What is Cold Agglutinin Disease (CAD)?

“It’s idiopathic, we don’t know what causes it,” Dr. Roy Smith, hematologist-oncologist at University of Pittsburgh Hillman Cancer Center, explains. “And it can be secondary to infections, like infectious mononucleosis or maybe an underlying lymphoma, even. So, it occurs in different settings that, for the patient, it tends to result in chronic anemia, fatigue. There is a predisposition to having blood clots with it, and it tends to be a very chronic disorder.”

When someone has CAD, their immune system mistakenly attacks and destroys their own red blood cells. It’s called “cold” agglutinin disease because when an affected person is exposed to cold temperatures, certain proteins that normally attack bacteria (known as IgM antibodies) instead attach themselves to red blood cells and bind them together into clumps (known as agglutination), and these cells are eventually prematurely destroyed. This can lead to anemia (low red blood cells) and other issues. These symptoms may get worse due to lower temperatures.

“Symptoms of CAD are more apparent and severe when you’re exposed to cold temperature,” Dr. Choi explained. “For example, during winter time, or when you are touching something cold, it can trigger the disease to act up. So, when your anemia becomes severe, your hemoglobin goes down. Then you can have symptoms of anemia.”

These symptoms may include:

• Fatigue
• Shortness of breath
• Dizziness

Dr. Choi pointed out that people with CAD may also experience symptoms associated with autoimmune disease, such as:

• Finger tips turning blue due to lack of oxygen
• Malaise (feeling unwell in general)

To determine how to go about treatment for CAD, first your doctor will need to figure out what’s causing it:

• Infection
• Autoimmune disease
• Blood cancer

When the disease is caused by cancer or infection, treatment will target the root cause of CAD.

Dr. Smith notes that because CAD is rare, it is often misdiagnosed. “It’s really very, very rare, and it’s a disease that is very, very commonly misdiagnosed because the doctors out the real world just don’t see very much of it,” Dr. Smith explains. “And you have to think about it in order to make the diagnosis.”

When CAD is Caused by Cancer

“You want to treat the underlying condition that’s driving CAD, so the standard-of-care for that condition is a chemotherapy or therapy to target those lymphoma cells. When CAD is acting up significantly, then you want to treat the [disease] itself,” Dr. Choi said.

“The first line treatment is something called Rituximab,” he explained. The drug “specifically targets lymphocytes, which is a type of white blood cell.”

Dr. Choi explained that most patients respond relatively well to Rituximab, which is a type of drug called a monoclonal antibody. The drug may also be used after a relapse.

According to Dr. Smith, when the underlying disease causing CAD is treated, CAD generally goes away. “As an example, if a person had cold agglutinin disease associated with lymphoma, you would treat the lymphoma and the cold agglutinin disease generally goes away,” he says.

Dr. Nicola Lamanna and Dr. Matthew Davids explain how monoclonal antibodies work for CLL.

“In the minority of patients who do not respond to this standard therapy … there are many other treatment options that are being developed in clinicial trials,” Dr. Choi said.

Other Treatments for CAD

When CAD is diagnosed in younger patients, it is typically caused by an infection, according to Dr. Choi, and treatment will again revolve around treating that root condition.

“CAD can also be caused by particular types of infections, such as mycoplasma, pneumonia, or other types of viruses … and this is more common in young patients,” Dr. Choi explained. “When it is caused by those infections, you want to really treat those infections with antibiotics and antivirus medication. Usually the CAD goes away when the infections are treated.”

In other CAD cases, Dr. Smith notes that weighing the need for treatment is important.

“The first step is to determine whether they actually need to be treated or not, because often it’s a matter of just telling a person to wear gloves or wear a coat or keep their house at a higher temperature or move to another place,” explains Dr. Smith. “That sounds funny, but the reality of the matter is, it’s not unreasonable to take a person who lives in Pennsylvania and say, ‘Look,  go to Florida or Arizona or someplace’.”

Dr. Choi also noted that it’s crucial to avoid cold temperatures, since it’s linked to CAD worsening.

“You want to avoid cold temperature, and when you need blood transfusions for low blood cells, we ask the blood bank to warm up the blood,” he explained. “So that cold temperature is avoided in every circumstances and that really helps to reduce the antibody from destroying your red blood cells and making your CAD progress.”

Incidence of CAD

CAD most commonly affects adults who are middle-aged or older, according to the Genetic and Rare Diseases Information Center. There are some studies that indicate that the disease is more common in older woman than men. People who have infectious mononucleosis, lymphoproliferative diseases, or mycoplasma pneumonia are more susceptible to CAD.

Questions to Ask Your Doctor

• Since CAD can be difficult to diagnose, could this be another disease?
• Will treatment be necessary?
• Do I need to avoid cold temperatures?
• Is there a clinical trial I should consider?

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