Childhood isolated C3d-positive AIHA: favorable prognosis but rare relapse or associated immunodeficiency

Autoimmune hemolytic anemia (AIHA) with an isolated C3d-positive direct antiglobulin test is a rare and understudied condition in children. It typically encompasses cold agglutinin syndrome and paroxysmal cold hemoglobinuria, both transient, infection-triggered disorders collectively referred to as cold AIHA. We report a national cohort of 142 pediatric patients with isolated C3d-positive AIHA, representing 21.6% of all childhood AIHA cases enrolled in the French OBS'CEREVANCE cohort over a 32-year period. The median age at diagnosis was 3.2 years (male-to-female ratio: 1.3), and median follow-up was 2.8 years. Infectious symptoms were present in 63.4% of cases. At diagnosis, median hemoglobin was 6.4 g/dL; 69.7% of patients had inadequate reticulocytosis (BMRI < 121), and 90.4% required transfusions. Eighteen patients (12.7%) had or developed immunopathological manifestations (IM) including five diagnosed with primary immunodeficiency (four with ALPS). Among eight (5.6%) relapsing patients, six had no IM at diagnosis, but four developed IM at relapse. Nine patients were ANA-positive; none progressed to systemic lupus over a median follow-up of 4.9 years. Corticosteroids were administered to 82.4% of patients (median duration: 4.5 months), with no clear benefit over untreated patients regarding hospital stay or transfusion needs. No deaths were reported. In conclusion, pediatric isolated C3d-positive AIHA generally follows a favorable course. However, a minority of patients may reveal underlying immune disorders, highlighting the importance of tailored evaluation at diagnosis. Cold agglutinin testing with thermal amplitude and Donath-Landsteiner testing, rarely performed in this cohort, warrant further study for their impact on diagnosis and clinical management.