Cold agglutinin disease (CAD) is a
rare autoimmune disease
An autoimmune disease is a condition that results from an anomalous response of the adaptive immune system, wherein it mistakenly targets and attacks healthy, functioning parts of the body as if they were foreign organisms. It is estimated tha ...
characterized by the presence of high concentrations of circulating
cold sensitive antibodies
Cold sensitive antibodies (CSA) are antibodies sensitive to cold temperature. Some cold sensitive antibodies are pathological and can lead to blood disorder. These pathological cold sensitive antibodies include cold agglutinins, Donath–Landst ...
, usually
IgM and autoantibodies that are also active at temperatures below ,
directed against
red blood cell
Red blood cells (RBCs), referred to as erythrocytes (, with -''cyte'' translated as 'cell' in modern usage) in academia and medical publishing, also known as red cells, erythroid cells, and rarely haematids, are the most common type of blood cel ...
s, causing them to
agglutinate and undergo
lysis
Lysis ( ; from Greek 'loosening') is the breaking down of the membrane of a cell, often by viral, enzymic, or osmotic (that is, "lytic" ) mechanisms that compromise its integrity. A fluid containing the contents of lysed cells is called a ...
.
It is a form of
autoimmune hemolytic anemia
Autoimmune hemolytic anemia (AIHA) occurs when a person's immune system produces antibodies directed against their own red blood cells (RBCs). These antibodies attach to red cells, causing them to break down ( lyse), and reducing the number of ox ...
, specifically one in which antibodies bind red blood cells only at low body temperatures, typically 28–31 °C.
When affected people's blood is exposed to cold temperatures ( to ), 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.
Cold agglutinin disease was first described in 1957.
Signs and symptoms
Symptoms of cold agglutinin disease (CAD) are often triggered or made worse by cold temperatures or a viral infection. Therefore, symptoms generally are worse during
winter
Winter is the coldest and darkest season of the year in temperate and polar climates. It occurs after autumn and before spring. The tilt of Earth's axis causes seasons; winter occurs when a hemisphere is oriented away from the Sun. Dif ...
months. Symptoms may arise suddenly leading to abrupt onset of severe anemia and hemoglobinuria or develop more gradually and insidiously in the background without patient's consciousness and precaution.
Most people with CAD have symptoms of
hemolytic anemia
Hemolytic anemia or haemolytic anaemia is a form of anemia due to hemolysis, the abnormal breakdown of red blood cells (RBCs), either in the blood vessels (intravascular hemolysis) or elsewhere in the human body (extravascular). This most commonl ...
(destruction of red blood cells, causing low levels of red blood cells).
However, the number of symptoms and severity of symptoms may depend on how severe the anemia is. Signs and symptoms of hemolytic anemia may include:
[ ]
* Tiredness (
fatigue
Fatigue is a state of tiredness (which is not sleepiness), exhaustion or loss of energy. It is a signs and symptoms, symptom of any of various diseases; it is not a disease in itself.
Fatigue (in the medical sense) is sometimes associated wit ...
)
*
Dizziness
Dizziness is an imprecise term that can refer to a sense of disorientation in space, vertigo, or lightheadedness. It can also refer to Balance disorder, disequilibrium or a non-specific feeling, such as giddiness or foolishness.
Dizziness is a ...
*
Headache
A headache, also known as cephalalgia, is the symptom of pain in the face, head, or neck. It can occur as a migraine, tension-type headache, or cluster headache. There is an increased risk of Depression (mood), depression in those with severe ...
s
* Cold hands and feet
*
Pale skin
*
Dark urine
*
Jaundice
Jaundice, also known as icterus, is a yellowish or, less frequently, greenish pigmentation of the skin and sclera due to high bilirubin levels. Jaundice in adults is typically a sign indicating the presence of underlying diseases involving ...
*
Chest pain
Chest pain is pain or discomfort in the chest, typically the front of the chest. It may be described as sharp, dull, pressure, heaviness or squeezing. Associated symptoms may include pain in the shoulder, arm, upper abdomen, or jaw, along with n ...
* Pain in the back or legs
*
Vomiting
Vomiting (also known as emesis, puking and throwing up) is the forceful expulsion of the contents of one's stomach through the mouth and sometimes the nose.
