Over the study period XM testing shifted from CDC- to Flow-based assays. CONCLUSIONS: A positive donor-specific T-cell CDC-XM was associated with rejection and death/allograft loss following pediatric HT. This association was not observed with a positive T-cell Flow-XM or B-cell XM result alone. The shift away from performing the CDC-XM may result in loss of important prognostic information unless the clinical relevance of quantitative Flow-XM results on heart transplant outcomes is systematically studied.

Medium-term Outcomes in Pediatric Heart Transplant Recipients Managed Using a Steroid Avoidance Immune Suppression Protocol.

BACKGROUND: Short-term outcomes using steroid avoidance immune suppression are encouraging in pediatric heart transplant (HT) recipients at low risk of antibody-mediated rejection. We assessed medium-term outcomes in pediatric HT recipients initiated on a steroid avoidance protocol at our institution using surveillance biopsies. METHODS: All primary HT recipients during 2006-2020 who did not have a donor-specific antibody were eligible for immune suppression consisting of 5-d Thymoglobulin/steroid induction followed by a tacrolimus-based, steroid-free regimen. We assessed freedom from graft failure (death or retransplant), acute rejection, posttransplant lymphoproliferative disease, and cardiac allograft vasculopathy. RESULTS: Overall, 150 of 181 primary HT recipients were eligible for steroid avoidance regimen. Their median age was 8.7 y, 41% had congenital heart disease, 23% were sensitized, and 35% were on a mechanical support. The median follow-up was 6.1 y. Eleven patients (8%) were on maintenance steroids at discharge and 13% at 1 y. Graft survival was 94% at 1 y and 87% at 5 y. Freedom from rejection was 73% at 1 y and 64% at 5 y. Freedom from posttransplant lymphoproliferative disease was 96% at 1 y and 95% at 5 y. Freedom from moderate cardiac allograft vasculopathy was 94% at 5 y. Eight patients developed diabetes. Estimated glomerular filtration rate was <60 mL/min/1.73 m 2 in 5% of the cohort at 5 y. CONCLUSIONS: Pediatric HT recipients at low risk of antibody-mediated rejection have excellent medium-term survival and relatively low incidence of posttransplant morbidities when managed using a steroid avoidance immune suppression protocol.

Extracorporeal Membrane Oxygenation Support After Heart Transplantation in Children-Outcomes of a Single Center Cohort.

OBJECTIVES: Extracorporeal membrane oxygenation is used for postcardiotomy low cardiac output but is less established following heart transplantation. We characterized outcomes for children supported with extracorporeal membrane oxygenation after heart transplantation. DESIGN: Single-center retrospective study. SETTING: Large pediatric cardiac referral center. PATIENTS: All patients who received heart transplantation and were cannulated to extracorporeal membrane oxygenation between 1995 and 2016. INTERVENTIONS: Primary outcome measure was mortality 12 months postextracorporeal membrane oxygenation. Patient characteristics were analyzed for association with outcome according to early graft failure (extracorporeal membrane oxygenation ≤ 7 d after heart transplantation), or late graft failure. MEASUREMENTS AND MAIN RESULTS: There were 246 heart transplants during the study period and 50 extracorporeal membrane oxygenation runs in 44 patients. Median time from transplant to extracorporeal membrane oxygenation was 1 day (range, 0-11.7 yr), with early graft failure in 28 patients (median 1, range 0-2 d) and 22 extracorporeal membrane oxygenation runs in 20 late graft failure patients (median, 0.8 yr; range, 8 d to 11.7 yr), including four patients with prior extracorporeal membrane oxygenation for early graft failure. Twenty-six patients (59%) survived to hospital discharge, and survival 12 months postextracorporeal membrane oxygenation was 24 patients (55%), lower in those with late graft failure (40% vs 67%; p 0.02). Independent risk factors for 12-month mortality were congenital heart disease, higher pulmonary vascular resistance indexed to body surface area (> 2.2 Woods U/m), and higher creatinine. Higher panel reactive antibody levels were associated with 12-month mortality in the late graft failure group only. CONCLUSIONS: Extracorporeal membrane oxygenation can be effectively used to rescue patients with graft dysfunction after heart transplantation but is associated with high early mortality. Factors associated with mortality within 12 months include presence of congenital heart disease, renal dysfunction, elevated pulmonary vascular resistance indexed to body surface area and in those supported with extracorporeal membrane oxygenation late after heart transplantation, significant human leukocyte antigen sensitization.

