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Cold agglutinin disease

Orpha number ORPHA56425
Synonym(s) CAD
CAS
Chronic cold agglutinin disease
Cold agglutinin syndrome
Prevalence 1-9 / 1 000 000
Inheritance Multigenic/multifactorial
Age of onset Adult
ICD-10
  • D59.1
ICD-O -
OMIM -
UMLS -
MeSH -
MedDRA -
SNOMED CT
  • 127055007
  • 398937006

Summary

Cold agglutinin disease is a type of autoimmune hemolytic anemia (see this term) defined by the presence of cold autoantibodies (autoantibodies which are active at temperatures below 30°C).

Cold agglutinin disease represents an estimated 16-32% of AIHA, whose annual incidence is estimated to be between 1/35,000-1/80,000 in North America and Western Europe.

It occurs more frequently after the age of 55. Cold agglutinin disease manifests as acute or chronic hemolytic anemia, with associated pallor and fatigue. Symptoms during hemolytic ``crises'' may include severe pain in the back and legs, headache, vomiting, diarrhea, dark urine and hepatosplenomegaly. A cold environment or a concurrent infection may trigger or exacerbate the condition, and episodes of acute hemolysis with hemoglobinemia and hemoglobinuria are more common in winter. The disease may appear abruptly with anemia and hemoglobinuria, or onset may be more gradual and insidious.

Cold agglutinin disease can be primary (idiopathic) or secondary, caused by an underlying condition, such as infection (Mycoplasma pneumoniae), lymphoproliferative disorders, systemic autoimmunity or neoplasm. The majority of cold agglutinin disease is secondary and is due to the presence of monoclonal IgM (kappa subtype in the majority of the cases), which has the properties of a cold agglutinin and is associated with an underlying low-grade B-cell lymphoma (Waldenström macroglobulinemia or lymphocytic lymphoma; see these terms). Idiopathic and lymphoma-associated cold AIHA tend to be chronic while infections tend to cause an acute disease.

In some cases, the diagnosis is made by chance on a standard complete blood count (CBC) detecting abnormal agglutination of the red blood cells. Diagnosis is based on clinical or laboratory evidence of hemolytic anemia and the detection of autoantibodies, specifically IgM, with the direct anti-globulin test (DAT, C3 positive pattern) with the presence of circulating cold agglutinins inthe serum. In secondary cases, lymphocytosis, with the presence of atypical lymphocytes on the smear, can be found in peripheral blood.

The differential diagnosis for cold agglutinin disease is mixed AIHA (see this term).

Patients with few clinical symptoms and mild anemia may not require treatment but only avoidance of cold. Keeping the patient warm may be sufficient treatment. The disease is usually refractory to corticosteroids. Rituximab may be an option for treatment in some cases. In the presence of underlying lymphoma, chlorambucil or oral cyclophosphamide may be helpful.

The disease has a chronic course and the outcome is usually benign, except in patients with recurrent episodes of severe anemia or in whom the underlying B-cell lymphoma has an aggressive course.

Expert reviewer(s)

  • Pr Marc MICHEL

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Detailed information

Clinical practice guidelines
  • FR (2009,pdf)
Article for general public
  • FR (2009,pdf)
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