Clinical Features and Lymphocyte Immunophenotyping Analysis in Primary Immunodeficiency Patients With Non-transplant Lymphoproliferative Disorders

Abstract Purpose: Lymphoproliferative disorders (LPD) comprise a heterogeneous group of diseases and can be classified categorized into the category as being immune dysregulation diseases in primary immunodeficiency diseases (PID) that typically represent as monogenetic X-linked and autoimmune lymphoproliferative diseases (XLP and ALPS). The LPD phenotype extends to other categories in PID and its distribution remains scarce. Methods: The clinical course and lymphocyte immunophenotyping in PID patients with the LPD phenotype who were referred to the PICAR (Primary Immunodeficiency Care And Research) institute were investigated between 2004 and 2020.Results: Of the 96 enrolled patients, 31 (32.3%) (median age 144, range 3-252 months) developed the LPD phenotype mainly encompassing lymphadenopathy (in 10 patients), refractory inflammatory bowel disease (IBD)-like with intestinal lymphadenopathy in 8 and hepatosplenomegaly (in 7) during long-term follow-up (median 144, range 3-252 months). The LPD phenotype was most frequently present in the categories of antibody deficiency (in 7: 2 CVID, 2 TTC37, PIK3CD, PIK3R1 and AICDA each), phagocyte (in 6: 4 CYBB, 1 STAT1 and 1 IFNRG1), immune dysregulation (in 6: 2 FOXP3, 2 XIAP and 2 HLH), combined immunodeficiencies (in 5: 2 IL2RG, 1 CD40L, 1 ZAP70 and 1 unknown) and syndromic features (in 4: 2 STAT3-LOF, 1 WAS and 1 ATM) as well as three patients with anti-IFN-γ autoantibodies. Those with the LPD phenotype had a significantly higher mortality rate than those without (p=0.0016) despite a similar age at onset (median 66 vs 44 months) and follow-up duration (138 vs 144 months). EBV virus load was only detectable in the PIK3CD and HLH patient each. An increased senescent (CD8+CD57+) and CD21-low components, and disturbed transitional B (CD38+IgM++), plasamablast B (CD38++IgM-), memory B (CD19+CD27+) and TEMRA (CD27-IgD-) components were often observed in cross-sectional immunophenotyping. However, except patients with CD40L and ZAP70 mutations, those with profound T cell defects who bear almost naïve (T and B cells) components and extreme low in the remaining subsets components trended to develop their LPD phenotype. Conclusion: The spectrum of the LPD phenotype in one third of the PID patients overriding the categorical boundaries had higher mortality and heterogeneous lymphocyte disturbances, especially higher senescent and CD21-low but lower memory B subpopulations. Large-scale longitudinal studies of PID patients are needed to validate the correlation between immunophenotype and the LPD status.