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Cold Agglutinin Disease
- Cold agglutinin disease (CAD) is a form of autoimmune hemolytic anemia (AIHA; see this term) defined by the presence of “cold” autoantibodies, i.e. active at lower temperatures at 30°C.
Synonyms
- CAD
- CASE
- Cold agglutinin syndrome
Incidence
How common is Cold Agglutinin Disease?
- 1-9 / 1,000,000
- It would represent 16 to 32% of AIHA, pathologies whose annual incidence is estimated between 1/80,000 and 1/35,000 in North America and Western Europe. It is more common after the age of 55.
Inheritance
Multigenic/multifactorial
Age of Onset
Adult
What are the symptoms of Cold Agglutinin Disease?
- It manifests as acute or chronic hemolytic anemia, with pallor and fatigue.
- During haemolytic “crises”, symptoms may include severe pain in the back and legs, headache, vomiting, diarrhea, dark urine and hepato-splenomegaly.
- The disease can be triggered or aggravated in a cold atmosphere or in the event of intercurrent infection; episodes of acute hemolysis with hemoglobinemia and hemoglobinuria are thus more frequent in winter.
- It can begin suddenly, with anemia and hemoglobinuria, or settle more gradually and insidiously.
- Sometimes, it is discovered fortuitously, on a routine blood count (NFS) showing abnormal agglutination of red blood cells.
Very Common Symptoms
- Arthralgia
- Autoimmunity
- Fatigue
- Hemolytic anemia
- Muscle weakness
- Pallor
Common Symptoms
- Abnormal urinary color
- Back pain
- Diarrhea
- Headache
- Hepatomegaly
- Lymphadenopathy
- Nausea and vomiting
- Splenomegaly
What causes this condition?
- FAD can be primary (idiopathic) or secondary to an underlying disease, such as Mycoplasma pneumoniae infection, lymphoproliferative syndrome, systemic autoimmune disease or neoplasia.
- The majority of FADs are secondary and due to the presence of a monoclonal IgM (most often of the kappa subtype) with cold agglutinin activity, related to an underlying low-grade B lymphoma (Waldenström’s macroglobulinemia or lymphocytic lymphoma ; see these terms).
- Idiopathic FADs and those secondary to lymphoma are more likely to be chronic, while infections are more likely to lead to acute forms.
How is this Cold Agglutinin Disease diagnosed?
- The diagnosis is made in front of clinical and biological signs of haemolytic anemia, associated with the demonstration of autoantibodies (usually of the IgM type) by a positive direct Coombs test of complement type (C3) and with the identification circulating cold agglutinins in serum.
- Secondary forms may be accompanied by blood lymphocytosis with the presence of atypical lymphocytes on the smear.
Differential Diagnosis
- The differential diagnosis is mixed AIHA.
How is this condition treated?
- Management of FAD is based on rewarming followed by avoidance of cold, which may be the only treatment in paucisymptomatic patients with only mild anemia.
- The disease is generally refractory to corticosteroids.
- Rituximab may be a treatment option in some cases.
- Oral chlorambucil or cyclophosphamide may be helpful for underlying lymphoma.
What are the prognosis?
- The course is usually chronic and benign, except in cases of recurrent episodes of severe anemia or aggressive course of the underlying B-cell lymphoma.