Warm autoimmune hemolytic anemia following epstein-barr virus reactivation: An uncommon clinical association

Abstract Introduction: Autoimmune hemolytic anemia (AIHA) is a rare condition characterized by the immune system's destruction of red blood cells (RBCs), leading to hemolysis. It is classified into warm and cold types based on the temperature at which autoantibodies are active. Warm AIHA, the most common form, accounts for approximately 60–70% of cases and typically involves IgG-mediated hemolysis. Triggers include infections, autoimmune diseases, and malignancies. Case Description: A 62-year-old male with hypertension and hyperlipidemia was referred for evaluation of abnormal liver and kidney function tests. He reported bilateral leg swelling, arm discomfort, jaundice, orthopnea, and exertional dyspnea. There was no history of fever, weight loss, night sweats, travel, or family history of malignancy. His only medications were atenolol and atorvastatin, and he denied use of herbal supplements or over-the-counter drugs. Laboratories revealed macrocytic, normochromic anemia (hemoglobin 6.6 g/dL, mean corpuscular volume 135.3 fL), elevated red cell distribution width (84 fL), and leukocytosis (white blood cell count 14,300/mm³). Hemolysis markers were significant: elevated indirect bilirubin 8.3 mg/dL and lactate dehydrogenase (LDH) 792 U/L, low haptoglobin (<30 mg/dL), and reticulocytosis (25.9%). Peripheral smear showed spherocytes, nucleated RBCs, vacuolization, immature neutrophils, and Howell-Jolly bodies suggestive of a leukoerythroblastic picture and functional hyposplenism. Direct antiglobulin test (DAT) was positive. Vitamin B12, folate, and iron deficiencies were excluded. Autoimmune (antinuclear antibody, anti-cyclic citrullinated peptide) and infectious (cytomegalovirus, human immunodeficiency virus) workups were negative; however, Epstein-Barr virus (EBV) serology indicated reactivation. The diagnosis was warm AIHA, likely triggered by EBV reactivation. The patient was treated with prednisone (1 mg/kg/day), with subsequent taper, and received two units of phenotype-matched RBCs. He showed clinical and laboratory improvement, including resolution of symptoms and normalization of hemolysis markers. Discussion: Warm AIHA is most commonly idiopathic but can also occur secondary to various conditions, including rheumatologic diseases (e.g., systemic lupus erythematosus), chronic lymphoblastic leukemia, non-Hodgkin's lymphoma, certain medications (e.g., cephalosporins, piperacillin), and infections. In this case, extensive evaluation ruled out common secondary causes such as autoimmune conditions, nutritional deficiencies, hematologic malignancies, and other infections. Interestingly, the patient's serology was positive for EBV reactivation, suggesting EBV as a potential trigger. While EBV is more commonly associated with cold AIHA due to cold agglutinins, reports of warm AIHA linked to EBV reactivation are rare. Warm AIHA typically presents with symptoms of anemia and hemolysis, including fatigue, pallor, jaundice, dyspnea, and splenomegaly. Laboratory findings often reveal anemia, elevated LDH, indirect hyperbilirubinemia, low haptoglobin, and reticulocytosis. A positive DAT confirms the presence of IgG on RBCs, complement C3 may or may not be present in warm AIHA. Initial corticosteroid therapy varies widely during the first 72 hours, ranging from 1–2 mg/kg of prednisone every 8–12 hours to high-dose intravenous methylprednisolone (250–1000 mg/day). After this initial period, the regimen is typically adjusted to a maintenance dose of 30–80 mg/day in adults. In cases refractory to steroids, additional therapies such as mycophenolate mofetil or sirolimus may be considered. In our case, the patient responded well to corticosteroids and transfusion, with clear clinical and laboratory improvement. Conclusion: This case highlights a rare presentation of warm AIHA likely triggered by EBV reactivation, an association that is infrequently reported in the literature.