Report Details Rare Case of Warm AIHA Following Epstein-Barr Virus Infection

The case of warm autoimmune hemolytic anemia (AIHA) highlights the potential for life-threatening acute hemolysis if patients do not receive timely treatment.

Warm autoimmune hemolytic anemia (AIHA) can be primary or occur secondary to other conditions, but warm AIHA secondary to Epstein-Barr virus (EBV)—which is commonly associated with cold AIHA—has been previously reported only once. A report published in the journal Cureus details a case of a patient who presented with warm AIHA secondary to EBV.

AIHA is a rare condition characterized by autoantibodies directed at red blood cells (RBCs), with the warm and cold subtypes referring to the antibodies involved and their optimal temperatures for reacting with RBC antigens. Causes of secondary AIHA can include malignancies, connective tissue and inflammatory diseases, infections, or reactions to drugs. Patients are typically anemic and diagnosed viaa positive direct antiglobulin (DAT) test.

The case study includes a 32-year-old Hispanic male who presented with weakness, occasional shortness of breath, intermittent fevers, and left knee pain and swelling intermittently for one month in November of 2021. His knee pain and swelling weretreated with 2 rounds of prednisoneby his primary care physician prior to visiting the Northeast Georgia Medical Center, but the pain became unbearable despite treatment. The patient had a history of COVID-19 infection in October of 2021, but no history or family history of hemolytic anemia. He reported no new medications other than steroids and ibuprofen, and no smoking, alcohol, or illicit drug use.

At presentation, he was tachycardic and tachypneic but had no fever, and he appeared pale and fatigued. The left knee was swollen and tender to the touch. Complete blood count testing showed a white blood cell count of 3.3 K/uL, hemoglobin of 7.5 g/dL, and a platelet count of 179 K/uL. His absolute neutrophil count was 0.66 x 103/uL, and reticulocyte count was 9.6%. Lactate dehydrogenase levelswere 268 U/L, haptoglobin was 2 mg/dL, total bilirubin was 2.20 mg/dL, and direct bilirubin measured 0.6 mg/dL. A DAT test was positive for immunoglobulin G (IgG) and complement C3.

Warm autoantibodies were present, and cold agglutinin titer levels were 1:32, and anti-nucleic acid titer was 1:40. Normocytic anemia was also present, and HIV and hepatitis tests were negative. EBV antibodies to nuclear antigen, early antigen, and IgG and immunoglobulin M (IgM) were high. Massive splenomegaly and small mesenteric and retroperitoneal lymph nodes were found in a chest CT scan.

“The serological investigations of a positive anti-EBV capsid IgG antibody and anti-EBV capsid IgM antibody in our patient likely suggested reinfection,” the authors wrote.“We were able to exclude other causes of AIHA by undergoing a thorough rheumatology and infectious workup, which were all unremarkable.”

The findings led to a diagnosis of warm AIHA, with the likely etiology being EBV infection. Prednisone and rituximab were given as treatment, and the patient’s hemoglobin improved and swelling in the knee improved. Four weekly doses of rituximab and continued steroid maintenance treatment produced improved laboratory tests at a 6-month follow-up.

While cold AIHA has been linked to EBV infection, the diagnosis of warm AIHA resulting from EBV infection is rare — only 1 report in a comprehensive literature review detailed a case of fatal AIHA due to IgG warm agglutination caused by EBV infection, the authors noted. In this case, the authors believe that AIHA is a result of a reactivation of a latent EBV infection.

“This case highlights the fact that a reactivation of a latent EBV infection may exacerbate a warm AIHA, which can lead to life-threatening acute hemolysis if prompt treatment is not provided,” the authors concluded.“Further studies are needed to delineate causation.”


Abidoye O, Adewunmi C, Macherla S. A case of warm autoimmune hemolytic anemia secondary to Epstein-Barr virus infection. Cureus. Published online June 27, 2022. doi:10.7759/cureus.26371

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