Secondary CAD May Cause Complications in Cases of Severe COVID-19, Report Suggests

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by Sara Guariglia |

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Cold agglutinin disease (CAD) may develop as a result of severe COVID-19, further complicating laboratory tests and treatment for these individuals, according to a case report in two patients.

The case study, “Cold agglutinin syndrome as a complication of Covid-19 in two cases,” was published in the journal Clinical Infection in Practice.

Cold agglutinins are autoantibodies, or immune proteins that mistakenly attack and destroy red blood cells at low body temperatures. The production of these self-reactive antibodies can be triggered by certain bacterial and viral infections, in which case patients are said to have secondary CAD.

Here, investigators from the University of North Carolina School of Medicine described two patients with severe COVID-19 who developed secondary CAD, which, in turn, complicated their treatment.

One of the patients, a 70-year-old man, was experiencing a fever and cough. Chest imaging tests revealed he had infiltrates — a general term used to refer to substances that are denser than air — in both lungs, which are typically associated with pneumonia and other respiratory infections.

The patient was intubated and tested positive for SARS-CoV-2, the virus that causes COVID-19. He went on to develop kidney failure, and required continuous renal replacement therapy (CRRT), a type of treatment that filters and cleans the blood and is used to compensate for the lack of kidney function.

After five days in the hospital, his healthcare providers noted that his blood had been clotting the CRRT circuit, which prompted further tests.

Initial blood tests revealed the patient had abnormally high platelet counts, as well as excessively high levels of fibrinogen, a protein involved in blood-clotting, and D-dimer, a protein fragment that forms when a blood clot dissolves. Other blood parameters were within a normal range.

Additional tests revealed the presence of cold-reactive autoantibodies that reacted with the patient’s red blood cells at a range of different temperatures. Despite having a minor impact on red blood cell destruction at normal body temperatures, the presence of these antibodies caused patient lab specimens to clot, making lab tests more difficult to perform.

Physicians managed his condition by warming the CRRT circuit and administering heparin, a blood thinner. Heparin lowered his platelet levels, which prompted physicians to switch his treatment to argatroban, another blood thinner. After that, CRRT was successfully carried out.

The second patient, a 67-year-old man, developed shortness of breath and tested positive for SARS-CoV-2 after returning from New York. He was intubated after being in the hospital for five days and developed kidney failure that required CRRT on the 10th day.

This patient also had high levels of D-dimer and fibrinogen, and like the first patient, a cold-reacting antibody was found. In this patient, antibodies only reacted with the patient’s own red blood cells at low temperatures.

Although the patient showed nearly no signs of red blood cell destruction, his condition was aggravated by septic shock and respiratory failure.  He died while being treated with comfort-oriented care.

In both patients, the autoantibodies found were anti-I. “I” is a universal antigen normally found on the surface of red blood cells. Many studies have identified anti-I antibodies as a post-infection complication in certain types of pneumonia and flu. In addition to anti-I antibodies, the first patient also had C3b and C3d autoantibodies, which target immune system proteins.

According to the authors, the presence of these antibodies made lab tests and treatment more challenging, especially in the first patient.

“For Case 1, lab specimens needed to be kept warm as clotting of specimens resulted in difficulties in laboratory testing and discrepant values on several occasions. The greater difficulties experienced for Case 1 may reflect differences in the thermal amplitude of the two antibodies,” the authors wrote.

“These antibodies are of clinical significance given their implications for laboratory assessment and renal replacement therapy, particularly with the frequency of multi-organ system dysfunction associated with severe COVID-19,” they wrote.