Cold Agglutinin Disease

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.
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