Cold agglutinin disease

Title

Other Names:

Anemia, hemolytic, cold antibody; Cold antibody hemolytic anemia; Cold antibody disease; Anemia, hemolytic, cold antibody; Cold antibody hemolytic anemia; Cold antibody disease; CAD See More

Categories:

Blood Diseases

Summary Summary

Cold agglutinin disease is a rare type of autoimmune hemolytic anemia in which the body's immune system mistakenly attacks and destroys its own red blood cells. When affected people's blood is exposed to cold temperatures (32º to 50º F), certain proteins that normally attack bacteria (IgM antibodies) attach themselves to red blood cells and bind them together into clumps (agglutination). This eventually causes red blood cells to be prematurely destroyed (hemolysis) leading to anemia and other associated signs and symptoms. Cold agglutinin disease can be primary (unknown cause) or secondary, due to an underlying condition such as an infection, another autoimmune disease, or certain cancers. Treatment depends on many factors including the severity of the condition, the signs and symptoms present in each person, and the underlying cause.^[1]^[2]^[3]

Last updated: 5/26/2016

Symptoms Symptoms

Cold agglutinin disease is a rare type of autoimmune hemolytic anemia in which the body's immune system mistakenly attacks and destroys its own red blood cells. When affected people's blood is exposed to cold temperatures (32º to 50º F), certain proteins that normally attack bacteria (IgM antibodies) attach themselves to red blood cells and bind them together into clumps (agglutination). The antibodies then activate other components of the blood, which eventually causes red blood cells to be prematurely destroyed. As the number or red blood cells drop, affected people typically experience anemia, which may be associated with pallor, weakness, fatigue, irritability, headaches, and/or dizziness.^[2]

Other signs and symptoms of cold agglutinin disease vary, but may include:^[1]^[2]^[3]

Painful fingers and toes with purplish discoloration
Abnormal behavior
Amenorrhea
Gastrointestinal issues
Dark urine
Enlargement of the spleen
Jaundice
Heart failure
Shock

Last updated: 5/26/2016

The Human Phenotype Ontology (HPO) provides the following list of features that have been reported in people with this condition. Much of the information in the HPO comes from Orphanet, a European rare disease database. If available, the list includes a rough estimate of how common a feature is (its frequency). Frequencies are based on a specific study and may not be representative of all studies. You can use the MedlinePlus Medical Dictionary for definitions of the terms below.

Signs and Symptoms	Approximate number of patients (when available)
Arthralgia	90%
Autoimmunity	90%
Hemolytic anemia	90%
Muscle weakness	90%
Pallor	90%
Abnormality of urine homeostasis	7.5%
Diarrhea	7.5%
Hepatomegaly	7.5%
Lymphadenopathy	7.5%
Migraine	7.5%
Nausea and vomiting	7.5%
Splenomegaly	7.5%

Last updated: 9/1/2016

Cause Cause

Cold agglutinin disease is typically classified as primary (unknown cause) or secondary (caused by an underlying condition). Secondary cold agglutinin disease may be associated with:^[1]^[3]

Bacterial Infections such as mycoplasma, Legionnaires' disease, syphilis, listeriosis, or E. Coli
Viral infections such Epstein-Barr virus, cytomegalovirus, mumps, varicella, rubella, adenovirus, HIV, influenza, or hepatitis C
Parasitic infections such as malaria or trypanosomiasis
Other autoimmune diseases such as systemic lupus erythematosus
Certain types of cancers such as lymphoma, chronic lymphocytic leukemia, Waldenström macroglobulinemia, multiple myeloma, and Kaposi sarcoma

Last updated: 5/26/2016

Inheritance Inheritance

Cold agglutinin disease is not an inherited condition. It is designated as either primary (unknown cause) or secondary (associated with or caused by another condition). In some cases, cold agglutinin may be multifactorial which means that multiple environmental factors and genes likely interact to predispose a person to developing the condition.^[4] However, to our knowledge, no disease-causing genes have been identified and no familial cases have been reported.

