Febrile Agglutinin

Febrile Agglutinin serologic studies are used to diagnose infectious diseases such as salmonellosis, rickettsial diseases, brucellosis, and tularemia. Neoplastic diseases, such as leukemias and lymphomas, are also associated with febrile agglutinins. Appropriate antibiotic treatment of the infectious agent is associated with a drop in the titer activity of febrile agglutinins. Cold agglutinins occur in patients who are infected by other agents, most notably Mycoplasma pneumoniae. Other diseases include influenza, mononucleosis, rheumatoid arthritis, lymphomas, and hemolytic anemia.

The febrile and cold agglutinins are antibodies that cause red blood cells (RBCs) to aggregate at high or low temperatures, respectively. They are believed to be a result of infection by organisms with antigenic groups similar to some of those found on the RBCs. Agglutination may occur normally in concentrated serum (less than 1:32 dilution).


Agglutination occurring at titers greater than 1:16 for cold agglutinins and 1:80 for febrile agglutinins is considered abnormal and diagnostic of the infectious agent or disease with which the agglutinins are associated. Agglutinins in high titers can attack RBCs and cause hemolytic anemias. Cold agglutinins are often obtained during the suspected acute phase of the disease and are repeated during the convalescence phase (7 to 10 days later). A fourfold or higher increase in antibody titer is considered diagnostic for the associated infectious diseases. Titer elevation is directly related to severity of infection. High titers of either cold or warm agglutinins can interfere with blood typing, crossmatching, and transfusion. In older adults, agglutinins can persist for years following an associated illness.
Temperature regulation is critical when performing these tests. For cold agglutinins, the red-top tube is previously warmed to over 37° C; for febrile agglutinins, the red-top tube is cooled. The specimen is taken to the laboratory immediately so that no hemolysis will occur. Under no circumstances should the cold agglutinin specimen be refrigerated or the febrile agglutinin be heated. At the laboratory the cold agglutinin specimen is chilled and evaluated for agglutination of RBCs. The febrile agglutinin specimen is heated and also inspected for agglutination of RBCs. Serial dilutions are performed to detect the dilution at which agglutination occurs.




Normal Febrile Agglutinin Titers

Febrile Agglutinins (Warm): no agglutination in titers ≤1:80

Cold Agglutinins: no agglutination in titers ≤1:16




Drugs that Affect Febrile Agglutinin Titers

Some Antibiotics (Cephalosporins and Penicillin) can interfere with the development of cold Agglutinins.




Indications of High Febrile Agglutinin Titers

The diseases are associated with high titers of Febrile Agglutinins:

  • Salmonella.
  • Rickettsia.
  • Brucellosis.
  • Tularemia.
  • Leukemia.
  • Lupus Erythematosus.
  • Lymphoma.




Indications of High Cold Agglutinins Titers

The fol diseases are associated with very high titers of cold agglutinins:

  • Viral Illness—rapid rise (7 days) peaking at 14 days and falling at 25 days.
  • Mycoplasma Pneumoniae.
  • Infectious Mononucleosis.
  • Influenza.
  • Nonbacterial Infection.
  • Collagen-vascular Diseases including Scleroderma Rheumatoid Arthritis).
  • Cirrhosis.
  • Lupus Erythematosus.
  • Leukemia.
  • Lymphoma.
  • Mmultiple Myeloma.