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A 73-year-old man with a medical history of stage III esophageal adenocarcinoma treated with neoadjuvant chemoradiotherapy, pulmonary embolism (PE) treated with a direct oral anticoagulant, and recent hospitalization for babesiosis presented with melena, persistent daily fevers, and hematuria. Infectious workup including chest radiography, blood and urine cultures, and comprehensive testing for multiple parasitic, zoonotic, and viral infections (e.g., Babesia, E. ewingii, E. chaffeensis, A. phagocytophilum, R. rickettsii, R. typhi, HIV, and cytomegalovirus [CMV]) yielded unremarkable findings. Computed tomography (CT) of the chest, abdomen, and pelvis with intravenous contrast did not demonstrate findings consistent with an abscess or hepatobiliary infections. Empiric atovaquone and azithromycin were initiated and continued for 21 days due to concerns of babesiosis relapse (negative parasite smear). In addition, the patient received empiric doxycycline for 10 days due to concerns of anaplasmosis (negative anaplasma serology). His fever improved with antibiotics, but his cytopenia did not; anemia and thrombocytopenia persisted (hemoglobin: 6.5 g/dL, platelets: 18,0000/mm³). Multiple packed red blood cell (RBC) and platelet transfusions were administered. The patient’s hemoglobin climbed to 9 g/dL before declining again, and his platelet count remained consistently less than 20,000/mm³.

The differential diagnosis for his anemia included gastrointestinal blood loss, given his known esophageal cancer and his presenting symptom of melena. However, his melena resolved, which may have explained the hemoglobin increase to 9 g/dl, although his hemoglobin started to decline afterward. Further testing revealed evidence of hemolysis (undetectable haptoglobin, lactate dehydrogenase [LDH] of 948 IU/L, and D-dimer >3,680 ng/L FEU). No schistocytes were observed on the peripheral blood smear. Initial and repeat direct antiglobulin testing (DAT) results were negative. A bone marrow aspirate and biopsy revealed normal cellularity for age and trilineage hematopoiesis without underlying dysplasia or pathology.

What is the most likely diagnosis?

• A. Hemophagocytic lymphohistiocytosis (HLH)
• B. Autoimmune hemolytic anemia (AIHA)
• C. Persistent Babesia infection
• D. Disseminated intravascular coagulation (DIC)

Answer: B

A four-day trial of dexamethasone (40 mg/day) was initiated, following which his hemoglobin (7 g/dL to 10 g/dL) and platelet count (20,000/mm³ to 70,000/mm³) improved. Prednisone was initiated at a dose of 90 mg/day, with a plan for a slow taper. Further diagnostic testing was performed, and a more sensitive DAT assay yielded positive results, confirming a diagnosis of autoimmune hemolytic anemia (AIHA).

AIHA is a rare disease with an incidence of 1.77 cases per 100,000 people per year.¹ Warm AIHA is the most common form and accounts for 70% of those cases.¹ The risk of AIHA, particularly warm AIHA, increases with age due to the epigenetic abnormalities and oxidative stress associated with aging.¹ DAT-negative AIHA is an atypical form that accounts for 3-11% of cases of warm AIHA.² Patients with DAT-negative AIHA have a lower density of IgG molecules per cell than DAT-positive patients. Commercial DAT reagents do not typically identify positivity below 500 molecules of IgG per cell. Although DAT-negative AIHA can be due to IgA or IgM instead of IgG,² commercial DAT reagents typically include anti-IgG only and may miss other antibodies. Additionally, RBC autoantibodies may have low binding affinity and can be removed during cell washings when performing DAT testing. This can be avoided by washing RBCs with isotonic or low-ionic strength saline, which improves the sensitivity of the DAT assay. Enhanced DAT assays can be obtained when suspicion for warm AIHA is high despite negative results on routine DAT tests, as was the case for our patient

Of note, the presence of persistent thrombocytopenia that improved with steroid use raises the possibility of Evans Syndrome, which is characterized by two or more types of cytopenia: anemia (warm AIHA due to IgG antibodies) and immune thrombocytopenia (ITP; antibodies against GPIIb/IIIa on platelets).³

Firstline treatment for warm AIHA includes corticosteroids (1-2 mg/kg of oral prednisone or intravenous methylprednisolone). When suspicion of warm AIHA is high despite a negative DAT result, confirmatory testing should not delay the administration of empiric corticosteroids. RBC transfusion is an important part of AIHA management, especially in patients with severe anemia and rapid hemolysis. Patients with limited response to steroids may require evaluation for an underlying malignancy or rheumatologic disorders. For patients with refractory disease, rituximab or splenectomy may be necessary.²

Acknowledgement: This article was edited by Dr. Xu Han and Dr. Rakesh Mehta

References

• Michalak S, Olewicz-Gawlik A, Rupa-Matysek J, et al. . Immun Ageing. 2020;17(1):38.
• Kalfa T. . Hematology Am Soc Hematol Educ Program. 2016;2016(1):690-697.
• Jaime-Pérez JC, Aguilar-Calderón PE, Salazar-Cavazos L, et al. . J Blood Med. 2018;9:171-184.

Drs. George, Abdallah, and Ganatra indicated no relevant conflicts of interest.