Key Takeaways

✅ Cold agglutinin disease (CAD) is defined as an AIHA mediated by cold agglutinins (CAs),

✅ CAD may be classified as primary and secondary

• Primary
  • Also called idiopathic CAD or simply CAD.
  • No evidence of underlying disease such as aggressive lymphoma, other overt malignancies, or specific infections.
• Secondary
  • Also called cold agglutinin syndrome
  • Complicating other specific diseases, such as Mycoplasma pneumoniae pneumonia, Epstein-Barr virus infection, or aggressive lymphoma

✅ CAD accounts for about 15% of autoimmune hemolytic anemias (AIHA).

✅ Cold agglutinins are autoantibodies (typically IgM) that are able to agglutinate red blood cells (RBCs) at an
optimum temperature of 3-4°C, but can also react at higher temperatures, depending on the thermal amplitude.

✅ Most CAs in CAD have specificity for the I carbohydrate antigen, which is almost universally present at the RBC surface in adults and children older than age 18 months.

✅ CAD is a distinct, clonal lymphoproliferative disease with monoclonal serum immunoglobulin present in majority of cases, typically immunoglobulin M-kappa (IgMk).

✅ Clinical presentation typically includes combination of cold-induced symptoms, anemia, and hemolysis.

✅ Febrile infections, major trauma, or major surgery can result in acute exacerbation of hemolytic anemia.

✅ The diagnostic criteria for CAD include:

• Chronic hemolysis
• Positive polyspecific DAT
• Positive monospecific DAT strongly positive for C3d
• CA titer >64 at 4°C
• No overt malignant disease by clinical (and, if required, radiological) examination

✅ Treatment includes

• Nonpharmacologic management
• Clonally-directed therapies
  • Rituximab monotherapy
  • Rituximab and fludarabine combination therapy
  • Complement modulation?