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

Abstract

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.

Two sides of the same coin: Balancing the risks of rejection and infection in transplanted Fontan patients with dysregulated pretransplant immune function

“…These studies highlight well a fundamental challenge that remains a critical element in the care of the post-transplant Fontan patient: how do we tailor immunosuppression to minimize both posttransplant infection and rejection in these children with such altered pretransplant immunophenotypes? In a group in which similar induction immunosuppression was used, infections predominated in those with PLE and/or lymphopenia 5 ; in a group with more frequent use of lower intensity immunosuppression (basiliximab vs. ATG) in the setting of PLE, AMR predominated. 6 Perhaps a more nuanced and individualized risk evaluation of both infection and rejection in these patients, in whom traditional measures may be unsatisfactory, may help guide us toward improved overall outcomes.…”

“…Mantell et al 5 leveraged detailed laboratory and diagnostic data within the Pediatric Heart Transplant Society database to characterize the pretransplant immunophenotype of 106 children with failing Fontan physiology who underwent heart transplant. The four immunophenotypes were those with lymphopenia and PLE (L+ P+), lymphopenia without PLE (L+ P−), no lymphopenia and PLE (L− P+), and neither lymphopenia nor PLE (L− P−).…”

Pediatric heart transplantation: Looking forward after five decades of learning

“…Nonetheless, many controversies still exist including timing of referral to advanced heart failure teams, indication for and timing of advanced heart failure therapies, indications and contraindications for transplantation, timing of listing for transplantation, the impact of renal and hepatic dysfunction on these decisions and on post‐transplant outcomes, and the role of combined heart‐liver transplantation, just to name a few. These are further clouded by Fontan‐related co‐morbidities that do not manifest as heart failure including protein‐losing enteropathy and plastic bronchitis 52,53 . Given the increasing post‐transplant survival and the burgeoning population of adult CHD patients with Fontan circulations, this is an evolving challenge for advanced heart failure and heart transplant teams.…”

“…These are further clouded by Fontan-related comorbidities that do not manifest as heart failure including proteinlosing enteropathy and plastic bronchitis. 52,53 Given the increasing post-transplant survival and the burgeoning population of adult CHD patients with Fontan circulations, this is an evolving challenge for advanced heart failure and heart transplant teams. However, over half of all pediatric heart candidates are sensitized with anti-HLA antibodies.…”

The association of lymphopenia and post‐transplant infection in children: Is it time to change induction in Fontan heart transplant recipients?

“…A recent analysis of the Pediatric Heart Transplant Study found that Fontan patients with lymphopenia and/or proteinlosing enteropathy had higher rates of infection post-HT compared to patients with neither at time of heart transplant (22.1 vs. 41.4%) with no corresponding difference in rejection, malignancy, or graft survival at 1 year. 3 However, this analysis was limited by varying induction regimens and limited granularity typical of registry analysis.…”