Liver abnormalities and post-transplant survival in pediatric Fontan patients.

The impact of liver parenchymal abnormalities on survival post-heart transplant remains unknown in pediatric Fontan patients. We assessed pediatric Fontan patients who underwent heart transplant and had documented pretransplant hepatic ultrasound (U/S) studies. Liver U/S findings were classified as normal (Group 1), mildly abnormal (Group 2, hepatomegaly/vascular congestion), or severely abnormal (Group 3, heterogeneous echotexture/nodularity). Among 30 study patients, 8 were classified as Group 1, 14 as Group 2, while 8 met Group 3 criteria. Pretransplant liver biochemistry and synthetic function were similar in all groups. Six Group 3 patients underwent liver biopsy; 4 demonstrated perisinusoidal or centrilobular fibrosis, and 2 had cirrhosis. Overall mortality was 30% (n = 9). Median follow-up was 5 years (range, 0.25-13 years). One-year survival was similar among all 3 groups (P = .37), with a trend toward higher cumulative 5-year survival in Group 1 (100%). The majority of pediatric Fontan patients who underwent heart transplant demonstrated abnormal preoperative liver ultrasound findings. Heterogeneous echotexture or nodularity detected on U/S frequently indicates underlying liver parenchymal abnormalities. The presence of severe liver abnormalities was not associated with higher early mortality post-heart transplant in pediatric Fontan patients; however, late outcomes must be further elucidated.

Maintenance steroid use at 30 days post-transplant and outcomes of pediatric heart transplantation: A propensity matched analysis of the Pediatric Heart Transplant Study database.

BACKGROUND: Maintenance steroid (MS) use in pediatric heart transplantation is variable. The purpose of this study was to evaluate the impact of MS use on graft outcomes. METHODS: All patients <18 years old in the Pediatric Heart Transplant Study database at the time of first heart transplant between 1993 and 2011 who survived ≥30 days post-transplant and were from centers with a protocolized approach to MS use were included (N = 2,178). Patients were grouped by MS use at 30 days post-transplant as MS+ or MS- (no MS use). Propensity score analysis was used to generate matched groups of MS+ and MS- patients based on pre-transplant and peri-transplant factors. Kaplan-Meier survival analysis was used to compare freedom from graft loss, graft loss secondary to rejection, rejection, rejection with severe hemodynamic compromise (RSHC), malignancy, and infection between groups. RESULTS: Of patients, 1,393 (64%) were MS+ and 785 (36%) were MS-. There were 315 MS- patients who had propensity matched MS+ controls. Kaplan-Meier estimates showed no difference in graft loss (p = 0.9) or graft loss secondary to rejection (p = 0.09). At 1 year post-transplant, there was no difference in freedom from rejection (p = 0.15) or malignancy (p = 0.07), but there was lower freedom from RSHC and infection in the MS- group (p = 0.05 and p = 0.02, respectively). CONCLUSIONS: MS use at 30 days post-transplant was not associated with enhanced graft survival after pediatric heart transplant. MS- patients had a higher incidence of RSHC and infection. These risks should be taken into consideration when determining MS use for pediatric recipients of heart transplants.

Antibody depletion for the treatment of crossmatch-positive pediatric heart transplant recipients.

