Researchers presented the case of an 83-year old woman with secondary cold agglutinin disease (CAD) whose disease worsened due to a COVID-19 infection, as published in Cureus.

“Association between COVID-19 and [cold agglutinin syndrome] is a recent and novel finding,” Yash V. Bhagat and the coauthors of the study wrote. “The lack of established evidence-based treatments for the disorder warrants further research in this area of medicine.”

The patient described here presented with shortness of breath, cough, worsening orthopnea, darkening fingers and urine, and jaundice. Laboratory test results revealed that she had a high white blood cell count, elevated total bilirubin, very low hemoglobin, and positive direct Coombs test.

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The patient tested positive for COVID-19 in a polymerase chain reaction test. The researchers, therefore, concluded that her condition was exacerbated due to COVID-19. She was treated with remdesivir for 5 days and given 6 mg of intravenous dexamethasone for 7 days. This treatment regimen led to a significant improvement in her condition.

Read more about CAD complications

CAD is characterized by the body’s immune system attacking its own red blood cells in cold conditions. Immunoglobulin M antibodies, also called cold agglutinins produced by B lymphocytes, bind to antigens on the surface of red blood cells and activate the complement pathway leading to hemolysis.

The disease can either be primary or secondary. Although the cause of primary CAD is not known, secondary CAD or cold agglutinin syndrome can be triggered by bacterial, viral, or parasitic infections or other autoimmune diseases and certain types of cancer.

The researchers hypothesized that a COVID-19 infection further activated the complement system, amplifying hemolysis caused by cold agglutinins.

“Therefore, COVID-19 infections, similar to infections with Epstein-Barr virus and Mycoplasma pneumoniae, may be an independent risk factor predisposing individuals to the exacerbation of [cold agglutinin syndrome],” they concluded.


Bhagat YV, Hussien S, Queenan H, Michael MB. Exacerbation of secondary cold agglutinin syndrome in the setting of SARS-CoV-2. Cureus. 2021;13(11):e19387. doi:10.7759/cureus.19387