From a research perspective, the increasing reports of strange medical occurrences, including people developing cold agglutinin disease (CAD), following COVID-19 vaccination have become an important window for clinicians to understand how vaccines can impact the course of certain diseases. 

Despite the COVID-19 pandemic being in the rearview mirror for most of the world, especially with the belated relaxing of COVID-19 restrictions in China early this year, it is still worth reflecting on the events that led to the pandemic and the swift development of vaccines that followed. 

The COVID-19 pandemic was first reported in early 2020, and its spread was alarming. In a matter of months, many parts of the world implemented strict lockdowns, and the term “social distancing” entered the global vocabulary. It is difficult to describe how devastating the initial months of the pandemic were—a yo-yo of good news and bad, stops and starts, an avalanche of misinformation and panic, a sense that something momentous and historical had arrived. 

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Immediately, attention turned toward the development of a vaccine. And to the credit of vaccine researchers around the world, COVID-19 vaccines were indeed developed at record speeds, passing the necessary regulatory loopholes, and changing the destinies of millions. 

Read more about CAD etiology 

As they say, the rest is history. However, researchers are beginning to ask serious questions about how the vaccines were approved and the extent to which they cause adverse events. It is not a conspiracy to discredit or undermine vaccines; rather, as responsible members of the scientific community, it is our duty to understand what transpired in the heady, anxiety-driven days of the pandemic and ensure that appropriate lessons are learned. 

Cold Agglutinin Disease Following COVID-19 Vaccination 

We first turn our attention to a case report by Suzuki and Shiba published in the International Journal of Hematology of a middle-age woman who developed CAD following administration of the third dose of the COVID-19 mRNA vaccination. 

One week after receiving her vaccine, she developed finger joint pain, fatigue, generalized pain, and dark urine. Her prior medical health was uneventful. Blood tests, performed after reheating at 37 ºC due to coagulation at room temperature, demonstrated normocytic normochromic anemia (hemoglobin, 8.2 g/dL). 

Her physicians initially suspected rheumatoid arthritis. Without the presence of an alternative diagnosis, she was prescribed analgesics, which did not improve her symptoms. 

She then visited a hematology outpatient clinic 4 months later. Her hemoglobin was rechecked and appeared to have improved to 11.7 g/dL. Further investigations revealed reticulocytosis, a positive Coombs test, and decreased haptoglobin. Her cold agglutinin titer was 1:16,384; a peripheral blood film revealed marked agglutination, thought to be caused by CAD. 

Investigations into the underlying cause were unfruitful. Because her symptoms had improved since her initial presentation, she was not prescribed further treatment but remained under close observation. 

Read more about CAD treatment 

“The present case indicates that it is possible for secondary CAD after mRNA vaccination to become chronic, and provides insights to the pathogenesis and treatment strategies,” the authors wrote. 

A Closer Look at COVID-19 Vaccinations

In Environmental Microbiology, Brüssow of the Laboratory of Gene Technology in Belgium had a critical view of the manner in which COVID-19 vaccines were developed and processed, raising important ethical concerns along the way. 

It is worth mentioning that over 200 vaccine candidates were in different stages of development—such was the competition for producing the ultimate preventative vaccine that would gain worldwide acceptance. Vaccine researchers were under constant pressure; every month of delay, as many were told, translated to the deaths of hundreds of thousands. 

However, Brüssow pointed out that many elements of the COVID-19 vaccination program subverted conventional protocol, from financing and regulation to the types of trials that were employed to prove their efficacy. This is to say nothing about how the vaccines were eventually distributed, which often went to the highest bidder instead of the people that needed it the most. 

In addition, Brüssow carefully highlighted the low standards at play with regard to how researchers assessed the efficacy of additional vaccine doses, with little attention afforded to individuals who achieved a low response or fears of waning immunity. Adverse events, such as fever, chills, and muscle aches, were hardly highlighted in the media. In fact, injection site pain after the first vaccine dose was reported in approximately 68% of individuals, with fatigue (31%) and headache (26%) also being common side effects. 

In the development of any vaccine, vaccine accidents in a small percentage of the population are to be expected. In 1995, a polio vaccine resulted in 51 cases of permanent paralysis and 5 deaths; more recently, dengue vaccines resulted in an antibody-dependent enhancement of the disease.

Read more about CAD complications

“These examples illustrate the importance of careful evaluation of any adverse reaction and of postlicensure surveillance to ensure vaccine safety,” Brüssow wrote. 

These statistics indicate that it is not uncommon for a small percentage of patients to experience adverse effects following vaccinations, such as in the case of the patient in this case study. However, difficult questions must then be raised, such as how informed were the public about these potential adverse effects of COVID-19 vaccines? Was the public given a accurate impression of the process involved in the development of these vaccines? How do we handle reports of severe vaccine accidents without further encouraging vaccine hesitancy? 

The fact remains that vaccines are overwhelmingly safe; herd immunity saves lives, and the end of a pandemic means that normal life can resume more quickly. The challenge for clinicians is to ensure that the public remains thoroughly informed about the vaccines that are injected into their bodies, and that engagement with vaccine-hesitant individuals is carried out in a respectful, empathetic, and thoughtful manner. 


Brüssow H. COVID-19: vaccination problemsEnviron Microbiol. 2021;23(6):2878-2890. doi:10.1111/1462-2920.15549

Suzuki Y, Shiba T. Chronic cold agglutinin disease after a third COVID-19 mRNA vaccinationInt J Hematol. 2023;117(4):618-621. doi:10.1007/s12185-022-03480-z