Paroxysmal Cold Hemoglobinuria

Paroxysmal cold hemoglobinuria (PCH) is a very rare subtype of autoimmune hemolytic anemia (AIHA, see this term), caused by the presence of cold-reacting autoantibodies in the blood and characterized by the sudden presence of hemoglobinuria, typically after exposure to cold temperatures.

Epidemiology

PCH is thought to account for at most 2-10% of cases of AIHA, whose annual incidence is estimated to be between 1/35,000-1/80,000 in North America and Western Europe.

Clinical description

Acute cases almost exclusively affect children and are often preceded by symptoms of infection. Chronic idiopathic cases also occur but are extremely rare. Acute cases of the disease are characterized by an abrupt onset with features of severe intravascular hemolysis including high fever, chills, back and/or leg pain. Other symptoms may include nausea, headache, vomiting and diarrhea. Typically hemoglobinuria occurs, producing dark red to black urine. Hemolysis can be severe and even life-threatening and results from exposure to cold, which may even be localized (eg from drinking cold water, from washing hands in cold water). Chronic forms of PCH are characterized by recurrent episodes of hemolysis precipitated by cold exposure.

Etiology

PCH is most often acute and occurs secondary to an infection, mainly upper respiratory, and the causative agent is often not identified. Late-stage or congenital syphilis was historically linked to cases of PCH in adulthood but this is becoming less and less common.

Diagnostic methods

Diagnosis is based on evidence of anemia linked to hemolysis, the presence of hemoglobin in urine, a positive result from the Donath-Landsteiner (DL) test and evidence of anti-P specificity of the IgG autoantibodies.

Differential diagnosis

The main differential diagnosis is acute cold AIHA (see this term) induced by an infection (for example Mycoplasma pneumoniae or the Epstein Barr virus) due to the presence of IgM autoantibodies which are cold agglutinins.

Management and treatment

Most cases of PCH are self-limited so treatment is usually symptomatic, including keeping the patient warm and red blood cell transfusion if necessary. Patients with few clinical symptoms and slight anemia may not require drug therapy. Corticosteroids and splenectomy are usually ineffective and should not be considered. In cases of life-threatening PCH, plasmapheresis can temporarily dampen the hemolysis. Some patients may respond to rituximab, although responses are usually short-lived. If syphilis is present, treatment with antibiotics generally eliminates the concurrent hemolysis.