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.

Donath-Landsteiner (DL) antibodies are immunoglobulins formed in response to a viral, bacterial, or spirochete infection and are capable of inducing paroxysmal cold hemoglobinuria (PCH), an autoimmune hemolytic anemia. In the past, PCH was most commonly associated with syphilitic infections; however, now, it is more frequently seen in children secondary to upper respiratory infections and DL test is the diagnostic test. We report a case of a 4-year-old male presented with a sudden drop in hemoglobin and hematuria with a 2-week history of fever and upper respiratory tract infection who was subsequently diagnosed as PCH with the help of DL Test.

We report the case of an 86-year-old male with chronic anemia who presented with indirect hyperbilirubinemia, undetectable haptoglobin, and reticulocytosis. The peripheral smear showed no schistocytes. The cold-agglutinin titer was mildly positive, and the Donath-Landsteiner antibody test was positive. Bone marrow biopsy revealed a small CD5⁺ B-cell clone consistent with monoclonal B-cell lymphocytosis (MBL). The patient was diagnosed with paroxysmal cold hemoglobinuria (PCH) associated with MBL and treated with rituximab, achieving clinical stability without transfusion requirement. This case illustrates a rare coexistence of PCH and MBL in an elderly patient and emphasizes the importance of comprehensive hematologic evaluation for unexplained chronic hemolysis.

Autoimmune hemolytic anemia (AIHA) is caused by premature erythrocyte destruction mediated by autoantibodies (auto-Ab) with or without complement activation. The most frequent form (60%-70% of cases) is warm AIHA (wAIHA), driven by immunoglobulin G auto-Ab that react at body temperature. Cold agglutinin disease (CAD, 20%-25%) is the second most common form and is caused by immunoglobulin M auto-Ab that usually react at temperatures <20°C and strongly activate complement. Rarer forms (5%-10%) include mixed AIHAs (wAIHA plus CAD), and paroxysmal cold hemoglobinuria. Here, we present the management of wAIHA, as CAD is discussed separately. Approximately 50% of wAIHA are primary, whereas the remainder are secondary to various conditions (infections, lymphoproliferative disorders, systemic or organ-specific autoimmune diseases, congenital immunodeficiencies, hematopoietic stem-cell transplantation, and several drugs, including immune checkpoint inhibitors). The disease is highly heterogeneous, ranging from fully compensated to life-threatening, and frequently has a relapsing course. Standard first-line therapy includes steroids with or without intravenous immunoglobulin, transfusions when anemia is clinically significant, prophylactic anticoagulation for severe hemolysis, and recombinant erythropoietin when reticulocytopenia/inadequate bone marrow compensation is present. For severe cases, high-dose steroids and plasma-exchange may be considered. Rituximab is now the preferred second-line option for relapsed/refractory patients, comparing favorably with the traditional splenectomy. The latter is increasingly reserved for later lines together with classic immunosuppressants. Several novel treatments are in development for refractory wAIHA, encompassing drugs targeting B-cells (parsaclisib, ibrutinib, rilzabrutinib, zanubrutinib, obexelimab, ianalumab, povetacicept), plasma cells (bortezomib, daratumumab), spleen tyrosine kinase (fostamatinib, sovleplenib), and the neonatal Fc receptor (nipocalimab).

Background: In Epstein-Barr virus infectious mononucleosis, hemolytic anemia occasionally occurs. Methods: To characterize hemolytic anemia linked to Epstein-Barr virus infectious mononucleosis, we performed a systematic review (PROSPERO CRD42024597183) in the United States National Library of Medicine, Excerpta Medica, and Web of Science with no restrictions on language. Only reports published since 1970 were included. Eligible were reports describing hemolytic anemia in subjects with clinical signs and microbiological markers of Epstein-Barr virus mononucleosis. Results: In the literature, we detected 56 reports released between 1973 and 2024, documenting 60 individuals (32 females and 28 males; 27 children and 33 adults) with hemolytic anemia linked to Epstein-Barr virus infectious mononucleosis. The mechanism underlying anemia was categorized as cold-antibody-mediated (N = 31; 52%), warm-antibody-mediated (N = 18, 30%), mixed warm- and cold-antibody-mediated (N = 4; 6.7%), or paroxysmal cold hemoglobinuria (N = 2; 3.3%). The remaining 5 cases (8.3%) remained unclassified. Observation alone was the chosen approach in 23% of cases (N = 14). Steroids (67%; N = 40) and blood transfusions (38%; N = 23) were the most commonly used treatment, while plasma exchange, intravenous polyclonal immunoglobulin, rituximab, and splenectomy were used less frequently. Observation was slightly but significantly (p = 0.032) more common in cases of cold-antibody-mediated anemia compared to all other cases combined. Patients recovered a median of 28 [interquartile range 21-39] days after disease onset. Two patients with warm-antibody-mediated hemolytic anemia died. Conclusions: This literature review points out that Epstein-Barr virus, like Mycoplasma pneumoniae, cytomegalovirus, or severe acute respiratory syndrome coronavirus 2, may act as a trigger for immune-mediated hemolytic anemia.