The COVID-19 pandemic that swept across the world in 2020 turned what was supposed to be a global celebration of the start of a new decade into a period of unprecedented illness. 

Today, in the United States and many other parts of the world, most remnants of the pandemic have been wiped out. Restaurants are back in business, large-scale concerts have returned, and public mask-wearing is slowly being phased out. 

In light of humanity’s quick return to normalcy, was the pandemic “full of sound and fury, signifying nothing?” It doesn’t have to be so. At its peak, the pandemic represented a significant health risk for individuals of all categories: the young, the elderly, and individuals with comorbidities. 

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Many individuals with chronic diseases found themselves in a quite a dilemma: they may choose to take the vaccines, but clinical trials usually do not test for individuals with rare diseases during initial phases. They certainly cannot ignore the risks of contracting the COVID-19 infection because little was known regarding how the virus interacted with various systems in the body. 

It was important then for message discipline to be enforced: that the public should take all reasonable measures to avoid spreading the disease, and that they should get vaccinated at the first opportunity. There was little room for second-guessing or vaccination denial. 

To highlight the risks of COVID-19 to vulnerable patients, we refer to 2 case studies of patients with COVID-19 who were later diagnosed with cold agglutinin disease (CAD). 

Unprecedented Vulnerability 

In the Journal of Clinical Laboratory Analysis, Imoto and colleagues present the cases of 2 patients who were diagnosed with CAD upon contracting COVID-19. 

The first was a 64-year-old man who presented with a 5-day history of fever. A polymerase chain reaction test revealed COVID-19 infection and X-rays revealed bilateral infiltrates. The patient was then hospitalized. 

On day 6 of admission, worsening hypoxia required that he be mechanically ventilated. The patient’s physicians started him on dexamethasone, tocilizumab, and piperacillin-tazobactam. 

Read more about CAD etiology 

A peripheral blood smear revealed high mean corpuscular hemoglobin concentration and erythrocyte agglutination. Additional investigations revealed macrocytic anemia and low zinc levels. A direct antiglobulin test was positive for C3d/C3d and was negative for IgG. Crucially, his cold agglutinin titer was very high at 1:512 (normal: 0-1:63). However, he was negative for Donath-Landsteiner antibodies. 

His physicians conducted a bone marrow biopsy that revealed no evidence of malignant lymphoma cells. Zinc supplements were prescribed, improving his hemoglobin levels. On day 38, his cold agglutinin titer dropped to 1:64 (near normal) and he was discharged following clinical improvement. 

The second patient was a 76-year-old woman who presented with hypoxia. She had been diagnosed 6 days previously with COVID-19 and was found to have pneumonia as well, which improved following treatment with remdesivir and dexamethasone. However, she developed a urinary tract infection during admission. 

Her hemoglobin levels were normal, and a direct antiglobulin test was positive for C3b/C3d but was negative for IgG. Her cold agglutinin titer was markedly elevated at 1:2048. 

Upon clinical improvement, the patient was discharged. During her first follow-up visit, her cold agglutinin titer fell to 1:512, which was still relatively high. 

Treatment in the Age of COVID-19 

“Individuals with COVID-19 may have various coagulation abnormalities that create a hypercoagulable state that can be thought of in terms of Virchow’s triad: endothelial injury, stasis, and a hypercoagulable state,” Imoto et al write. “The presence of cold agglutinin disease may increase the risk of thrombosis.” 

There were many unique challenges to treating patients with COVID-19 during the pandemic. First, extreme precautions were taken to avoid the spread of the disease (such as health care professionals being required to don full personal protective equipment). In addition, many governments published daily COVID-19 figures; a slight swing indicating greater infectivity often caused widespread alarm. Hence, many physicians were understandably focused on resolving the infection above all else. 

Read more about CAD treatment

Because COVID-19 was a novel disease, many of its more mysterious symptoms could plausibly be attributed as complications of the virus. This meant that many comorbidities and complications were left unexplored. 

In Le Infezioni in Medicina, Ochani and colleagues write about the spectrum of symptoms associated with COVID-19: fever, cough, dyspnea, diarrhea, taste alterations, olfactory disturbances, erythematous rashes, urticaria, cardiovascular complications, headache, an altered conscious state, dizziness, cerebrovascular disease, liver injury, immune-mediated damage, thrombotic events, and ophthalmological involvement. 

This is quite a long list of reported signs and symptoms of COVID-19. CAD and other rare diseases were diagnosed as well during the long slog of COVID-19.  

The COVID-19 pandemic continues to teach us lessons about public health, disaster management, and infection control. The question we should be asking ourselves is this: are we prepared for the next great pandemic when it occurs? Will we have the resources to continue treating patients with chronic illnesses, as well as patients with newly acquired symptoms (such as CAD)? To future-proof our health care system, these questions need to be addressed now. 

It is also imperative that those with CAD and other rare diseases are receiving the best care possible, keeping up with medication regimens, and other treatments and therapies, so that if disaster strikes again, and we encounter another pandemic, they, and we, are as prepared as possible.


Imoto H, Yoshioka S, Nakagawa D, et al. Cold agglutinin anti-I antibodies in two patients with COVID-19. J Clin Lab Anal. 2022;36(9):e24629. doi:10.1002/jcla.24629

Ochani R, Asad A, Yasmin F, et al. COVID-19 pandemic: from origins to outcomes. A comprehensive review of viral pathogenesis, clinical manifestations, diagnostic evaluation, and managementInfez Med. 2021;29(1):20-36.