COLD AGGLUTININ DISEASE (CAD)
Cold agglutinin disease (CAD) is a rare autoimmune disorder characterized by the premature destruction of red blood cells (hemolysis). Autoimmune diseases occur when one’s own immune system attacks healthy tissue. More specifically, CAD is a subtype of autoimmune hemolytic anemia. In this type of disorder, red blood cells are “tagged” by antibodies and are then destroyed by other types of immune cells.
The disease is termed “cold” because the antibodies are active and cause hemolysis at cold temperatures, usually 3 to 4◦C (37 to 39◦F), which is not necessarily the case in other types of autoimmune hemolytic anemia. CAD affects about one person per million every year, and mostly develops between the ages of 40 and 80 years. Normally, the red blood cells have a life span of approximately 120 days before they are destroyed by the spleen. In individuals with CAD, the red blood cells are destroyed prematurely and the rate of production of new cells in the bone marrow can no longer compensate for their loss.
A decreased number of red blood cells (anemia) may cause fatigue, weakness, a pale skin color (pallor), dizziness, palpitations, and shortness of breath (dyspnea). Hemolysis leads to an increased release from red blood cells of hemoglobin, a protein responsible for carrying oxygen in the blood. Degradation of hemoglobin into bilirubin can result in yellowing of the skin and whites of the eyes (jaundice). Hemoglobin can also pass in the urine and give it a dark brown color.
Other symptoms that can be triggered by exposure to cold include sweating and coldness of the fingers and/or toes (digits) and painful bluish or reddish discoloration of the skin of the digits, ankles, and wrists (acrocyanosis or Raynaud sign).
Treatment of CAD includes avoidance of cold temperatures, treating anemia and hemolysis (if needed) and medications that modulate the immune system to decrease the production of antibodies against red blood cells. If applicable, the underlying disease that caused CAD should be treated.
Symptoms and Signs
In chronic cold agglutinin disease, symptoms related to red blood cell agglutination occur on exposure to cold, and patients may complain of mottled or numb fingers or toes, acrocyanosis, episodic low back pain, and dark-colored urine. Hemolytic anemia is occasionally severe, but episodic hemoglobinuria may occur on exposure to cold. The hemolytic anemia in acute postinfectious syndromes is rarely severe.
Mild anemia is present with reticulocytosis and rarely spherocytes. The blood smear made at room temperature shows agglutinated red blood cells (there is no agglutination on a blood smear made at body temperature). The direct antiglobulin (Coombs) test will be positive for complement only. Serum cold agglutinin titer will semi-quantitate the autoantibody. A monoclonal IgM is often found on serum protein electrophoresis and confirmed by serum immunoelectrophoresis. There is indirect hyperbilirubinemia and the haptoglobin is low during periods of hemolysis.
Treatment is largely symptomatic, based on avoiding exposure to cold. Splenectomy and prednisone are usually ineffective (except when associated with a lymphoproliferative disorder) since hemolysis takes place in the liver and blood stream. Rituximab is the treatment of choice. The dose is 375 mg/m2 intravenously weekly for 4 weeks. Relapses may be effectively re-treated.
High-dose intravenous immunoglobulin (2 g/kg) may be effective temporarily, but it is rarely used because of the high cost and short duration of benefit. Patients with severe disease may be treated with cytotoxic agents, such as cyclophosphamide, fludarabine, or bortezomib, or with immunosuppressive agents, such as cyclosporine. As in warm IgG-mediated autoimmune hemolysis, it may be difficult to find compatible blood for transfusion. Red blood cells should be transfused through an in-line blood warmer.