Two- to Six-Year Clinical Outcomes Prior to Treatment with Cultured Thymus Tissue Implantation in Children with Congenital Athymia

Background Congenital athymia (CA), a T cell immunodeficiency due to absent thymus development during embryogenesis, results in profound T cell lymphopenia and defective self-tolerance unless treated with cultured tissue thymus implantation (CTTI). Prior to national newborn screening (NBS) for T cell deficiency, the majority of infants with CA died by 3 years of age. There has not been an assessment of CA clinical outcomes since NBS implementation. Methods Duke is the only center in the United States performing CTTI. Prior to 2021 FDA approval of Rethymic®, there was a hiatus in CTTI. This single-center retrospective analysis of infants referred to Duke between 2018 and 2022 assessed survival and incidence of infectious and autoimmune outcomes prior to CTTI. Inclusion criteria included an abnormal NBS, T cell negative, B cell and NK cell positive lymphocyte enumeration, and naïve T counts <50 cells/µL. Data were collected from review of referral information and the EMR. Data were stored in a secure REDCap® database with data transfer through protected analytics computing. Results Sixty-three infants were eligible. 22q11.2 deletion syndrome was most common (36%), followed by maternal diabetes (24%), CHARGE syndrome (24%), PAX1 (5%), TBX1 (5%), TP63 (1.5%), or EXTL3 (1.5%). Disrupted pharyngeal arch syndromic features were evident in 93% of cases. Autoimmunity was the most prevalent comorbidity (51%), including thyroid disease, autoimmune cytopenia, and/or autologous GVHD, defined as rash, lymphadenopathy, and/or eosinophilia. Median day of life (DOL) onset for autoimmunity was 127 (min-max 9-1468). Despite prophylaxis for most infants, infections were common with SARS-CoV-2 (17%), adenovirus (10%), HHV-6 (8%), norovirus (8%), EBV (5%), CMV (3%), Mycobacterium avium (5%), and Pneumocystis (5%). Clinical outcomes included: 36 (57%) successfully received CTTI at median DOL 965, 6 (9.5%) experienced spontaneous T cell reconstitution (naïve T cells >100 cells/mm3 by median DOL 1359 (1214-2284), and 20 (32%) died at median DOL 362 (71-2068). Conclusion Despite early diagnosis and prophylaxis, mortality remains high in CA without CTTI. Prior to definitive therapy, the risk of autoimmunity and community-acquired infection remains high. Spontaneous T cell recovery occurs in <10% of CA. Taken together, early implementation of CTTI with appropriate isolation and prophylaxis is the optimal management of CA.