A Lifelong Journey with Common Variable Immunodeficiency: Lessons from a Cohort Spanning Childhood to Old Age

Introduction Common variable immunodeficiency (CVID) is a highly heterogeneous immunodeficiency affecting individuals of all ages. We aim to characterize its clinical and immunological features throughout all stages of life. Methods We retrospectively reviewed patients with hypogammaglobulinemia evaluated at Hospital Italiano de Buenos Aires (2000–2025). After excluding secondary causes, only those fulfilling the 2019 European Society for Immunodeficiencies criteria for CVID were included and classified into three age-at-diagnosis groups: Group 1 (4–18 years), Group 2 (19–50 years), and Group 3 (51–80 years). Results Among 138 patients with hypogammaglobulinemia, 31 CVID patients from 30 families were included: 13 in Group 1, 11 in Group 2, and 7 in Group 3. The median follow-up was 8 years (interquartile range [IQR] 5–12). Group 2 had the longest diagnostic delay (median 6 years, IQR 4.5–19). Group 1 presented predominantly with infections and maintained this phenotype over a median of 14 years (IQR 4–22), except two patients with NFkB1 variants. Group 2 commonly exhibited combined infections and dysregulation, while Group 3 showed heterogeneous presentations. Bronchiectasis was diagnosed in three patients per group. Two patients developed lymphoma after age 40, and three in Group 3 developed solid tumors, all in remission. Notably, six patients in groups 2 and 3 had agammaglobulinemia with normal total B cells, of which two women (67 and 71 years) had no history of infections. Additionally, two female patients presented with hypogammaglobulinemia and absent B cells, with predominant multiorgan autoimmunity. No pediatric patients showed agammaglobulinemia at diagnosis. Genetic variants were identified in 3 of 10 tested patients: NFκB1 (two siblings), TRAF3, and a heterozygous variant of uncertain significance in DOCK8. No genetic studies were performed in Group 3. All patients are on immunoglobulin replacement therapy. One patient (aged 68) died from COVID-19. Conclusions Most childhood-onset CVID cases preserved their initial phenotype. In adults, unexplained agammaglobulinemia or absent B cells warrant genetic evaluation. In elderly patients, findings suggest late-onset rather than delayed diagnosis. Group 1 (4-18 years)Group 2 (19-50 years)Group 3 (51-80 years)n = 13n = 11n = 7Female sex*665Age at diagnosis13 (6-16)38 (33-40)60 (58-69)Current age27 (18-28)46 (39-49)71 (67-75)Follow-up14 (4-22)8 (5-10)5 (4.5-12.5)Diagnostic delay1 (0-4)6 (4.5-19)2 (0-4)Current phenotype*-Only infections812-Only dysregulation22-Both383-Asymptomatic2Phenotype progression*​​​-Only infections that adds dysregulation133-Dysregulation that adds infections11​Infections*1195-Sinusitis141-Otitis30​-Pneumonia964-Gastrointestinal1​Bronchiectasis*333Autoimmunity*385-Cytopenias223-IBD132-Hepatitis3-Alopecia areata11Lymphoproliferation292-Splenomegaly182-Granulomatous and lymphocytic interstitial lung disease2​Neoplasia*​-Lymphoma​11-Lung cancer​2-Prostate​1-Pre-neoplastic lesions (cervical or vulvar intraepithelial neoplasm)​2Median (interquartile range 25-75).*Absolute frequency.