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

Autoimmune hemolytic anemia (AIHA) with an isolated C3d+ 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+ 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 (bone marrow responsiveness index of <121), and 90.4% required transfusions. Eighteen patients (12.7%) had or developed immunopathological manifestations (IM) including 5 diagnosed with primary immunodeficiency (4 with autoimmune lymphoproliferative syndrome). Among 8 (5.6%) patients with relapsing disease, 6 had no IM at diagnosis but 4 developed IM at relapse. Nine patients were antinuclear antibodies (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+ 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.

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Journal
Blood Advances
Published
2025-10-21
DOI
https://doi.org/10.1182/bloodadvances.2025017309
Citations
1
Primary Topic
Blood groups and transfusion
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article
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1.77
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article

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

Isabelle Pellier, Catherine Paillard, Pascal Chastagner, Corinne Guitton et al.
1 citations
Blood Advances
Blood groups and transfusion
1.77
article

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

Isabelle Pellier, Catherine Paillard, Pascal Chastagner, Corinne Guitton, M Deparis, Nathalie Cheikh, Claire Pluchart, Nathalie Garnier, Nathalie Aladjidi, Despina Moshous, Steffen Gay, Marlène Pasquet, Thomas Modot, Julien Lejeune, Wadih Abou Chahla, Guy Leverger, Arnaud Petit, Stéphane Ducassou, Marion Blachez, Helder Fernandes, Vincent Barlogis, Joy Benadiba, Martin Castelle, Capucine Pïcard, Christophe Piguet, Liana Carausu, Sébastien Heritier, Corinne Armari‐Alla, Frédéric Rieux‐Laucat, Éric Jeziorski, Frédéric Millot, Jean‐Louis Stéphan, Caroline Thomas, Thierry Leblanc, Aude Marie‐Cardine, Mony Fahd, Sophie Bayart, Valérie Li Thiao Te, Aurélia Alimi
article en
1 citations

Abstract

Autoimmune hemolytic anemia (AIHA) with an isolated C3d+ 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+ 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 (bone marrow responsiveness index of <121), and 90.4% required transfusions. Eighteen patients (12.7%) had or developed immunopathological manifestations (IM) including 5 diagnosed with primary immunodeficiency (4 with autoimmune lymphoproliferative syndrome). Among 8 (5.6%) patients with relapsing disease, 6 had no IM at diagnosis but 4 developed IM at relapse. Nine patients were antinuclear antibodies (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+ 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.

Blood AdvancesVol. 10(2)
Université de Tours (FR), Hôpital Necker-Enfants Malades (FR), Centre National de la Recherche Scientifique (FR), Université de Bordeaux (FR), Inserm (FR), Université Fédérale de Toulouse Midi-Pyrénées (FR), Université Côte d'Azur (FR), Université Paris Cité (FR), Centre Hospitalier Universitaire de Grenoble (FR), Centre Hospitalier Universitaire de Bordeaux (FR), Centre Hospitalier Universitaire de Lille (FR), Centre Hospitalier Universitaire de Nice (FR), Centre Hospitalier Universitaire de Nantes (FR), Université Rennes 2 (FR), Université de Poitiers (FR), Sorbonne Université (FR), Institut Necker Enfants Malades (FR), Hôpital Armand-Trousseau (FR), Assistance Publique Hôpitaux de Marseille (FR), Centre Hospitalier Universitaire de Besançon (FR), Institut d’Hématologie et d’Oncologie Pédiatrique (FR), Sorbonne Paris Cité (FR), Centre de Recherche en Cancérologie et Immunologie Intégrée Nantes Angers (FR), Centre Hospitalier Universitaire de Montpellier (FR), Methodology and Quality of Life Unit in Oncology (FR), Centre Hospitalier Universitaire de Tours (FR), Centre Hospitalier Universitaire Amiens-Picardie (FR), Assistance Publique – Hôpitaux de Paris (FR), Centre Hospitalier Régional et Universitaire de Nancy (FR), Hospices Civils de Lyon (FR), Hôpital Jeanne de Flandre (FR), Hôpital d'Enfants (FR), Centre Hospitalier Universitaire de Reims (FR), Bordeaux Population Health (FR), Laboratoire de Thermique et Energie de Nantes (FR), Hôpital Saint- Camille (FR), Centre Hospitalier Universitaire d'Angers (FR), Hôpital Robert-Debré (FR), Centre d'Investigation Clinique de Nantes (FR), Établissement Français du Sang (FR), Centre Hospitalier Régional Universitaire de Brest (FR), Hôpital Mère-Enfant (FR), Centre de Recherche Saint-Antoine (FR), Hôpital Purpan (FR), Hôpital Arnaud de Villeneuve (FR), Centre Hospitalier Universitaire de Rennes (FR), Centre Hospitalier Universitaire de Saint-Étienne (FR), Hôpital d'Hautepierre (FR), Hôpital de la Timone (FR), Bicêtre Hospital (FR), Institut des Maladies Génétiques Imagine (FR), Université d'Angers (FR), Université de Rennes (FR), Université de Rouen Normandie (FR), Université de Limoges (FR), Université Grenoble Alpes (FR), Université de Reims Champagne-Ardenne (FR), Nantes Université (FR), Université de Caen Normandie (FR)
Openalex Percentile: Top 12%
Blood groups and transfusion
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