people with secondary CAD (associated with another underlying condition), there may be additional signs and symptoms depending on the condition present. For example: 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. 80–99% of people have these symptoms Arthralgia Autoimmunity Fatigue Hemolytic anemia Muscular weakness Pallor 5–29% of people have these symptoms Abnormal urine color Back pain Diarrhea Headache Hepatomegaly Lymphadenopathy Nausea and vomiting Splenomegaly Cause Cold agglutinin disease can be either primary (unknown cause) or secondary (a result of another pathology/ caused by an underlying condition). Primary cold agglutinin disease The primary form is caused by excessive cell proliferation of B lymphocytes, characterized by clonal lymphoproliferative disorder. Primary cold agglutinin disease occurs after the fifth decade of life and peaks prevalence in a person's 70s and 80s. Secondary cold agglutinin disease Secondary cold agglutinin syndrome occurs when autoantibodies bind to red blood cells, rendering them subject to attack by the complement system. It is a result of an underlying condition potentially associated with either monoclonal cold-reacting autoantibodies or polyclonal cold-reacting autoantibodies predominantly caused by infection or lymphoproliferative disorders. In adults, this is typically due to: 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. In children, cold agglutinin disease is often secondary to an infection, such as Mycoplasma pneumonia, mononucleosis, and HIV. Inheritance 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. However, no disease-causing genes have been identified and no familial cases have been reported. Pathophysiology All individuals have circulating antibodies directed against red blood cells, but their concentrations are often too low to trigger disease (titers under 64 at 4 °C). In individuals with cold agglutinin disease, these antibodies are in much higher concentrations (titers over 1000 at 4 °C). At body temperatures of 28–31 °C, such as those