Cold Agglutinin Disease 

In 1903, Landsteiner was the first to describe the presence of cold agglutinins in the blood, which were capable of agglutinating red blood cells (RBCs).^[1] He described the finding of a low titer of these agglutinins in healthy individuals. Later, the appearance of the I antigen on human RBCs in the postnatal period due to modification of the fetal i antigen structure (a change occurring over the first 18 mo) was found to lead to the development of low levels of anti-I agglutinins. These antibodies induce hemagglutination mainly at 4°C but not at 37°C and were therefore termed cold agglutinins.

Subsequent observations have led to the understanding that cold agglutinins are usually immunoglobulin (Ig) M antibodies (less commonly, IgA or IgG) that may result in hemolytic anemia due to complement-mediated RBC destruction in the reticuloendothelial system. Slowing of blood flow with occlusion of superficial blood vessels by agglutinated RBCs can cause a Raynaudlike syndrome (acrocyanosis).^{[2, 3, 4]}

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Cold agglutinin disease usually develops as a result of the production of a specific IgM antibody directed against the I/i antigens (precursors of the ABH and Lewis blood group substances) on RBCs. These cold agglutinins commonly have variable heavy-chain regions encoded by V_H,^{[4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21]} with a distinct idiotype identified by the 9G4 rat murine monoclonal antibody.^[4]

This 9G4 idiotope is localized to the V4-34 encoded portion of the variable region.^[22] It is found on cold agglutinin-producing malignant lymphoid cells in the bone marrow in persons with lymphoproliferative disorders, on a small proportion of normal lymphoid cells, and in the spleen of a 15-week-old fetus. In contrast, the cold agglutinins found in healthy individuals, those with no clinical symptoms, are often derived from a variable segment other than V4-34 portion.^{[23, 24]}

The V_H genes appear to regulate not only the production of cold agglutinins, but also the formation of normal antibodies to other carbohydrate antigens, both sharing the same fundamental mechanism of production. The I/i antigen analogues are present on human lymphocytes, neutrophils, and monocytes and in human saliva, milk, and amniotic fluid. Thus, in disease states, the finding of a clone of B cells producing this antibody may be the result of expansion of a normal clone that is specific for the production of an immunoglobulin with these properties. Autoimmune and lymphoproliferative disorders can also be associated with the production of cold agglutinins.

The hemolytic anemia associated with monoclonal cold agglutinins is typically more serious than that associated with polyclonal cold agglutinins. The monoclonal form is usually chronic, whereas the polyclonal form is often limited.^[25] Some polyclonal IgM cold agglutinins arise in association with Mycoplasma pneumoniae infections, infectious mononucleosis, influenza B, human immunodeficiency virus (HIV), and other infections.

Cytomegalovirus (CMV), rubella virus, varicella-zoster virus (VZV), parvovirus B19, and Chlamydia psittaci have also been implicated.^[26] In the case of infectious mononucleosis, hemolysis tends to develop 1-2 weeks after the onset of illness, but it may occur simultaneously for up to 2 months after onset.^[26] Furthermore, increased expression of both I/i antigens have been described on hemoglobin SS (HbSS) erythrocytes, which suggests that such patients may have increased susceptibility to cold-mediated hemolysis.^[27]

In its classic presentation, with hemolytic anemia and Raynaud syndrome, cold agglutinin disease is usually idiopathic. As with most autoimmune diseases of a chronic nature, stimulated B lymphocytes begin to produce pathogenic antibodies against an antigen that is normally present in human tissue. In cold agglutinin disease, the antibody is an IgM, usually monoclonal, with kappa (κ) or lambda (λ) light chains. In chronic cold agglutinin disease, the antibody is usually directed against the I antigen on the membrane of normal adult RBCs.

Uncommonly, the antibody may be directed against only the i antigen found on fetal cord blood RBCs, which lack the mature I antigen; this has been reported in association with infectious mononucleosis.^[9] In a study of 78 patients, κ light-chain specificity was found in the majority of patients with chronic cold agglutinin disease or Waldenstrom macroglobulinemia, whereas two thirds of cold agglutinins found in patients with lymphomas had light-chain specificity. The type of light chain appears to correlate with the antigen specificity of the cold agglutinin.

Fifty-eight percent of IgM/κ (usually κIII variable region subgroup) were anti-I, but 75% of IgM/λ had other antigen specificities.^[12] Antigen specificities of cold agglutinins other than the I/i system that have been described include those against Pr, M, P, and Lud and anti-Gd, anti-Fl, and anti-Sa.^{[6, 11, 14]} Exclusive occurrence of κ chains has also been shown with some cold agglutinins.^[5] Thus, benign and malignant cold agglutinins exhibit differences in their light chains and their specificities toward membrane antigens.

In vivo, the IgM antibody attaches to RBCs and causes them to agglutinate at temperatures below 37°C and maximally at 0-5°C, resulting in impaired blood flow to the digits, nose, and ears (ie, areas more likely to have colder temperatures [in the 30°C range]) when exposed to the cold. Fixation of the C3 component of complement to the RBC by the cold agglutinin usually occurs in vivo at higher temperatures compared with those required by the IgM cold agglutinin to attach to the RBC, but it is generally less than 31°C. When the IgM/C3b-coated RBC circulates to warmer tissues, the IgM dissociates, leaving complement C3b on the original RBC.

The dissociated IgM cold agglutinin can then bind to another RBC at lower temperatures. Fixation of complement results in C3b and/or C4b components on the RBC membrane, which may lead to phagocytosis by macrophages in the reticuloendothelial system, particularly in the liver, where the macrophages have specific complement receptors. With time, the C3b components are converted enzymatically to C3dg, which is not recognized by macrophage receptors.