Sensitization to HLA is a risk factor for adverse outcomes after heart transplantation. Requiring a negative prospective CM results in longer waiting times and increased waitlist mortality. We report outcomes in a cohort of sensitized children who underwent transplant despite a positive CDC CM+ using a protocol of antibody depletion at time of transplant, followed by serial IVIG administration. All patients <21 yrs old who underwent heart transplantation at Boston Children's Hospital from 1/1998 to 1/2011 were included. We compared freedom from allograft loss, allograft rejection, and serious infection between CM+ and CM- recipients. Of 134 patients in the cohort, 33 (25%) were sensitized prior to transplantation and 12 (9%) received a CM+ heart transplant. Serious infection in the first post-transplant year was more prevalent in the CM+ patients compared with CM- patients (50% vs. 16%; p = 0.005), as was HD-AMR (50% vs. 2%; p < 0.001). There was no difference in freedom from allograft loss or any rejection. At our center, children transplanted despite a positive CM had acceptable allograft survival and risk of any rejection, but a higher risk of HD-AMR and serious infection.

Impact of medication non-adherence on survival after pediatric heart transplantation in the U.S.A.

BACKGROUND: Medication non-adherence (NA) can result in life-threatening illness in children after solid-organ transplantation. Little is known about the incidence, risk factors and outcomes of NA in large numbers of pediatric heart transplant (HT) recipients. METHODS: Organ Procurement Transplant Network (OPTN) data were used to identify all children <18 years of age in the U.S.A. who underwent HT from October 1999 to January 2007. Cox proportional hazards analysis was used to identify risk factors for NA and the effect on graft survival. RESULTS: Of 2,070 pediatric heart transplants performed the median age at transplant was 6 years (interquartile range [IQR] 0 to 13 years); 40% had congenital heart disease (CHD), 7% were re-transplants, 42% were non-white and 43% had Medicaid insurance. Overall, 186 (9%) children had a report of NA at a median age of 15 years with more than two-thirds of NA episodes occurring after 12 years of age. Factors independently associated with NA were: adolescent age at transplant (hazard ratio [HR] 7.0, 95% confidence interval [CI] 4.1 to 12, compared with infants); black race (HR 2.3, 95% CI 1.7 to 3.3, compared with white); Medicaid insurance (HR 2.0, 95% CI 1.5 to 2.7, compared with non-Medicaid insurance); and ventilator or ventricular assist device (VAD) support at transplant. The risk of mortality conditional upon report of NA was 26% at 1 year and 33% at 2 years. CONCLUSIONS: Medication NA is an important problem in pediatric HT recipients and is associated with high mortality. Adolescent age, black race, Medicaid insurance and invasive hemodynamic support at transplant were associated with NA, whereas time on the wait list and gender were not. Targeted interventions among at-risk populations may be warranted.

Socioeconomic position and graft failure in pediatric heart transplant recipients.

BACKGROUND: Socioeconomic (SE) position may affect availability of resources, health-related behavior, and outcomes. We assessed whether patient SE position, determined for the block group of patient residence (average population 1000, smallest census unit with SE data), is associated with graft failure in pediatric heart transplant recipients. METHODS AND RESULTS: We used the US Census 2000 database to derive a composite SE score for the block group of residence for all patients who underwent their first heart transplant at Children's Hospital Boston between 1991 and 2005 (n=135). Cox proportional hazards models were used to determine the risk of graft failure (death or retransplant) in the lowest tertile SE group (low SE group) compared with the remaining 2 of 3 patients (controls). The 2 groups were similar with respect to age, gender, diagnosis, and year of transplant. White race was less frequent in low SE group (64% versus 90%, P=0.001). Graft failure occurred in 46 transplant recipients (40 deaths, 6 retransplant). Low SE group (hazard ratio 2.4, 95% CI 1.3 to 4.3) and nonwhite race (hazard ratio 2.7, 95% CI 1.4 to 5.2) were both associated with higher risk of graft failure. In a multivariable model controlling for diagnosis and pretransplant support, race, and low SE position (hazard ratio 2.0, 95% CI 1.0 to 3.7, P=0.04) remained associated with graft failure. Low SE position group had a higher incidence rate of graft rejection and was at a higher risk of late rejection. CONCLUSIONS: Low SE position may be an independent risk factor for graft failure in pediatric heart transplant recipients.

