Cold agglutinin disease: symptoms, causes, diagnosis and treatment

The immune system normally makes antibodies against infections. In autoimmune haemolytic anaemia it makes antibodies against the body's own red blood cells, which are then destroyed faster than they are replaced, causing anaemia. NICE's evidence summary notes that the condition is normally divided into warm and cold antibody types. Cold antibody types include cold haemagglutinin disease (cold agglutinin disease) and paroxysmal cold haemoglobinuria, and in the cold type autoantibodies react at lower temperatures of 20 degrees C or below.

The National Organization for Rare Disorders (NORD) explains that red blood cells normally live about 120 days. In people with CAD they are destroyed prematurely and the bone marrow cannot keep up with the loss. The antibodies, mostly of the IgM class, bind to red blood cells, causing them to clump (agglutinate), and are then bound by the complement system and attacked by immune cells.

NORD estimates that CAD develops in about one person per million every year, mostly between the ages of 40 and 80 with a median age of onset around 65, and that it is almost twice as common in women as in men.

NORD says symptoms are mostly the result of either haemolysis or circulatory symptoms, both triggered by exposure to cold. Some people, especially with mild haemolysis and a gradual onset of anaemia, may have no obvious symptoms at all.

• Tiredness, weakness and pallor from anaemia.

• Shortness of breath, dizziness and palpitations.

• Yellowing of the skin and whites of the eyes (jaundice) and dark urine when red cells break down rapidly.

• Cold, painful, bluish or reddish fingers, toes, ears or nose in the cold (acrocyanosis or Raynaud phenomenon).

• In severe cases, ulcers on the fingers or toes.

The Blood Project says CAD can occur on its own, called primary CAD, after certain infections, or alongside another immune or blood condition. In many adults with primary CAD the antibody comes from a slow-growing group of immune cells in the bone marrow, which it says does not mean an aggressive cancer, and many people remain stable for years.

NORD lists infections associated with secondary CAD such as mycoplasma, mumps, cytomegalovirus and infectious mononucleosis, immunoproliferative diseases such as non-Hodgkin lymphoma and chronic lymphocytic leukaemia, and connective tissue disorders such as rheumatoid arthritis and lupus. NICE says the cold antibody type is more often secondary to another condition such as lymphoma. Most cases are not caused by anything a person did or could have prevented, according to the Blood Project.

The Blood Project says evaluation focuses on confirming the diagnosis and understanding how active the condition is. Tests may include blood counts to measure anaemia, markers of red blood cell breakdown, tests that detect cold antibodies or complement activity and evaluation for related conditions. A bone marrow biopsy is not needed for everyone and is used when doctors need more information about the antibody-producing cells or when results are unclear.

Diagnosis is usually made by haematologists. Paroxysmal cold haemoglobinuria and warm autoimmune haemolytic anaemia are the main conditions to be distinguished, according to NORD.

NORD says treatment includes avoidance of cold temperatures, treating anaemia and haemolysis if needed, and medicines that modulate the immune system to decrease production of antibodies against red blood cells, and that any underlying disease should be treated. The Blood Project says treatment depends on symptoms, anaemia severity and how active the disease is, with control-focused therapies that block the complement reaction and cause-focused therapies that target the cells making the antibody.

NICE's evidence summary says that if treatment is required in cold haemagglutinin disease, corticosteroids, splenectomy and conventional immunosuppressants are much less effective, and that rituximab has become first-line treatment on the basis of limited published data. That summary dates from 2015, and newer complement-blocking treatments have since been developed, so ask the haematology team what is currently recommended and funded.

NORD says CAD can be chronic, but can be self-limited and clinically silent, especially when associated with infections, and that although it can be caused by severe diseases it does not itself seem to be associated with a significantly decreased life expectancy. It notes that people with CAD may be at higher risk of blood clots, although more studies are needed. The Blood Project says that having CAD does not automatically mean a dangerous or life-threatening illness and that many people live well with it for years.

Doctors become more concerned, according to the Blood Project, when anaemia worsens, symptoms interfere with daily life, red blood cells are being destroyed rapidly or haemoglobin drops significantly. Symptoms may temporarily worsen during infections or cold weather. Tell any surgical or anaesthetic team that you have CAD before an operation or transfusion, since the Blood Project notes that warming IV fluids and blood products may be needed.

Contact your GP or haematology team promptly if you become more breathless or tired, notice dark urine or yellowing of the skin or eyes, or develop painful discoloured or ulcerated fingers or toes. Call 999 for chest pain, collapse or severe breathlessness. If you have not been diagnosed but have unexplained tiredness with cold-triggered colour changes in the fingers, see your GP for a blood count.

On the NHS, CAD is managed by haematologists, often at a larger centre because of rarity, and treatment access depends on NHS commissioning. Recommendations and funding for newer medicines may change over time. Private haematology consultation is possible, but medicines that are not routinely funded generally have to be obtained through specific funding routes, so ask your haematologist what is available to you.