In chronic cold agglutinin disease, complement tends to be depleted. Thus, the hemolysis is self-controlled, and anemia may only be mild or moderate, because these C3dg-coated RBCs are no longer capable of reacting with the IgM antibody in the cold, the C3dg-coated RBCs are not recognized by the macrophages, and low complement levels become rate limiting.

Temporary increases in complement levels, as can occur with intercurrent febrile illnesses, can increase hemolysis. Lytic components of complement C5-C9 generally do not form on these cells, and intravascular hemolysis by complement is less likely to occur.^[16] Hemolysis develops acutely following M pneumoniae infections and lasts approximately 1-3 weeks. Subclinical mild hemolysis with reticulocytosis may also occur, and the results of a direct Coombs test may be weakly positive, especially with M pneumoniae infections.

Monoclonal cold agglutinin IgM antibodies found in patients with lymphoma are the product of the abnormal clone. Progression of an idiopathic cold agglutinin disease to malignant lymphoma may occur in some cases; thus, affected patients require close long-term follow-up, with obvious therapeutic implications.^{[9, 14]} One study of 86 patients in Norway showed clonal light chain predominance in 90% of patients, evidence of lymphoplasmacytic lymphoma in 50%, and lymphoma of any type in 76% overall.^[28]

Hemolysis due to cold agglutinins can sometimes be accompanied by a warm antibody (IgG), resulting in a mixed autoimmune hemolytic anemia,^{[9, 13]} that is, cold agglutinin syndrome and warm antibody autoimmune hemolysis, with the direct antiglobulin (direct Coombs) test results positive for the presence of both IgG and complement on the surface of the sensitized RBC. In mixed antibody syndromes, the IgG and IgM antibody components can be separated. The cold autoantibodies reactive at temperatures of 30°C or higher often show blood group specificity to the adult I antigen, whereas the warm autoantibodies are not directed against this system. A combination of cold agglutinins and cryoglobulins has also been reported with an IgM κ monoclonal antibody, with specificity to the Pr2 antigen system.^[20]

Several factors play a role in determining the ability of a cold agglutinin to induce an active hemolytic anemia. These factors include the ability to initiate; the extent of antibody-induced complement activation; the concentration of the antibody; the range of temperatures, including the highest temperature at which the antibody interacts with the RBC (its thermal amplitude); the qualitative binding of IgM to the RBC; and modification of the antibody's ability to fix complement components onto the RBCs.^{[10, 28]} In addition, the presence of biphasic hemolysins implicates more severe disease. Biphasic hemolysins bind to RBCs at low temperatures and activate complement to produce invitro hemolysis at warmer temperatures (37°C), whereas monophasic hemolysins bind to RBCs and activate complement at the same temperature.^[29]

In vitro studies have shown that human monoclonal antibodies encoded by the V4-34 gene segment not only have cold agglutinin properties, but they also exhibit multireactivity. This is in contrast to the generally monospecific I/i reactivity of sera from patients with cold agglutinin disease.^[19] Data have confirmed an immunomodulatory/immunosuppressive role of the naturally occurring anti-F(ab')₂ antibodies in the production of cold agglutinins, with an inverse correlation between the titers of IgG-anti-F(ab')₂ and cold agglutinins.^[18] This inverse correlation was found only in patients with anti-I/i and in the presence of a monoclonal lymphocyte population.

Frequency

United States

Low titers of cold agglutinins (1:64 or less) reactive at low temperatures are commonly found in the sera of healthy persons. Postinfectious elevations in the cold agglutinin titers (eg, M pneumoniae, Epstein-Barr virus [EBV], CMV) are transient. Cold agglutinins develop in more than 60% of patients with infectious mononucleosis, but hemolytic anemia is rare.

Development of the cold agglutinin syndrome is relatively uncommon, at least in the classic chronic form. Various reports state that 7-25% of cases of autoimmune hemolytic anemia are cold agglutinin mediated. Incidence of both cold and warm autoimmune hemolytic anemia (combined) is approximately 1 in 80,000; the incidence of cold agglutinin disease, which is approximately one fourth of the total, is approximately 1 in 300,000. Among autoimmune hemolytic anemias, cold agglutinin disease is the second most common cause, after warm autoantibody–induced immune hemolysis.

International

Data regarding incidence of cold agglutinin disease are lacking. Frequency figures listed for the United States probably also apply to Canada and the United Kingdom.

Mortality/Morbidity

Morbidity in chronic cold agglutinin disease is usually limited to symptoms precipitated by exposure to the cold. Transfusions for life-threatening symptoms due to severe anemia require prewarming and the use of washed RBCs (not cold). Occasionally, peripheral gangrene and, rarely, fatalities, have occurred after inadvertent and perhaps prolonged exposure to the cold.

Race

A racial predilection has not been reported for cold agglutinin disease.

Sex

Women are affected more commonly than men.^{[4, 9]} The incidence of mixed autoimmune hemolysis has a male-to-female ratio of 1:1.5.

Age

Infants and children are rarely affected with chronic cold agglutinin disease, although M pneumoniae and infectious mononucleosis are diseases of young persons. Chronic cold agglutinin disease appears to affect adults who are of middle age and older, with an average age more commonly older than 60 years (peaking in the seventh and eighth decades of life). Although found in persons of all age groups, mixed autoimmune hemolysis is also more frequent in later life.