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Commentary: Set me free—cell-free DNA may soon provide reprieve to pediatric heart transplant recipients

      Figure thumbnail fx1
      Dennis A. Wells, MD, and David L. S. Morales, MD
      Novel application of cell-free DNA testing in pediatric cardiac transplant recipients may lead to practical benefits, including surveillance protocols requiring less-frequent invasive procedures.
      See Article page 460.
      Recent studies evaluating the potential of cell-free DNA testing in adult cardiac transplant recipients have demonstrated promise in creating a so-called “liquid biopsy” to serve as a screening laboratory test to assess for allograft rejection.
      • Agbor-Enoh S.
      • Shah P.
      • Tunc I.
      • Hsu S.
      • Russell S.
      • Feller E.
      • et al.
      Cell-free DNA to detect heart allograft acute rejection.
      ,
      • Richmond M.E.
      • Zangwill S.D.
      • Kindel S.J.
      • Deshpande S.R.
      • Schroder J.N.
      • Bichell D.P.
      • et al.
      Donor fraction cell-free DNA and rejection in adult and pediatric heart transplantation.
      The authors should be commended for expanding on these efforts and including pediatric cardiac transplant recipients in their analysis.
      • Richmond M.
      • Deshpande S.R.
      • Zangwill S.D.
      • Bichell D.P.
      • Kindel S.J.
      • Mahle W.T.
      • et al.
      Validation of donor fraction cell-free DNA with biopsy proven cardiac allograft rejection in children and adults.
      Endomyocardial biopsy remains the standard screening and diagnostic study for allograft rejection among heart transplant recipients. While less-invasive options for transplant surveillance would benefit patients of any age, such a test would be particularly beneficial in pediatrics. Endomyocardial biopsies are relatively safe, but they are not without risk in children.
      • Daly K.P.
      • Marshall A.C.
      • Vincent J.A.
      • Zuckerman W.A.
      • Hoffman T.M.
      • Canter C.E.
      • et al.
      Endomyocardial biopsy and selective coronary angiography are low-risk procedures in pediatric heart transplant recipients: results of a multicenter experience.
      Risks include tricuspid valve injury and vascular access complications. Although a minor invasive procedure, most pediatric patients require general anesthesia for endomyocardial biopsy. Certainly, beyond the low but quantifiable risks of repeated procedures and anesthesia encounters, the stress pediatric patients incur with these repeated events is difficult to quantify but best avoided if an alternative existed. In addition, as a gold standard for screening and diagnosis for allograft rejection, endomyocardial biopsy is not without its limitations. The histologic changes that occur with rejection may be heterogenous both in severity and geographic distribution, with sampling bias impacting the yield of endomyocardial samples. The grading of these samples is not without some subjectivity among pathologists. Also, the histologic changes observed are results of injury that has already occurred. In the recent era and considering advances in immunosuppression, some have questioned the utility and cost-effectiveness of surveillance protocols that include endomyocardial biopsies in pediatric transplant patients beyond the first year following transplant.
      • Power A.
      • Baez Hernandez N.
      • Dipchand A.I.
      Rejection surveillance in pediatric heart transplant recipients: critical reflection on the role of frequent and long-term routine surveillance endomyocardial biopsies and comprehensive review of non-invasive rejection screening tools.
      Donor fraction cell-free DNA is based on a simple blood draw. In the authors’ analysis, blood samples obtained from patients before undergoing endomyocardial biopsies and correlated with results demonstrated excellent negative predictive values for antibody- or cellular-mediated rejection among both adult and pediatric patients. The current form of their laboratory analysis did not require donor graft tissue sampling or previous genotyping, and processing appears to have been simple and consistent, with standard laboratory analyses with results in 48 hours. This seems promising as a screening tool for rejection, with practical applications to serve as an alternative to routine endomyocardial biopsy, thereby providing reprieve to our pediatric patients by freeing them of frequent invasive procedures within their transplant surveillance protocols. It would likely prove to be a cost-effective alternative to the traditional standard biopsy as well. Further refinement of this testing and future analysis may even demonstrate potentials for this as a diagnostic test rather than merely screening. As mentioned previously, endomyocardial biopsy limitations include sampling bias due to potentially heterogeneous distribution within the myocardium as well as subjectivity in the pathologic analysis. One can imagine indexed values of donor fraction cell-free DNA being validated as quantitative measures of severity of rejection that may prove as reliable as pathologic analysis in the future.
      For now, it may be time to employ donor fraction cell-free DNA as a standard screening tool in our transplant surveillance protocols and set our pediatric patients free from frequent invasive procedures.

      References

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        • Shah P.
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        • Hsu S.
        • Russell S.
        • Feller E.
        • et al.
        Cell-free DNA to detect heart allograft acute rejection.
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        Donor fraction cell-free DNA and rejection in adult and pediatric heart transplantation.
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        • et al.
        Validation of donor fraction cell-free DNA with biopsy proven cardiac allograft rejection in children and adults.
        J Thorac Cardiovasc Surg. 2023; 165: 460-468.e2
        • Daly K.P.
        • Marshall A.C.
        • Vincent J.A.
        • Zuckerman W.A.
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        • Canter C.E.
        • et al.
        Endomyocardial biopsy and selective coronary angiography are low-risk procedures in pediatric heart transplant recipients: results of a multicenter experience.
        J Heart Lung Transplant. 2012; 31: 398-409https://doi.org/10.1016/j.healun.2011.11.019
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        Rejection surveillance in pediatric heart transplant recipients: critical reflection on the role of frequent and long-term routine surveillance endomyocardial biopsies and comprehensive review of non-invasive rejection screening tools.
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