Last updated: 5/26/2016

Diagnosis Diagnosis

A diagnosis of cold agglutinin disease may be made after several types of tests are performed by a health care provider. In some cases, the diagnosis is first suspected by chance if a routine complete blood count (CBC) detects abnormal clumping (agglutination) of the red blood cells. In most cases, the diagnosis is based on evidence of hemolytic anemia (from symptoms and/or blood tests). A person may also be physically examined for spleen or liver enlargement. An antiglobulin test (called the Coombs test) may be performed to determine the presence of a specific type of antibody. In people with cold agglutinin disease, the Coomb's test is almost always positive for immunoglobulin M (IgM).^[1]^[2]

Detailed information about the various tests used to make a diagnosis of cold agglutinin disease is available on Medscape Reference's website. Please click on the link to access this resource.

Last updated: 5/26/2016

Treatment Treatment

The treatment of cold agglutinin disease depends on many factors including the severity of the condition, the signs and symptoms present in each person, and the underlying cause. For example, in those affected by secondary cold agglutinin disease, it is important to diagnose and treat the underlying condition which may include certain types of cancer; bacterial, viral, or parasitic infections; and/or other autoimmune disease. People with few symptoms and/or mild anemia may not require any specific treatment. These cases are often managed by simply avoiding exposure to the cold. ^[3]^[5]

In severe cases of hemolysis, medical interventions may be necessary. Rituximab (an antibody that selectively reduces specific types of immune cells) is effective in about 60% of cases of severe cold agglutinin disease. Medical researchers have found the response to rituximab is seen on average within 1 to 2 months of treatment and the effect of the treatment lasts for about 1 to 2 years. Rituximab may be used after a second and even a third relapse, however the success rate is less. Combined treatment with rituximab and fludarabine has resulted in higher response rates (76% of cases) and longer periods of remissions (on average, 6.5 years). However the combined treatment may include serious side effects so is presently only recommended when rituximab has not worked alone. Finally, plasmapheresis, which involves filtering blood to remove antibodies, may be useful in acute hemolytic crisis and before surgery requiring hypothermia, however its effect is only short term. It should be noted, removing the spleen is not recommended for cold agglutinin disease. In addition, because severe cold agglutinin disease requires very high doses of corticosteroids (levels not considered safe), corticosteroid treatment is no longer a recommended treatment in severe cases.^[3]^[5]

Several possible therapies have been reported in a few case reports to have successfully treated people who are not responding to the treatments listed above.^[3]^[5] However more studies need to be performed before the safety and effectiveness of these therapies can be determined. Click the link to view the therapies presently being studied in cold agglutinin clinical trials.

Last updated: 5/26/2016

Prognosis Prognosis

The long-term outlook (prognosis) for people with cold agglutinin disease varies based on many factors including the severity of the condition, the signs and symptoms present in each person and the underlying cause. For example, people with cold agglutinin disease caused by bacterial or viral infections tend to have an excellent prognosis; in these cases, the symptoms typically disappear within 6 months after the infection has resolved. Mild to moderate primary (unknown cause) cold agglutinin disease can also be associated with a good prognosis if excessive exposure to the cold is avoided. Those with cold agglutinin disease caused by HIV infection or certain types of cancer generally have a poor prognosis due to the nature of the underlying condition.^[1]

Last updated: 5/26/2016

Statistics Statistics

Cold agglutinin disease most commonly affects adults who are of middle age and older. Some studies also report a slight bias in favor of females in the incidence of cold agglutinin disease, particularly in older populations. People with infectious mononucleosis, lymphoproliferative diseases, or mycoplasma pneumonia are more susceptible to this condition.^[1]^[2]^[3]

Last updated: 5/26/2016

Research Research

Research helps us better understand diseases and can lead to advances in diagnosis and treatment. This section provides resources to help you learn about medical research and ways to get involved.

Clinical Research Resources

ClinicalTrials.gov lists trials that are studying or have studied Cold agglutinin disease. Click on the link to go to ClinicalTrials.gov to read descriptions of these studies.

