Cold agglutinin disease

Symptoms of cold agglutinin disease (CAD) are often triggered or made worse by cold temperatures or a viral infection. Therefore, symptoms generally are worse during winter months. Symptoms may arise suddenly or gradually.^[4]

Most people with CAD have symptoms of hemolytic anemia (destruction of red blood cells, causing low levels of red blood cells).^[5] However, the number of symptoms and severity of symptoms may depend on how severe the anemia is. Signs and symptoms of hemolytic anemia may include:^[2][4][5][6]

• Tiredness (fatigue).
• Dizziness.
• Headaches.
• Cold hands and feet.
• Pale skin.
• Dark urine.
• Jaundice.
• Chest pain.
• Pain in the back or legs.
• Vomiting or diarrhea.
• Heart problems such as an irregular heartbeat (arrhythmia), a heart murmur, an enlarged heart, or heart failure. These may occur because the heart has to work harder to make sure the body gets enough healthy red blood cells.

Many people with CAD also experience pain and bluish coloring of the hands and feet (acrocyanosis) or Raynaud's disease.^[1][5][7] These symptoms result from slow or poor circulation and can range from mild to disabling.^[5]

Other signs and symptoms of CAD may include enlargement of the spleen (splenomegaly) and mottled discoloration of the skin (livedo reticularis).^[2][4][7]

In people with secondary CAD (associated with another underlying condition), there may be additional signs and symptoms depending on the condition present. For example:^[1]

• Mycoplasma pneumoniae infection (the most common cause of secondary CAD) may cause respiratory symptoms.
• Various infections or cancers may cause enlarged or swollen lymph nodes.

Cold agglutinin disease is typically classified as primary (unknown cause) or secondary (caused by an underlying condition). Secondary cold agglutinin disease may be associated with:^[1][3]

• Bacterial Infections such as mycoplasma, Legionnaires' disease, syphilis, listeriosis, or E. Coli
• Viral infections such Epstein-Barr virus, cytomegalovirus, mumps, varicella, rubella, adenovirus, HIV, influenza, or hepatitis C
• Parasitic infections such as malaria or trypanosomiasis
• Other autoimmune diseases such as systemic lupus erythematosus
• Certain types of cancers such as lymphoma, chronic lymphocytic leukemia, Waldenström macroglobulinemia, multiple myeloma, and Kaposi sarcoma

Cold agglutinin disease is not an inherited condition. It is designated as either primary (unknown cause) or secondary (associated with or caused by another condition). In some cases, cold agglutinin may be multifactorial which means that multiple environmental factors and genes likely interact to predispose a person to developing the condition.^[4] However, to our knowledge, no disease-causing genes have been identified and no familial cases have been reported.

A diagnosis of cold agglutinin disease may be made after several types of tests are performed by a health care provider. In some cases, the diagnosis is first suspected by chance if a routine complete blood count (CBC) detects abnormal clumping (agglutination) of the red blood cells. In most cases, the diagnosis is based on evidence of hemolytic anemia (from symptoms and/or blood tests). A person may also be physically examined for spleen or liver enlargement. An antiglobulin test (called the Coombs test) may be performed to determine the presence of a specific type of antibody. In people with cold agglutinin disease, the Coomb's test is almost always positive for immunoglobulin M (IgM).^[1][2]

Detailed information about the various tests used to make a diagnosis of cold agglutinin disease is available on Medscape Reference's website. Please click on the link to access this resource.

The treatment of cold agglutinin disease depends on many factors including the severity of the condition, the signs and symptoms present in each person, and the underlying cause. For example, in those affected by secondary cold agglutinin disease, it is important to diagnose and treat the underlying condition which may include certain types of cancer; bacterial, viral, or parasitic infections; and/or other autoimmune disease. People with few symptoms and/or mild anemia may not require any specific treatment. These cases are often managed by simply avoiding exposure to the cold. ^[3][8]

In severe cases of hemolysis, medical interventions may be necessary. Rituximab (an antibody that selectively reduces specific types of immune cells) is effective in about 60% of cases of severe cold agglutinin disease. Medical researchers have found the response to rituximab is seen on average within 1 to 2 months of treatment and the effect of the treatment lasts for about 1 to 2 years. Rituximab may be used after a second and even a third relapse, however the success rate is less. Combined treatment with rituximab and fludarabine has resulted in higher response rates (76% of cases) and longer periods of remissions (on average, 6.5 years). However the combined treatment may include serious side effects so is presently only recommended when rituximab has not worked alone. Finally, plasmapheresis, which involves filtering blood to remove antibodies, may be useful in acute hemolytic crisis and before surgery requiring hypothermia, however its effect is only short term. It should be noted, removing the spleen is not recommended for cold agglutinin disease.  In addition, because severe cold agglutinin disease requires very high doses of corticosteroids (levels not considered safe), corticosteroid treatment is no longer a recommended treatment in severe cases.^[3][8]

Several possible therapies have been reported in a few case reports to have successfully treated people who are not responding to the treatments listed above.^[3][8] However more studies need to be performed before the safety and effectiveness of these therapies can be determined.  Click the link to view the therapies presently being studied in cold agglutinin clinical trials. 

The long-term outlook (prognosis) for people with cold agglutinin disease varies based on many factors including the severity of the condition, the signs and symptoms present in each person and the underlying cause. For example, people with cold agglutinin disease caused by bacterial or viral infections tend to have an excellent prognosis; in these cases, the symptoms typically disappear within 6 months after the infection has resolved. Mild to moderate primary (unknown cause) cold agglutinin disease can also be associated with a good prognosis if excessive exposure to the cold is avoided. Those with cold agglutinin disease caused by HIV infection or certain types of cancer generally have a poor prognosis due to the nature of the underlying condition.^[1]

Cold agglutinin disease most commonly affects adults who are of middle age and older. Some studies also report a slight bias in favor of females in the incidence of cold agglutinin disease, particularly in older populations. People with infectious mononucleosis, lymphoproliferative diseases, or mycoplasma pneumonia are more susceptible to this condition.^[1][2][3]