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

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.

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).

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.

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.