DeCure for Immunodeficiency 99 with hypogammaglobulinemia and autoimmune cytopenias

In a cohort of 138 patients with hypogammaglobulinaemia, 31 met 2019 European Society for Immunodeficiencies criteria for common variable immunodeficiency (CVID) and were grouped by age at diagnosis: 13 aged 4–18 years, 11 aged 19–50, and 7 aged 51–80. The median follow-up was 8 years. Diagnostic delay was longest in the 19–50 group (median 6 years, interquartile range 4.5–19). Among childhood-onset patients, the initial infection-predominant phenotype persisted over a median of 14 years, except in two patients with NFkB1 variants. Adults more often had combined infections and immune dysregulation. Six patients in the two older groups had agammaglobulinaemia with normal total B cells; two of these women (aged 67 and 71) had no history of infections. Two female patients had hypogammaglobulinaemia with absent B cells and predominant multiorgan autoimmunity. No paediatric patient had agammaglobulinaemia at diagnosis. Genetic variants were found in 3 of 10 tested patients: NFκB1 (two siblings), TRAF3, and a heterozygous variant of uncertain significance in DOCK8. No genetic testing was done in the oldest group. All patients received immunoglobulin replacement therapy. One patient (aged 68) died from COVID-19.

Earlier reports describe granulomatous disease in 17 hypogammaglobulinaemic CVID patients, 8 of whom had granulomas before hypogammaglobulinaemia was diagnosed. Sixteen of the 17 had deficient T-cell proliferation to mitogens. Despite standard intravenous immunoglobulin, they had substantial illness including frequent autoimmune disease. A 1993 review notes that CVID patients have increased incidence of autoimmune disease and malignancy. A 2013 case report describes a 12-year-old boy with all clinical signs of immunodeficiency, confirmed by laboratory tests, whose main treatment was lifelong immunoglobulin substitution. A 2015 case report describes an 84-year-old patient with over 30 years of recurrent infections and serum IgG below 134 mg/dL; strong hypogammaglobulinaemia had been present for over 14 years on review of earlier examinations.

A 2024 case report describes a 34-year-old man with Evans syndrome, prolonged severe CD4+ lymphocytopenia (below 60/µL for 56 months after treatment including steroids and rituximab), and hypogammaglobulinaemia. Repeated HIV tests were negative. A gene panel for immunodeficiency using next-generation sequencing found no pathogenic variants. He used continuous trimethoprim-sulfamethoxazole to prevent pneumocystis pneumonia. The report notes that common variable immunodeficiency is the most common primary immunodeficiency causing secondary autoimmune haemolytic anaemia and Evans syndrome, and that serum immunoglobulins should be tested in such patients, but that CD4+ cell count may also be needed in those with hypogammaglobulinaemia or recurrent infections.

What is still missing: prospective studies that stratify patients by age at onset, genetic findings, and lymphocyte subsets; trials testing whether earlier immunoglobulin initiation or additional immunomodulation alters the course of granulomatous or autoimmune complications; and systematic genetic evaluation in older patients to distinguish late-onset CVID from delayed diagnosis of a monogenic form.