Waiting list mortality among children listed for heart transplantation in the United States.

BACKGROUND: Children listed for heart transplantation face the highest waiting list mortality in solid-organ transplantation medicine. We examined waiting list mortality since the pediatric heart allocation system was revised in 1999 to determine whether the revised allocation system is prioritizing patients optimally and to identify specific high-risk populations that may benefit from emerging pediatric cardiac assist devices. METHODS AND RESULTS: We conducted a multicenter cohort study using the US Scientific Registry of Transplant Recipients. All children <18 years of age who were listed for a heart transplant between 1999 and 2006 were included. Among 3098 children, the median age was 2 years (interquartile range 0.3 to 12 years), and median weight was 12.3 kg (interquartile range 5 to 38 kg); 1294 (42%) were nonwhite; and 1874 (60%) were listed as status 1A (of whom 30% were ventilated and 18% were on extracorporeal membrane oxygenation). Overall, 533 (17%) died, 1943 (63%) received transplants, and 252 (8%) recovered; 370 (12%) remained listed. Multivariate predictors of waiting list mortality include extracorporeal membrane oxygenation support (hazard ratio [HR] 3.1, 95% confidence interval [CI] 2.4 to 3.9), ventilator support (HR 1.9, 95% CI 1.6 to 2.4), listing status 1A (HR 2.2, 95% CI 1.7 to 2.7), congenital heart disease (HR 2.2, 95% CI 1.8 to 2.6), dialysis support (HR 1.9, 95% CI 1.2 to 3.0), and nonwhite race/ethnicity (HR 1.7, 95% CI 1.4 to 2.0). CONCLUSIONS: US waiting list mortality for pediatric heart transplantation remains unacceptably high in the current era. Specific high-risk subgroups can be identified that may benefit from emerging pediatric cardiac assist technologies. The current pediatric heart-allocation system captures medical urgency poorly. Further research is needed to define the optimal organ-allocation system for pediatric heart transplantation.

Ventricular assist devices as a bridge to heart transplantation in children.

UNLABELLED: The increase in time waiting for appropriate pediatric allografts for heart transplantation has mandated the use of long-term mechanical assistance in the pediatric population. Extracorporeal membrane oxygenation support has been routinely used but is limited by both its inability to provide support without life-threatening complications for longer than 2 to 3 weeks as well as the inability of patients to achieve mobility. For the past 10 years, pediatric programs have increasing experience with the use of ventricular assist devices (VADs) to bridge patients to heart transplant. This retrospective study analyzed the clinical features and outcomes of 99 pediatric patients who underwent VAD implant as a bridge to heart transplant. METHODS: Between 1993 and 2003, the Pediatric Heart Transplant Study Group enrolled 2,375 patients (age 1 day-17.9 years) listed for heart transplant from 23 participating centers. Four percent (99 patients) of those listed received VAD support as a bridge to transplantation. Seventy-seven (77%) patients survived to transplant with a mean time on support of 57 days. There were 17 deaths on support and 5 bridged to recovery. Overall incidence of adverse events was similar to the adult data with a 19% risk of stroke. There was no difference in 5-year survival after transplant for patients on VAD at time of transplant compared with those (n = 2,293) not requiring VAD (77% vs 73%, P = .8). These data suggest that despite the lack of pediatric specific devices and relatively high adverse event rate, VADs may be used as a bridge to transplant therapy in appropriate-sized children with the expectation of a successful outcome in most patients.

Parenting stress and parental post-traumatic stress disorder in families after pediatric heart transplantation.

