Bronchiectasis and chronic active EBV (CAEBV) as first signs of IRF8-deficiency

Introduction: Pediatric bronchiectasis is caused by cystic fibrosis, primary ciliary dyskinesia, severe infection and/or Inborn Errors of Immunity (IEI). Immunological workup is often limited to humoral immunity, delaying or missing the diagnosis of other IEI. Biallelic and monoallelic mutations in IRF8 , coding for the transcription factor IRF8, had previously been described in patients, who predominately presented with mycobacterial disease. Methods: Whole exome sequencing was performed on blood DNA, scRNAseq on PBMCs. Immunological phenotyping including conventional type 1 dendritic cells (cDC1), type 2 (cDC2), and plasmacytoid dendritic cells (pDC) as well as IRF8 expression was assessed in PBMCs by flow cytometry. The variant was functionally validated by expressing WT and mutant IRF8 in HEK293T cells, followed by immunoblotting and nuclear translocation and transcriptional activity assays. Results: The patient has recurrent lower respiratory infections with productive cough and impaired lung function (FEV1 58%, VC 68%, LCI 13), bronchiectasis on CT (BAL adenovirus 20600 copies/mL), generalized lymphadenopathy and hepatosplenomegaly, and chronic active EBV-infection (CAEBV, EBV-positive interface hepatitis on biopsy, blood EBV about 2000 copies/mL). In peripheral blood, T and NK cells are broadly normal. IgG is elevated, the BCR repertoire restricted, and vaccine titers low. Monocytes are mildly elevated, whereas cDC1s are absent, cDC2s within normal range, and pDC reduced. A novel heterozygous loss-of-stop mutation was found in IRF8 leading to C-terminal elongation of the IRF8 protein. The mutant IRF8 showed normal nuclear localization but impaired transcriptional activities. Discussion: We present a 10-year-old boy with bronchiectasis with a novel dominant-negative loss-of-stop mutation in IRF8 . Despite a defect in dendritic cells, requiring hematopoietic stem cell transplantation, our patient has reached the age of nine without any indication of mycobacterial disease. This, together with another report on another dominant-negative loss-of-stop IRF8 variant, suggests that the phenotype of monoallelic IRF8-deficiency due to dominant-negative mutations is broader than originally described within the context of mycobacterial disease and should be considered in any patient with bronchiectasis, and/or persistent viral infection, including CAEBV. Our patient highlights that bronchiectasis can be the first sign not only of humoral, but also of cellular IEI. Publication History Article published online: 26 February 2026 © 2026. Thieme. All rights reserved. Georg Thieme Verlag KG Oswald-Hesse-Straße 50, 70469 Stuttgart, Germany