Cold Agglutinin Disease (CAD)

Cold agglutinin disease (CAD) is a rare autoimmune disease that occurs when autoantibodies produced by the immune system bind to red blood cells and cause them to clump together when exposed to cold stimuli. The immune system then targets and destroys these red blood cells.1 Approximately 90% of CAD cases are caused by immunoglobulin (Ig) M autoantibodies, and CAD is rarely caused by IgA, IgG, or λ light chain restriction. Warm autoimmune hemolytic anemia (AIHA) is predominantly caused by IgG autoantibodies.2

CAD accounts for approximately 15% of AIHA cases2; various sources indicate that anywhere from 7% to 25% of cases of AIHA are caused by CAD.3


CAD develops in 1 person per million people every year.1 In the United States, the incidence is approximately 1 in 300,000 persons.3 In North America, the annual incidence of all AIHA cases is estimated to be between 1 in 35,000 and 1 in 80,000 persons.4 In Nordic countries, the incidence is estimated to be around 1 to 1.8 per million people.5  


According to retrospective studies from Nordic countries, CAD is present in approximately 13 to 16 individuals per million people.1,5 

Affected Populations


CAD typically presents in individuals between 40 and 80 years of age, with the median age of onset around 65 years of age.1 CAD peaks at the seventh and eighth decades of life.3 CAD rarely affects infants or children.3


The National Organization for Rare Diseases claims that CAD is twice as common in women than in men,1 while other sources reported roughly equal prevalence between men and women.2,6  Berentsen et al analyzed 86 patients with CAD and described a 0.55 ratio of men to women.7 This slightly increased preponderance of CAD in women is suggested to occur due to the likelihood of women living to older ages, when disease onset is more common.6


CAD is naturally more prevalent in colder climates given the disease’s mechanism of action.1 A population-based study performed on nearly all individuals with CAD in the Lombardy region in Northern Italy and Norway discovered prevalence rates of approximately 5 per million and 20.5 per million, respectively. This suggests a 4-fold greater prevalence in colder climates.8 

Disease Types

CAD is subdivided into primary CAD and secondary CAD. Primary CAD, also called idiopathic CAD, occurs in the absence of underlying infection or malignancy.5 Primary CAD is believed to be the result of a low-grade lymphoproliferative bone marrow disorder that manifests in biopsies and flow cytometry with B cell expansion.6 Although a very small sample size of 14 patients was studied, investigators from a 1997 study asserted that CAD was a monoclonal lymphoproliferative disorder in the majority of these patients.9 

Secondary CAD occurs as a result of underlying immunoproliferative lymphoid malignancies such as non-Hodgkin’s lymphoma, chronic lymphocytic leukemia, or monoclonal gammopathy; infections such as Mycoplasma pneumoniae, Epstein-Barr virus, mumps, or cytomegalovirus; or other autoimmune disorders such as rheumatoid arthritis or systemic lupus erythematosus.1 

While some studies assert that primary CAD is much more common,6 it is estimated that up to 70% of affected individuals have secondary CAD.1 In another study conducted from 1946 to 1995 in Denmark on 496 individuals with Mycoplasma pneumoniae infections, 407 patients (82%) demonstrated the presence of cold agglutinins, most of whom did not manifest clinically with hemolytic anemia.10

Disease Severity

When determining disease severity, thermal amplitude, or the highest temperature at which agglutination occurs, is considered the most clinically relevant test. Cold agglutinins have a higher thermal amplitude in individuals with CAD (>30 °C).6 

Patients with CAD often have mild to moderate anemia, but the anemia has the potential to become severe. The median hemoglobin level in individuals with CAD living in cool climates is approximately 8.9 g/dL, and several studies of larger, unselected cohorts report that around 40% to 50% of patients with CAD require transfusions.11 


  1. Cold agglutinin disease. National Organization for Rare Disorders. Accessed September 3, 2021. 
  2. Swiecicki PL, Hegerova LT, Gertz MA. Cold agglutinin disease. Blood. 2013;122(7):1114-1121. doi:10.1182/blood-2013-02-474437
  3. Aljubran SA. Cold agglutinin disease: epidemiology. Medscape. Updated August 23, 2021. Accessed September 3, 2021.
  4. Cold agglutinin disease. Orphanet. Updated August 2010. Accessed September 3, 2021.
  5. Brugnara C, Berentsen S. Cold agglutinin disease. UpToDate. Updated April 22, 2021. Accessed September 3, 2021.
  6. Mullins M, Jiang X, Bylsma LC, et al. Cold agglutinin disease burden: a longitudinal analysis of anemia, medications, transfusions, and health care utilization. Blood Adv. 2017;1(13):839-848. doi:10.1182/bloodadvances.2017004390
  7. Berentsen S, Ulvestad E, Langholm R, et al. Primary chronic cold agglutinin disease: a population based clinical study of 86 patients. Haematologica. 2006;91(4):460-466.
  8. Berentsen S, Barcellini W, D’Sa S, et al. Cold agglutinin disease revisited: a multinational, observational study of 232 patients. Blood. 2020;136(4):480-488. doi:10.1182/blood.2020005674
  9. Berentsen S, Bø K, Shammas FV, Myking AO, Ulvestad E. Chronic cold agglutinin disease of the “idiopathic” type is a premalignant or low-grade malignant lymphoproliferative disease. APMIS. 1997;105(5):354-362. doi:10.1111/j.1699-0463.1997.tb00581.x
  10. Lind K, Benzon MW, Jensen JS, Clyde WA Jr. A seroepidemiological study of Mycoplasma pneumoniae infections in Denmark over the 50-year period 1946-1995. Eur J Epidemiol. 1997;13(5):581-586. doi:10.1023/a:1007353121693
  11. Berentsen S, Małecka A, Randen U, Tjønnfjord GE. Cold agglutinin disease: where do we stand, and where are we going? Clin Adv Hematol Oncol. 2020;18(1):35-44.

Reviewed by Debjyoti Talukdar, MD, on 9/7/2021.