Late‐Onset Combined Immune Deficiency: A Subset of Common Variable Immunodeficiency with Severe T Cell Defect

TLDR

Common variable immunodeficiency is a primary immune deficiency characterized by defective antibody production. The study aims to use systematic T‑cell phenotyping to distinguish late‑onset combined immune deficiency from typical CVID, enabling tailored diagnosis, treatment, and genetic insights. Among 313 CVID patients, 8.9% had late‑onset combined immune deficiency, which was associated with consanguinity, higher rates of splenomegaly, granuloma, gastrointestinal disease, lymphoma, increased antibiotic use and hospitalizations, markedly reduced CD4 T‑cell counts (especially naive subsets), and lower B‑cell numbers, distinguishing it clinically and immunologically from classic CVID.

Abstract

Common variable immunodeficiency (CVID) is a primary immune deficiency defined by defective antibody production. In most series, a small proportion of patients present with opportunistic infections (OIs).The French DEFI study has enrolled patients with primary hypogammaglobulinemia and allows a detailed clinical and immunologic description of patients with previous OIs and/or at risk for OIs.Among 313 patients with CVID, 28 patients (8.9%) presented with late-onset combined immune deficiency (LOCID), defined by the occurrence of an OI and/or a CD4(+) T cell count <200 x 10(6) cells/L, and were compared with the remaining 285 patients with CVID. The patients with LOCID more frequently belonged to consanguineous families (29% vs 8%; P = .004). They differed from patients with CVID with a higher prevalence of splenomegaly (64% vs 31%), granuloma (43% vs 10%), gastrointestinal disease (75% vs 42%), and lymphoma (29% vs 4%). Even on immunoglobulin substitution, they required more frequent antibiotics administration and hospitalization. Lymphocyte counts were lower, with a marked decrease in CD4(+) T cell counts (158 x 10(6) vs 604 x 10(6) cells/L; P < .001) and a severe defect in naive CD45RA(+)CCR7(+)CD4(+) T cell counts (<20% of total CD4(+) T cells in 71% of patients with LOCID vs 37% of patients with CVID; P = .001). The CD19(+) B cell compartment was also significantly decreased (20 x 10(6) vs 102 x 10(6) cells/L; P < .001).LOCID differs from classic CVID in its clinical and immunologic characteristics. Systematic T cell phenotype may help to discriminate such patients from those with CVID. Identification of this phenotype should result in a more fitted diagnostic and therapeutic approach of infections and could provide insights for genetic diagnosis.