Human Herpesvirus 6 (HHV-6) Infection Impairs T Cell Development in Children with Congenital Athymia Who Have Received Allogeneic Processed Thymus Tissue–agdc (RETHYMIC)

BackgroundCongenital athymia (CA) is a rare T cell immune deficiency, fatal without curative treatment with allogeneic processed thymus tissue–agdc (RETHYMIC) implantation (here termed CTTI). The rate and extent of T cell reconstitution following CTTI are variable and may be influenced by infection or autoimmunity prior to implantation. Human herpesvirus 6 (HHV-6), the cause of roseola infantum, is a common infection affecting infants under age 2 years. HHV-6 demonstrates thymocyte tropism and impairs T cell development in murine models. We hypothesize that HHV-6 infection prior to CTTI results in lower T cell reconstitution in children with CA.MethodsProspective, single-center study included 29 children with CA who received allogeneic processed thymus tissue–agdc at Duke University between March 2022 and April 2024. Following consent (NCT05329935), participants received similar immune suppression (anti-thymocyte globulin and calcineurin inhibitor) prior to, and following CTTI. HHV-6 PCR test results prior to CTTI categorized the cohorts into HHV-6(positive) or HHV-6(negative). Lymphocyte enumeration at 3, 6, 9, and 12 months post CTTI for CD3+, CD4+, CD8+, and naïve CD4+ T cells was compared in the HHV-6 groups using a Mann-Whitney U test. Outcomes included survival at 24 months post CTTI.ResultsA total of 23 children were characterized as HHV-6(negative) and six as HHV-6(positive). Groups were similar in sex, ethnicity, and etiology of CA. Two participants in the HHV-6(negative) group had prior infection with varicella and EBV, and one participant in the HHV-6(positive) group had dual infection with HHV-6 and EBV. Median age at CTTI was similar among the two groups. At 12 months, median CD3+ counts were significantly lower in HHV-6(positive), 190 cells/mm3, compared to 512 cells/mm3 in HHV-6(negative), also with lower CD4+, CD8+, and naïve T cells (p = 0.016, 0.011, 0.04, and 0.029, respectively). Overall mortality at 24 months was higher in HHV-6(positive) compared to HHV-6(negative) but did not reach significance (0.099).ConclusionHHV-6 infection prior to CTTI is associated with delayed T cell immune recovery after CTTI and potentially reduced survival. Children with CA should adhere to strict isolation, regular surveillance, and have aggressive treatment for HHV-6.Figure 1.Changes in T cell subpopulations over time following cultured thymus tissue implantation (CTTI) for infants with congenital athymia. HHV-6positive are shown as a black line and HHV-6negative in red. The y axis shows median T cell numbers (cells/mm3), with interquartile ranges of 3 months, 6 months, 9 months, and 12 months post CTTI (x axis). Panel A is CD3+ T cells, panel B CD4+ T cells, panel C CD8+ T cells, and panel D naïve CD4 CD45RA and either CD62L, CCR7, CD27, or CD31 T cells. (*) denotes p< 0.05 Mann-Whitney U test.Tabular data are included as downloadable supplement files.