Organizations Organizations

Nonprofit support and advocacy groups bring together patients, families, medical professionals, and researchers. These groups often raise awareness, provide support, and develop patient-centered information. Many are the driving force behind research for better treatments and possible cures. They can direct people to research, resources, and services. Many groups also have experts who serve as medical advisors. Visit their website or contact them to learn about the services they offer. Inclusion on this list is not an endorsement by GARD. Suggest an organization to add.

Organizations Supporting this Disease

American Autoimmune Related Diseases Association (AARDA)
22100 Gratiot Avenue Eastpointe
East Detroit, MI 48201-2227
Toll-free: 800-598-4668
Telephone: 586-776-3900
Fax: 586-776-3903
E-mail: aarda@aarda.org
Website: http://www.aarda.org/

Social Networking Websites

Visit the CADdy chatter group on Facebook.

Cold Agglutinin Disease (CAD) Support Site
E-mail: Kolbysmum@aol.com
Website: http://coldagglutinindisease.org/

Learn More Learn More

These resources provide more information about this condition or associated symptoms. The in-depth resources contain medical and scientific language that may be hard to understand. You may want to review these resources with a medical professional.

Where to Start

The Merck Manual provides information on this condition for patients and caregivers.
The National Organization for Rare Disorders (NORD) has a report for patients and families about this condition. NORD is a patient advocacy organization for individuals with rare diseases and the organizations that serve them.

In-Depth Information

Medscape Reference provides information on this topic. You may need to register to view the medical textbook, but registration is free.
The Merck Manual for health care professionals provides information on Cold agglutinin disease.
MeSH® (Medical Subject Headings) is a terminology tool used by the National Library of Medicine. Click on the link to view information on this topic.
The Monarch Initiative brings together data about this condition from humans and other species to help physicians and biomedical researchers. Monarch’s tools are designed to make it easier to compare the signs and symptoms (phenotypes) of different diseases and discover common features. This initiative is a collaboration between several academic institutions across the world and is funded by the National Institutes of Health. Visit the website to explore the biology of this condition.
Orphanet is a European reference portal for information on rare diseases and orphan drugs. Access to this database is free of charge.
PubMed is a searchable database of medical literature and lists journal articles that discuss Cold agglutinin disease. Click on the link to view a sample search on this topic.

News & Events News & Events

NCATS Co-Sponsored Conferences

20th Congress of the International Organization for Mycoplasmology (IOM) Sunday, June 1, 2014 - Friday, June 6, 2014
Location: Federal Universidade Regional de Blumenau , Santa Catarina, Brazil
Description: The Congress provides a unique international forum to exchange scientific findings, discuss recent research progress, identify areas requiring greater emphasis, set research goals for the next biennium, recognize outstanding achievement in the field, and promote the study of mycoplasmas to young scientists. The Congress is also significant because it creates important opportunities for career development, networking and formal international recognition of early career achievements by the next generation of mycoplasmologists. Direct international exchange of new findings on the biology, epidemiology and control of these pathogens is contributing to improved diagnostics and intervention strategies necessary to reduce the substantial burden of infectious diseases involving these organisms, and helps to excite and create career opportunities for rising young biomedical scientists.

Contact: Barbara L. Mulach, Ph.D.,(301) 402-4199,bmulach@niaid.nih.gov

Co-funding Institute(s): National Institute of Allergy and Infectious Diseases, Office of Rare Diseases Research

GARD Answers GARD Answers

Questions sent to GARD may be posted here if the information could be helpful to others. We remove all identifying information when posting a question to protect your privacy. If you do not want your question posted, please let us know. Submit a new question

Is there a genetic component to CAD? My mother has it so we're naturally curious. See answer
Are there any tests that can be done to identify the presence of a cold agglutinin disorder in a patient? It is helpful to know what populations of patients might have a predisposition for the disorder. However, should one identify a patient who might fall into that catagory, is there a way to identify the presence of the disorder? See answer
What is the difference between cryoglobulinemia and cold agglutinin disease? See answer