A case study authored by Mateus Fernandes, MD, presented a patient with warm agglutinin autoimmune hemolytic anemia (AIHA) associated with Epstein-Barr virus (EBV). AIHA consists of a group of diseases that includes warm agglutinin AIHA and cold agglutinin disease (CAD), which has previously been associated with EBV.

The study was presented at the Chest 2021 Annual Meeting and published in Chest. Dr. Fernandes is an internal medicine resident at the Woodhull Medical and Mental Health Center at New York University Langone Medical Center in Brooklyn, New York.


A 79-year-old woman was referred from the outpatient clinic after blood tests demonstrated her hemoglobin levels to be 6.7 mg/dL. She had a past medical history of hypothyroidism. Her primary complaints were fatigue and difficulty breathing for 5 days. Her skin was visibly yellow, and she mentioned passing dark urine for 2 days. 

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The patient’s vitals revealed a blood pressure of 87/27 mmHg and a heart rate of 87 bpm. Her hemoglobin levels were tested again and had dropped to 4.7 mg/dL, with a mean corpuscular volume (MCV) of 111.6 fL. She had an elevated white cell count at 18 and her leukocyte alkaline phosphatase score was elevated at 50.

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Direct Coombs test revealed that the patient was positive for immunoglobulin G (IgG) and anti-C3 with warm agglutinins. Her haptoglobin was less than 10 mg/dL, her lactate dehydrogenase was 900 U/L, and her ferritin was 1747.

Treatment and Diagnosis 

Her physicians decided to administer 3 units of packed red blood cells and initiate corticosteroids. A peripheral blood smear demonstrated a left shift with increased bands, as well as megaloblastic granulocytes. Serum vitamin B12 levels were low at 63 ng/mL, while intrinsic factor was normal. EBV IgG titers were elevated at 50 times the upper limit of normal.

A thorough investigation revealed that the patient had no other infectious causes of AIHA. Her past drug history did not include any medications known to cause AIHA.

By day 2, the patient’s symptoms had resolved, with her hemoglobin levels rising to 9.4 mg/dL and her MCV reduced to 94.8 fL. The patient was prescribed vitamin B12 supplementation and was discharged. She remained symptom-free 4 weeks later. 

Clinical Significance 

EBV has previously been associated with CAD. “EBV has a well-established connection with cold agglutin AIHA,” Dr. Fernandes wrote. “IgM antibodies formed against EBV can cross-react against erythrocytes, reacting at 1-3 degrees Celsius, hence classified as cold agglutinin hemolytic anemia.” However, its association with warm agglutinin AIHA is unclear.

Fernandes wrote that “it is not known if EBV can also induce warm agglutination” and that “an extensive literature review returned a single report of fatal AIHA due to IgG warm agglutination exacerbated by EBV.” This case study suggests that EBV, in addition to CAD, may also be associated with warm agglutinin AIHA. 


Fernandes M. Warm agglutinin autoimmune hemolytic anemia associated with Epstein Barr virus. Chest. 2021;160(4):A986. doi:10.1016/j.chest.2021.07.918