COVID-19 Infection, Vaccine May Trigger CAD, AIHA, Review Suggests

Patricia Inácio, PhD avatar

by Patricia Inácio, PhD |

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Infection by SARS-CoV-2, the virus that causes COVID-19, may trigger cold agglutinin disease (CAD) in adults, according to a small systematic review.

mRNa-based vaccines against SARS-CoV-2 were also shown to trigger CAD and other forms of autoimmune hemolytic anemia (AIHA), although only four cases were analyzed.

Overall, these findings highlight the need for vigilance for CAD symptoms among people vaccinated for or with COVID-19.

The study, “COVID-19 and Immune-Mediated RBC Destruction: A Systematic Review,” was published in the American Journal of Clinical Pathology.

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Case Report: Warm AIHA Plus CAD Possibly Triggered by COVID-19

AIHA is an umbrella term for a group of rare disorders characterized by the production of autoantibodies that target and destroy red blood cells. AIHAs are largely grouped into two categories, CAD and warm AIHA. In CAD, autoantibodies — called cold agglutinins — bind more easily to red blood cells at lower temperatures, while in warm AIHA they do so at higher temperatures.

Both warm AIHA and CAD can be triggered by certain autoimmune diseases and infections, such as those caused by the human immunodeficiency virus (HIV) and the Epstein-Barr virus, as well as by a bacterium called Mycoplasma pneumoniae.

An increasing body of evidence suggests that infection by SARS-CoV-2 may also trigger AIHA. However, this stems mainly from single case reports.

In this study, two physicians, one at Yale School of Medicine and another at Vanderbilt University Medical Center, conducted a systematic review to gather and summarize evidence from studies focused on AIHA in people infected or vaccinated against SARS-CoV-2.

After a search in four online databases — PubMed, Web of Science, Scopus, and Google Scholar — they selected 43 studies (published by Sept. 24, 2021) to be included in their final analysis.

Of the 43 studies, 39 focused on the association between AIHA and COVID-19, while the other four focused on the link between AIHA and SARS-CoV-2 vaccination.

In total, 50 patients (22 women and 28 men, with a mean age of 50.8) with COVID-19 and four patients (two women and two men, with a mean age of 73.5) who had been vaccinated against SARS-CoV-2 developed AIHA.

The most common subtype of AIHA was CAD (18 patients), followed by warm AIHA (14 patients). In the remaining patients, the majority (10 patients) were not analyzed for the AIHA subtype in the original study, and the other eight were diagnosed with even rarer AIHA subtypes. However, according to the authors’ own analysis, three out of the 10 patients lacking a AIHA subtype probably had CAD.

Patients with COVID-19 took a median of seven days to develop the first symptoms of AIHA (range from zero to 20 days). The mean levels of hemoglobin — the protein in red blood cells that is responsible for oxygen transport — at the time of AIHA diagnosis was 6.5 g/dL, which is below the normal range.

Cold agglutinins were detected in all 14 patients tested. In nine of them, the levels of these self-reacting antibodies were quantified using a cold agglutinin titer test. This is a standard lab test that assesses the number of dilutions after which antibodies can still cause red blood cell agglutination, or clumping.

This analysis revealed that seven of them (78%) had titers deemed clinically significant. Further testing was conducted for five patients, and all had clinically significant cold agglutinins.

From the 42 patients with COVID-19–associated AIHA, eight died (19%) at a mean age of 55.8. Five of them had CAD. Most patients who died (88%) had multiple underlying medical conditions.

All four patients who were vaccinated for SARS-CoV-2 ended up developing AIHA. Two of them received the Pfizer-BioNTech mRNA vaccine and one the Moderna mRNA vaccine. In one of the patients, the specific mRNA vaccine was not disclosed.

Three patients developed AIHA after the first vaccine dose (median of five days), while the fourth patient developed it within two days after the second dose. One patient had CAD and another warm AIHA. Although not specified, according to the authors’ analysis, the two remaining patients likely also had warm AIHA. None of the patients said they had signs or symptoms of infection.

Overall, this systematic review suggests that “SARS-CoV-2 infection and vaccination are associated with multiple AIHA subtypes, beginning approximately 7 days after infectious symptoms and 5 days after vaccination,” the researchers wrote.

“Patients with COVID-19 should be monitored for this potential AE [adverse event] to mitigate morbidity and potential mortality,” they wrote.