Faculty Bibliography

Purpose of Review: Diagnosis of pediatric heart transplant rejection has historically relied on endomyocardial biopsy and clinical assessment. This review will describe novel techniques that may aid and refine diagnosis of rejection. Recent Findings: Donor-derived cell-free DNA and gene expression profiling assays provide diagnostics of rejection that are less invasive than surveillance endomyocardial biopsy. Imaging with echocardiography, cardiac magnetic resonance, and cardiac computed tomography are common for pediatric cardiology patients, and their role in detecting and monitoring rejection of heart transplants continues to be modified and expanded. Summary: Novel diagnostic tools have the potential to lead to less invasive and more precise diagnosis of transplant rejection, ideally improving the long-term care of pediatric heart transplant recipients.

Human leukocyte antigen (HLA) molecular mismatch is a powerful biomarker of rejection. Few studies have explored its use in assessing rejection risk in heart transplant recipients. We tested the hypothesis that a combination of HLA Epitope Mismatch Algorithm (HLA-EMMA) and Predicted Indirectly Recognizable HLA Epitopes (PIRCHE-II) algorithms can improve risk stratification of pediatric heart transplant recipients. Class I and II HLA genotyping were performed by next-generation sequencing on 274 recipient/donor pairs enrolled in the Clinical Trials in Organ Transplantation in Children (CTOTC). Using high-resolution genotypes, we performed HLA molecular mismatch analysis with HLA-EMMA and PIRCHE-II, and correlated these findings with clinical outcomes. Patients without pre-formed donor specific antibody (DSA) (n=100) were used for correlations with post-transplant DSA and antibody mediated rejection (ABMR). Risk cut-offs were determined for DSA and ABMR using both algorithms. HLA-EMMA cut-offs alone predict the risk of DSA and ABMR; however, if used in combination with PIRCHE-II, the population could be further stratified into low-, intermediate-, and high-risk groups. The combination of HLA-EMMA and PIRCHE-II enables more granular immunological risk stratification. Intermediate-risk cases, like low-risk cases, are at a lower risk of DSA and ABMR. This new way of risk evaluation may facilitate individualized immunosuppression and surveillance.