Cold Agglutinin Disease (CAD)

Cold agglutinin disease (CAD) is classified as primary or secondary if it is caused by an underlying condition such as infection or malignancy.1 

Genetics and Geography

CAD, a type of autoimmune hemolytic anemia (AIHA), is not an inherited disease, and no genes have been implicated thus far in the pathogenesis. In addition, no familial cases have been reported.2 Prevalence is up to 4 times higher in regions with colder climates. Many patients have subclinical disease and may remain undiagnosed in warm regions of the world, explaining this geographical discrepancy.3 


Epstein-Barr virus infection results in infectious mononucleosis, which is associated with the production of cold-type autoantibodies.4 Hemolysis is rare and experienced by 1% to 3% of hospitalized patients. Hemolysis plus hepatic dysfunction may prompt investigation for underlying Epstein-Barr virus infection, especially if a direct antiglobulin test is positive for C3d.5

Mycoplasma pneumoniae infection is also associated with CAD, as well as warm autoimmune hemolytic anemia. Hemolysis occurs during 2 to 3 weeks of illness and has a good prognosis, but severe cases resulting in death have been reported.6 Data for AIHA are in the form of case reports, and frequency has not been concretely established. 

Other infections associated with CAD include cytomegalovirus, hepatitis B and C, and HIV. Screening for these conditions is recommended for the initial workup of patients with any type of autoimmune hemolytic anemia.3 Tuberculosis infection has also been described as a precipitating factor, and screening for tuberculosis is also recommended by some.7 Parvovirus B19, Treponema pallidum, Brucella, hepatitis A, and respiratory syncytial virus have also been described as precipitants in case reports.3 

Autoimmune Disorders

Systemic lupus erythematosus is associated with some form of AIHA in 3% to 14% of cases and is of higher prevalence in infants compared with adult patients. Patients with Sjogren syndrome also develop AIHA in 2.8% of cases, and in most cases, a direct antiglobulin test is negative. Rarely, patients with inflammatory bowel disease, particularly ulcerative colitis, develop AIHA (4.1 out of 100,000 patients). There are case reports of patients with autoimmune thyroiditis and systemic sclerosis who develop AIHA.7

Underlying Malignancy

Previously, lymphoplasmacytic lymphoma was described as the underlying cause of CAD in up to 75% of cases. Using immunohistochemistry, flow cytometry, and gene sequencing analysis, it was revealed that biopsy specimens of patients with CAD had unique characteristics and therefore were categorized as a distinct entity: primary CAD-associated lymphoproliferative disorder. Furthermore, testing for the MYD88 L265P mutation, which is commonly seen in lymphoplasmacytic lymphoma, was negative in the tested samples.8 The probability of transformation to aggressive lymphoma is approximately 3.5% during 10 years.9 Common late-onset hematologic malignancies include diffuse large B-cell lymphoma, acute myelogenous leukemia, acute lymphocytic leukemia, and myelodysplastic syndrome. Some patients also develop late-onset solid tumors.10 

Post Allogeneic Hematopoietic Stem Cell Transplant

Following allogeneic hematopoietic stem cell transplant, AIHA (cold or warm) has an incidence of between 4% to 6%.11 


  1. Michalak SS, Olewicz-Gawlik A, Rupa-Matysek J, Wolny-Rokicka E, Nowakowska E, Gil L. Autoimmune hemolytic anemia: current knowledge and perspectives. Immun Ageing A. 2020;17:38. doi:10.1186/s12979-020-00208-7
  2. Cold agglutinin disease. Genetic and Rare Diseases Information Center (GARD) – an NCATS Program. Accessed September 2, 2021. 
  3. Jäger U, Barcellini W, Broome CM, et al. Diagnosis and treatment of autoimmune hemolytic anemia in adults: recommendations from the first international consensus meeting. Blood Rev. 2020;41:100648. doi:10.1016/j.blre.2019.100648
  4. Dematapitiya C, Perera C, Chinthaka W, et al. Cold type autoimmune hemolytic anemia- a rare manifestation of infectious mononucleosis; serum ferritin as an important biomarker. BMC Infect Dis. 2019;19:68. doi:10.1186/s12879-019-3722-z
  5. Mantadakis E, Chatzimichael E, Kontekaki E, Panopoulou M, Martinis G, Tsalkidis A. EBV-related cold agglutinin disease presenting with conjugated hyperbilirubinemia: a pediatric case report and mini review. J Pediatr Hematol Oncol. 2019;41(4):324-327. doi:10.1097/MPH.0000000000001184
  6. Han X, He B, Wang F. Mycoplasma pneumonia associated with hemolytic anemia: case report and literature review. Zhonghua Jie He He Hu Xi Za Zhi Zhonghua Jiehe He Huxi Zazhi Chin J Tuberc Respir Dis. 2011;34(11):832-836.
  7. Barcellini W, Giannotta J, Fattizzo B. Autoimmune hemolytic anemia in adults: primary risk factors and diagnostic procedures. Expert Rev Hematol. 2020;13(6):585-597. doi:10.1080/17474086.2020.1754791
  8. Randen U, Trøen G, Tierens A, et al. Primary cold agglutinin-associated lymphoproliferative disease: a B-cell lymphoma of the bone marrow distinct from lymphoplasmacytic lymphoma. Haematologica. 2014;99(3):497-504. doi:10.3324/haematol.2013.091702
  9. 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.
  10. 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
  11. Barcellini W, Fattizzo B, Zaninoni A. Management of refractory autoimmune hemolytic anemia after allogeneic hematopoietic stem cell transplantation: current perspectives. J Blood Med. 2019;10:265-278. doi:10.2147/JBM.S190327

Reviewed by Harshi Dhingra, MD, on 9/7/2021.