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Paroxysmal cold haemoglobinuria (PCH) is an autoimmune haemolytic anaemia, caused by cold-reacting immunoglobulins. It primarily affects children and tends to cause quite severe, but transient, disease. The usual trigger for the formation of the cold-reacting polyclonal immunoglobulin G (IgG) autoantibodies is an episode of infection. The episode usually, but not always, follows a period of exposure to cold. It is usually a transient postinfectious or postvaccination problem that resolves, but it may cause significant morbidity. The degree of haemolysis is variable but may lead to an acute onset of intravascular haemolysis and haemoglobinuria.
Cross-reactivity (between antibodies formed against microbial antigens and the red-cell membrane P-antigen) induces intravascular haemolysis through complement activation. The antibodies detectable in the blood of those who suffer from PCH are known as 'Donath-Landsteiner antibodies'.
- It is a very rare illness; there are no reliable population-incidence figures, but it is believed to be responsible for about 40% of all autoimmune haemolytic anaemias that affect children (lower percentage for adults). Autoimmune haemolytic anaemias are, however, very rare, with an annual incidence of <1 per 100,000 population.
- Although the vast majority of cases occur in children, adults may rarely be affected. The acute, transient form of paroxysmal cold haemoglobinuria (by far the most usual modern presentation) is much more common in children than in adults.
- Viral infections - measles, mumps, adenovirus, chickenpox, influenza A, cytomegalovirus, Epstein-Barr virus.
- Bacterial infections - Haemophilus influenzae, Mycoplasma pneumoniae and Treponema pallidum (a chronic recurrent form is associated with secondary, tertiary or congenital syphilis).
- Postvaccination syndrome - particularly measles vaccine.
- Rarely, when it affects adults, it may be precipitated by an underlying neoplasm.
- Very rare chronic idiopathic/primary autoimmune disease form (usually seen in adults).
- There is often a history consistent with antecedent respiratory or other acute viral/bacterial infection. After a period of subsequent cold exposure, symptoms follow minutes to hours later.
- Some patients suffer the syndrome without a clear history of getting cold.
- Jaundice and the passage of dark urine - red or reddy-brown - strongly suggest the diagnosis in conjunction with the following symptoms:
- Vasomotor occlusion causes urticaria after cold exposure, paraesthesiae of the hands and feet, peripheral cyanosis, Raynaud's phenomenon and peripheral infarction with gangrene.
- Anaemia may cause parents to notice their child's pallor, or it may lead to tiredness, exertional dyspnoea and poor feeding in babies/infants.
- Oliguria or anuria may be a presenting feature.
- Affected adult males may suffer impotence due to microvascular occlusion.
- Haemoglobinuria does not occur in the less severe cases, so jaundice and dark urine are not always present.
- There may be an urticarial rash or an exanthem due to precipitating viral illness.
- In the acute phase there will be a high fever, often >40°C.
- Pallor and tachycardia are likely to be present and the abdomen should be examined for evidence of hepatosplenomegaly (possible underlying neoplasm).
- Lymph node areas should be examined and the chest checked for evidence of current infection.
- The condition used to be strongly associated with congenital syphilis before its decline in developed countries; there may be signs of congenital syphilis, particularly for children in/from countries with a high incidence of syphilis.
A large follow-up series found occasional associations with lymphoproliferative disorders, collagen disease, myelodysplastic syndrome, delayed haemolytic transfusion reaction and other types of autoimmune haemolytic anaemia.
- Warm antibody-induced autoimmune haemolytic anaemia/drug-induced haemolysis.
- Other causes of acute childhood anaemia.
- Cold agglutinin disease (the other major cryopathic haemolytic syndrome; it affects adults and tends to cause mild or subclinical illness).
- Autoimmune lymphoproliferative syndrome (ALPS).
- Lymphoproliferative disorders.
- Non-Hodgkin's lymphoma.
- Systemic lupus erythematosus.
- Renal disorders in children causing haematuria.
- Paroxysmal nocturnal haemoglobinuria.
- Severe malaria.
Investigations include assessment of the haemolytic anaemia and identification of any underlying cause.
- Urinalysis: haemoglobinuria will be present to varying degrees at presentation; examine the urine for colour and dipstick for haemoglobin, proteinuria may also occur.