BACKGROUND: There has been little research on the stress experienced by parents of children who have undergone heart transplantation. METHODS: Parents of 52 consecutive pediatric heart transplant recipients completed questionnaires assessing illness-related parenting stress and post-traumatic stress symptoms at a routine clinic visit. Medical charts were reviewed retrospectively to gather peri- and post-operative information. RESULTS: The average age of patients at transplant was 12 years (range 1 to 18 years), and participation occurred 3 months to 10 years post-transplant (median 2.5 years). Nearly 40% of parents indicated moderately severe to severe post-traumatic stress symptoms. Ten of the 52 participating parents met DSM-IV-TR clinical diagnostic criteria for current post-traumatic stress disorder. Parents also identified significant levels of illness-related parenting stress in the areas of communication around the child's illness, emotional distress, managing the child's medical care, and balancing role functions. CONCLUSIONS: Illness-related parenting stress and post-traumatic stress symptoms are significant concerns among parents of pediatric heart transplant patients. Parents' psychologic functioning post-transplant should be routinely assessed and addressed by transplant teams.

Outcomes of children bridged to heart transplantation with ventricular assist devices: a multi-institutional study.

BACKGROUND: Current ventricular assist devices (VADs) in the United States are designed primarily for adult use. Data on VADs as a bridge to transplantation in children are limited. METHODS AND RESULTS: A multi-institutional, prospectively maintained database of outcomes in children after listing for heart transplantation (n=2375) was used to analyze outcomes of VAD patients (n=99, 4%) listed between January 1993 and December 2003. Median age at VAD implantation was 13.3 years (range, 2 days to 17.9 years); diagnoses were cardiomyopathy (78%) and congenital heart disease (22%). Mean duration of support was 57 days (range, 1 to 465 days). Seventy-three percent were supported with a long-term device, with 39% requiring biventricular support. Seventy-seven patients (77%) survived to transplantation, 5 patients were successfully weaned from support and recovered, and 17 patients (17%) died on support. In the recent era (2000 to 2003), successful bridge to transplantation with VAD was achieved in 86% of patients. Peak hazard for death while waiting was the first 2 weeks after VAD placement. Risk factors for death while awaiting a transplant included earlier era of implantation (P=0.05), female gender (P=0.02), and congenital disease diagnosis (P=0.05). There was no difference in 5-year survival after transplantation for patients on VAD at time of transplantation as compared with those not requiring VAD. CONCLUSIONS: VAD support in children successfully bridged 77% of patients to transplantation, with posttransplantation outcomes comparable to those not requiring VAD. These encouraging results emphasize the need to further understand patient selection and to delineate the impact of VAD technology for children.

The longitudinal impact of psychological functioning, medical severity, and family functioning in pediatric heart transplantation.

BACKGROUND: Few data are available on the longitudinal psychological functioning of patients after pediatric heart transplantation. The objective of this study was to determine whether pre-transplant psychological functioning, post-transplant medical severity, and family functioning relate to the psychological functioning of pediatric patients after heart transplantation. METHODS: The study included 23 patients who underwent heart transplantation between ages 3 and 20 years, survived at least 1 year after transplantation, and had been assessed previously after transplantation between 1993 and 1995. This study reports a second post-transplant assessment between 1999 and 2000. We assessed psychological functioning using the Children's Global Assessment Scale before and after heart transplantation. We assessed medical severity using the number of outpatient visits, hospitalizations, and biopsies and using the Side Effect Severity Scale. We used the Global Assessment of Family Relational Functioning Scale to rate family functioning. RESULTS: The majority of patients (15/23) were alive at the second follow-up. They had survived a median of 9.6 (6.1-12.9) years after transplantation. Similar to their first follow-up assessments, 73% demonstrated good psychological functioning after heart transplantation. Although we found no correlation between medical severity and post-transplant psychological functioning, we did find a significant correlation between family functioning during the first 2 years of transplantation and post-transplant emotional adjustment. CONCLUSIONS: The majority of children and adolescents have the capacity for healthy psychological functioning after heart transplantation. Nevertheless, ongoing psychological assessment and intervention is necessary for patients and their families who face pediatric heart transplantation because >25% probably will have emotional adjustment difficulties.