Secondary CAD

Secondary cold agglutinin disease (CAD) is the name given to CAD that is caused by infections, other autoimmune disorders, or lymphoid malignancies.


Secondary CAD may result from infections such as atypical pneumonia caused by the bacterium Mycoplasma pneumonia; infectious mononucleosis caused by the Epstein-Barr virus; autoimmune disorders such as Lupus erythematosus; lymphoproliferative disorders such as monoclonal gammopathy; and lymphoid or plasma-cell malignancies such as B-cell lymphoma, chronic lymphocytic leukemia, and Waldenström macroglobulinemia.

These conditions cause the production of cold agglutinins, which are mostly IgM antibodies that bind to red blood cells (RBCs) at low temperatures. The RBC-IgM complex promotes the activation and binding of complement proteins such as C3b to the complex. Complement-coated RBCs are ingested by immune cells such as macrophages and are destroyed. Because of excessive RBC lysis (disintegration), patients experience hemolytic anemia, which is reflected by low hemoglobin levels in the blood.

Signs and symptoms

The main symptoms of secondary CAD are similar to those of primary CAD. These include signs of hemolysis upon exposure to cold such as acrocyanosis (discoloration of fingertips, nose, toes, and ears), livido reticularis (patchy, spider-web-like blood vessels on the skin with a red-blue or violet coloration), Raynaud’s phenomenon (color changes in the skin of the fingers, toes, nose, and ears in response to cold), fatigue, headaches, jaundice, cold hands and feet, and dark urine caused by the presence of hemoglobin.


The diagnosis of secondary CAD is the same as that of primary CAD. A positive diagnosis is based on the following signs:

  • Evidence of hemolysis or destruction of RBCs based on blood tests showing high reticulocyte (immature RBCs) counts, high levels of lactate dehydrogenase enzyme and bilirubin, and low levels of haptoglobin.
  • Positive direct antiglobulin (Coombs) test for complement proteins such as C3d or IgM antibodies.
  • Cold agglutinin titer that is detectable at 1:64 dilutions or greater at 4 degrees Celsius.


The symptoms of secondary CAD may disappear when the underlying disease causing it is treated.

When secondary CAD is associated with a lymphoproliferative disorder, the primary treatment will most likely be rituximab alone or combined treatment with rituximab plus bendamustine.


Last updated: August 1, 2019


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