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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.

Methods: We infused MSC using a dose escalation model: 3 patients received a low volume infusion (1 million MSC/Kg), 3 received an intermediate volume (2 million MSC/kg) and 3 received high volume infusion (4 million MSC/Kg). Blood samples were collected as baseline (day-1), on day +1 and day +7 following infusion to measure biomarker assays (B cells, natural killer-NK-cells), and T cell enumerations (T-regulatory cells). We used a multiplex cytokine assay to assess pro-inflammatory cytokine (TH1) and tolerogenic cytokine (TH2) levels and pro-angiogenic factors (vascular endothelial growth factor-VEGF). Changes in cytokine levels greater or less than 1 standard deviation from the mean baseline levels was considered significant. Results: We observed no increment in circulating MSC on days +1 and +7 regardless of the volume of MSC infused, suggesting that MSC were trapped in the lung as has been reported. Blood levels of tolerance-inducing T regulatory cells doubled in patients receiving low infusion MSC. NK and B cell numbers decreased in the low volume group. Contrarily, an increase or no change was observed in the other groups. Epidermal Growth Factor (EGF), a potent promoter of cell proliferation, anti-apoptotic and pro-angiogenic factor was significantly increased in the low volume group while no significant change was observed in other groups. Tolerance-inducing TH2 cytokines such as IL-4 significantly increased on patients receiving low and intermediate volume MSC infusion. Pro-inflammatory TH1 cytokines(IL-1, IL-6, and IL-8), and pro-inflammatory chemokines (MCP-1, MIP-1α , and MIP-1β) significantly decreased in patients receiving low volume infusion. Overall, the biological effects of the MSC therapy appeared to decrease with increasing cell volumes infused. Conclusion: Low volume MSC infusion induces anti-inflammatory effects and promotes cell proliferation and angiogenesis in patients with obstructive CLAD. Higher MSC volumes appear to have less positive biological effects. These results need clinical correlation.

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