A rare occurrence of cold agglutinin disease (CAD) that accompanied a COVID-19 infection has been reported in a woman with the hemoglobin E (HbE) heterozygous phenotype. Findings from this case study were recently published in the Annals of Clinical Case Reports.

Few case reports of autoimmune hemolytic anemia (AIHA), of which CAD is a type, have been described in association with COVID-19. The present case study apparently is the first report of CAD associated with COVID-19 infection in the presence of the HbE phenotype.

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Autoimmune hemolysis comprises warm autoimmune anemia, paroxysmal cold hemoglobinuria, CAD, and drug/toxic agent–associated disease. Unlike warm AIHA, CAD is a rare disorder that affects approximately one-fifth to one-fourth of all patients with AIHA. Females have a slightly higher prevalence of CAD than do men. The median age at diagnosis of CAD is in the 60s or 70s.

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CAD been reported in association with lymphoid malignancies and autoimmune disorders. The disease occurs often during the course of Epstein-Barr virus and Mycoplasma pneumoniae infection. Typically, CAD will appear around 2 weeks following the onset of the primary infection and resolves spontaneously after resolution of the infection. Blood levels usually return to normal in a few weeks to a few months.

The current case report describes a 45-year-old female who resides in Meghalaya, India. The patient was referred by a primary care hospital to Nazareth Hospital in Shilong, Megalaya, India, because of a diagnosis of severe anemia of unexplained origin. She complained of generalized weakness, yellowish discoloration of her skin and eyes, increased thirst, and urinary frequency over the last 5 days. Following routine testing, COVID-19 was incidentally detected as well.

The clinicians suspected CAD because of the presence of COVID-19 and the algorithm was followed for the processing of blood in the laboratory. She was provided with supportive treatment, which included being kept in a warm environment, with a room heater and blankets, and avoiding any exposure to cold. The patient was transfused with 3 units of whole blood; she also received oral glucocorticoids to prevent additional deterioration of her COVID-19 infection. She received supplemental folate for her hemoglobin phenotype.

She was discharged home on the fourth day of hospitalization, with advice for home isolation in a warm environment and to follow up after her isolation ended.

The researchers concluded that the results of this case study confirm the fact that conservative treatment with blood transfusion, temperature regulation, and glucocorticoids in patients with a COVID-19-associated inflammatory reaction can lead to positive outcomes in resource-limited settings.

“The significance of disease in association with [an] HbE heterozygous condition [warrants] more reporting and further study,” they wrote.


Bhuyan D, Dkhar H, Bhuyan B, et al. HbE heterozygous patient presenting with cold agglutinin syndrome with COVID-19 infection – case report. Ann Case Rep. 2022;7:1-4.