Autoimmune Hemolytic Anemia Secondary to COVID-19 Vaccine: A Case Report

Autoimmune hemolytic anemia (AIHA) is an acquired hemolysis caused by one's immune system targeting red blood cell surface antigens, resulting in a shortening of the normal red-cell lifespan of 120 days. In this case report, we present an unusual case of a middle-aged woman with no known autoimmune diseases. After ruling out all other possible etiologies, she was later diagnosed with AIHA about two months after receiving her first dose of the Oxford-AstraZeneca COVID-19 vaccine (COVISHIELD). We discuss the possible underlying cause, the COVID-19 vaccine, for the precipitation of AIHA. The importance of identifying rare adverse events that could occur during mass vaccination is highlighted in this case. The patient was treated with oral steroids and received three blood transfusions. She was discharged after 21 days from the hospital and followed up after six months with no relapse.


Introduction
The COVID-19 pandemic has been one of the greatest health crises in history.To limit the spread of the virus, multiple vaccines have been developed and approved.Along with the common side effects, these vaccines also include some rare adverse effects.New-onset autoimmune phenomena after COVID-19 vaccination has been recently reported.Autoimmune hemolytic anemia (AIHA) is an acquired hemolysis caused by the host's immune system acting against its red blood cells [1].Molecular mimicry, the production of specific autoantibodies, and certain vaccine adjuvants seem to play a significant role in this autoimmune phenomenon [2].Despite the numerical difference in the frequency of these events, we report a rare case of warm antibody AIHA secondary to the Oxford-AstraZeneca COVID-19 vaccine (COVISHIELD) manufactured by the Serum Institute of India.

Case Presentation
A 53-year-old female homemaker presented to the emergency department with complaints of generalized weakness, breathlessness on exertion, yellowish discoloration of the sclera for the past 10 days, and passing dark-colored urine for the past seven days.There was no history of drug or toxin exposure, acute or chronic illnesses, blood transfusions, comorbidities, or autoimmune diseases in the past.The patient had no history of passing blood in vomit or stool and no history of passing red-colored urine.She had received first dose of the Oxford-AstraZeneca COVID-19 vaccine (COVISHEILD) two months prior.She also has not received any other vaccines recently.
On examination, the patient was afebrile, with a heart rate of 116 beats per minute, a respiratory rate of 28 cycles per minute, a blood pressure of 100/80 mm Hg, and an oxygen saturation of 97% on room air.The patient was conscious and oriented to time, place, and person, with a Glasgow Coma Scale (GCS) score of 15/15.Other systemic examinations were unremarkable, with moderate pallor and mild icterus present.
Laboratory analysis (Table 1) showed a hemoglobin level of 4.8 g/dL, a total leucocyte count (TLC) of 7100 cells/dL, a platelet count of 261,000 cells/dL, and a hematocrit of 14.5%.Liver function tests revealed a total bilirubin level of 7.1 mg/dL, with an indirect fraction of 4.29 mg/dL and normal enzyme levels.The urine analysis was normal.The reticulocyte count was 6%, and the corrected reticulocyte count was 4%.Direct anti-globulin testing (DAT) showed 4+ IgG without C3, haptoglobin was <30 mg/dL, and lactate dehydrogenase (LDH) was 2566 U/L.A peripheral blood smear examination showed anisopoikilocytosis with hypochromia, a moderate number of spherocytes, and no sickle cells or target cells.A bone marrow study showed a hypercellular marrow with erythroid hyperplasia and a normal myeloid lineage.The ECG was suggestive of sinus tachycardia.Imaging studies, including chest X-ray and USG abdomen, were both normal, with no evidence of organomegaly.The clinical presentation and laboratory parameters were consistent with hemolysis, leading to the diagnosis of AIHA.Further investigations were conducted to identify the underlying cause.Blood and urine cultures were negative.The serology for hepatitis C virus (HCV), human immunodeficiency virus (HIV), Epstein Barr virus (EBV), and cytomegalovirus (CMV) was negative.Rheumatoid factor and antinuclear antibody were also negative (Table 1).
After ruling out possible underlying etiologies for AIHA, such as drug, toxin, viral or bacterial infection, malignancies, and other autoimmune diseases, and given the recent correlation with the COVISHIELD vaccination with positive anti-SARS-CoV-2 IgG antibody titers, the possibility of COVID-19 vaccine-induced AIHA was considered.The patient was started on tab prednisone at 1 mg/kg/day after consultation with a hematologist and received three units of packed red blood cells (PRBCs).Hemoglobin and hematocrit began to normalize within two weeks of treatment, and there was no relapse thereafter.

Discussion
AIHA following the COVID-19 vaccine is a rare manifestation of the disease.For COVID-19, more than 200 vaccines are being developed, including conventional inactivated vaccines, mRNA vaccines, protein subunit vaccines, and viral vector vaccines.Both COVAXIN (an inactivated vaccine) and COVISHEILD (a viral vector vaccine) are readily available in India [3].In our patient, clinical and laboratory findings were consistent with hemolysis, leading to the diagnosis of AIHA.After excluding all possible underlying etiologies for AIHA and considering the recent correlation with the COVISHIELD vaccine, we assumed the possibility of AIHA following vaccination, which was later supported by the patient's response to oral steroids.
COVID-19 vaccine-induced AIHA is seldom reported, with only three case reports so far, all secondary to mRNA-based COVID-19 vaccines [4,5].To the best of our knowledge, this is the first time that AIHA has been reported in an exclusive association with the Oxford-AstraZeneca COVID-19 vaccine (COVISHEILD).The direct causal relation between COVID-19 vaccination and AIHA is yet questionable.One theory proposes that it is an autoimmune response due to molecular memory of host antigens causing the polyclonal activation of T or B cells, which cross-react with red cell surface antigens [4,6].Post-vaccination AIHA is manageable, and the advantages of immunization can outweigh these rare risks.
We propose that the delayed onset (two months after the first dose of the vaccine), moderate severity, and different immunohematology (strong IgG4+ without C3) suggest that the case reported here may involve a different immunologic process.