- Full blood count: may show acute anaemic picture, ranging from mild to severe. Usually normochromic, normocytic pattern. May appear as macrocytic anaemia during acute haemolytic phase. Paradoxically for a haemolytic anaemia, there is often a low reticulocyte count in the early stages. Subsequently reticulocytosis tends to occur as the marrow pushes out cells to replace those that have been lost. White cell count can be low in early stages but tends to be normal or high if infection is a factor.
- Blood film: shows spherocytes, polychromasia, nucleated red cells, and occasionally neutrophil-mediated erythrophagocytosis.
- Biochemistry: indirect bilirubin, lactate dehydrogenase (LDH) and plasma haemoglobin are elevated due to haemolysis.
- Autoantibody detection: a specialist indirect IgG antiglobulin test performed at low temperature may detect anti-P Donath-Landsteiner antibodies. The Donath-Landsteiner bithermic haemolytic test is not very sensitive but quite specific, especially if utilising the cells of a patient with paroxysmal nocturnal haemoglobinuria. The patient's red blood cells are incubated with serum and complement at a low temperature and then at body temperature; the presence of haemolysis indicates a positive test.
- Blood typing: group and save in case of need for transfusion. Cross-matching can be difficult as autoantibody may agglutinate donor cells that would not normally be reactive. Specialist transfusion medicine input may be required.
- Direct Coombs' test: is negative.
- Children suspected of suffering from the condition should be referred urgently to their local acute paediatric service.
- Keep the patient warm with extremities covered during the acute phase of the illness.
- Blood transfusion:
- Severe or symptomatic anaemia is an indication for blood transfusion.
- Cross-matching requires special attention due to the interfering effect of the autoantibody. Most banked blood donations are P-antigen positive but can be used safely in most cases, after rigorous specialist testing.
- Transfusions should be given washed, warmed and in packed-cell format. If active bacterial infection is suspected then treat with appropriate intravenous antibiotics.
- Renal complications such as acute tubular necrosis may occur and expert input is needed in some cases.
- Close attention must be paid to fluid status and consideration given to alkalinisation of urine.
- Steroids are occasionally used but there is no good evidence for their effectiveness.
- After the acute phase is over, patients should be followed up for a few months in the haematology clinic. They may require daily/weekly review at first. Regular blood counts and other tests will be used to check the problem is resolving.
- The syndrome may recur and patients should be advised to avoid cold exposure during this time.
- Folic acid intake through diet or supplementation may be a useful and presumably harmless, cheap adjunct during/after acute haemolytic disease in children. In the rare chronic (usually adult) forms, ongoing folate supplementation is advised.
- Severe, acute anaemia
- Organ failure due to anaemia, eg cardiac arrest or respiratory failure.
- Acute renal failure.
- Death due to acute haemolytic crisis may occur, but is unusual.
- Children who have an acute postinfectious onset usually have an excellent outcome as the illness is transient and self-limiting.
- Adult idiopathic disease is often chronic but relatively mild.
- Cancer-associated adult disease resolves if the relevant malignancy responds to treatment.
- After acute episodes, children should avoid cold exposure for a few months. This is similarly so for adults with chronic forms of the disease.
- Awareness of the symptoms of remission and anaemia that should prompt medical attention should be discussed with the patient.
Further reading and references
Gramatges MM; Donath-Landsteiner Hemolytic Anemia, eMedicine, May 2009
Donath-Landsteiner Antibodies; whonamedit.com
Goldberg C; Hemoglobinuria, Paroxysmal Cold, eMedicine, Nov 2008
Sokol RJ, Booker DJ, Stamps R; The pathology of autoimmune haemolytic anaemia. J Clin Pathol. 1992 Dec45(12):1047-52.
Papalia MA, Schwarer AP; Paroxysmal cold haemoglobinuria in an adult with chicken pox. Br J Haematol. 2000 May109(2):328-9.
Sokol RJ, Booker DJ, Stamps R; Erythropoiesis: Paroxysmal Cold Haemoglobinuria: A Clinico-Pathological Study of Patients with a Positive Donath-Landsteiner Test. Hematol. 19994(2):137-164.