COVID-19 infection or vaccination may trigger the development of several types of cold agglutinin disease (CAD), according to results of a systematic review published in the American Journal of Clinical Pathology.

These types included cold autoimmune hemolytic anemia (AIHA), warm AIHA, mixed-type AIHA, direct antiglobulin test (DAT)-negative AIHA, DAT-negative Evans syndrome, Evans syndrome, and unreported subtypes. AIHA symptoms started on an average of 7 days following COVID infection and 5 days following vaccination.

Investigators searched for studies related to COVID-19 and AIHA and reported on 50 patients who developed AIHA associated with COVID-19 infection and 4 patients who developed AIHA associated with COVID-19 vaccination.

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Of the 50 patients infected with COVID-19 who developed AIHA, 18 had cold AIHA, 14 had warm AIHA, 3 had mixed-type AIHA, 1 had DAT-negative AIHA, 1 had DAT-negative Evans syndrome, 3 had Evans syndrome, and 10 had unreported AIHA subtypes.

The investigators classified 3 of the 10 undetermined AIHA cases as probable cold AIHA and 4 as probable warm AIHA, while 3 were left unclassified due to insufficient data. The mean age of patients who developed AIHA following COVID-19 infection was 50.8 years. The median period from COVID-19 symptom onset to AIHA symptom onset was 7 days.

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Of the 50 patients with reported transfusion therapy data, 74% (n=28) received at least 1 unit of red blood cells. Most patients (n=35) underwent a therapeutic course of corticosteroids, primarily prednisone. Remaining treatments included intravenous immunoglobulin therapy (n= 9), rituximab (n=5), cyclophosphamide (n=1), and simultaneous plasma exchange with corticosteroids (n=1).

Of the 4 patients who developed AIHA following COVID-19 vaccination, 2 received the Pfizer-BioNTech vaccine, 1 received the Moderna vaccine, and 1 received an unspecified mRNA vaccine. In total, 3 of the 4 patients developed AIHA symptoms following only 1 dose of the vaccine.

The mean age of these 4 patients was 73.5 years. The median period from the initial COVID-19 mRNA vaccination dose to AIHA symptom onset was 5 days. Three patients received corticosteroid treatment, while the remaining patient received rituximab. Three patients received at least 1 unit of red blood cells via transfusion.

“Increased awareness of this potential complication is warranted to mitigate morbidity and mortality in these patients,” the authors concluded.


Jacobs JW, Booth GS. COVID-19 and immune-mediated RBC destruction: a systematic review. Am J Clin Pathol. Published online December 17, 2021. doi:10.1093/ajcp/aqab210