Vomiting can be the result of ailments like food poisoning, gastroenteritis, pre ...
or
diarrhea
Diarrhea (American English), also spelled diarrhoea or diarrhœa (British English), is the condition of having at least three loose, liquid, or watery bowel movements in a day. It often lasts for a few days and can result in dehydration d ...
* Heart problems such as an irregular heartbeat (
arrhythmia
Arrhythmias, also known as cardiac arrhythmias, are irregularities in the cardiac cycle, heartbeat, including when it is too fast or too slow. Essentially, this is anything but normal sinus rhythm. A resting heart rate that is too fast – ab ...
), a
heart murmur
Heart murmurs are unique heart sounds produced when blood flows across a heart valve or blood vessel. This occurs when turbulent blood flow creates a sound loud enough to hear with a stethoscope. The sound differs from normal heart sounds by th ...
, an
enlarged heart, or
heart failure
Heart failure (HF), also known as congestive heart failure (CHF), is a syndrome caused by an impairment in the heart's ability to Cardiac cycle, fill with and pump blood.
Although symptoms vary based on which side of the heart is affected, HF ...
. These may occur because the heart has to work harder to make sure the body gets enough healthy red blood cells.
Many people with CAD also experience pain and bluish coloring of the hands and feet (
acrocyanosis) or
Raynaud's disease
Raynaud syndrome, also known as Raynaud's phenomenon, is a medical condition in which the spasm of small arteries causes episodes of reduced blood flow to end arterioles. Typically the fingers, and, less commonly, the toes, are involved. Rare ...
.
These symptoms result from slow or poor circulation and can range from mild to disabling.
Other signs and symptoms of CAD may include enlargement of the spleen (
splenomegaly
Splenomegaly is an enlargement of the spleen. The spleen usually lies in the left upper quadrant (LUQ) of the human abdomen. Splenomegaly is one of the four cardinal signs of ''hypersplenism'' which include: some reduction in number of circulat ...
) and mottled discoloration of the skin (
livedo reticularis
Livedo reticularis is a common skin finding consisting of a mottled reticulated vascular pattern that appears as a lace-like purplish discoloration of the skin. The discoloration is caused by reduction in blood flow (ischemia) through the arter ...
).
In people with secondary CAD (associated with another underlying condition), there may be additional signs and symptoms depending on the condition present. For example:
''
Mycoplasma pneumoniae'' infection (the most common cause of secondary CAD) may cause
respiratory symptoms.
Various infections or cancers may cause enlarged or
swollen lymph node
Lymphadenopathy or adenopathy is a disease of the lymph nodes, in which they are abnormal in size or consistency. Lymphadenopathy of an inflammation, inflammatory type (the most common type) is lymphadenitis, producing swelling (medical), swolle ...
s.
;80–99% of people have these symptoms:
*
Arthralgia
Arthralgia () literally means ' joint pain'. Specifically, arthralgia is a symptom of injury, infection, illness (in particular arthritis), or an allergic reaction to medication
Medication (also called medicament, medicine, pharmaceuti ...
*
Autoimmunity
In immunology, autoimmunity is the system of immune responses of an organism against its own healthy cells, tissues and other normal body constituents. Any disease resulting from this type of immune response is termed an " autoimmune disease ...
*
Fatigue
Fatigue is a state of tiredness (which is not sleepiness), exhaustion or loss of energy. It is a signs and symptoms, symptom of any of various diseases; it is not a disease in itself.
Fatigue (in the medical sense) is sometimes associated wit ...
*
Hemolytic anemia
Hemolytic anemia or haemolytic anaemia is a form of anemia due to hemolysis, the abnormal breakdown of red blood cells (RBCs), either in the blood vessels (intravascular hemolysis) or elsewhere in the human body (extravascular). This most commonl ...
*
Muscular weakness
*
Pallor
Pallor is a pale color of the skin that can be caused by illness, emotional shock or stress, stimulant use, or anemia, and is the result of a reduced amount of oxyhaemoglobin and may also be visible as pallor of the conjunctivae of the eye ...
;5–29% of people have these symptoms:
*
Abnormal urine color
*
Back pain
Back pain (Latin: ''dorsalgia'') is pain felt in the back. It may be classified as neck pain (cervical), middle back pain (thoracic), lower back pain (lumbar) or coccydynia (tailbone or sacral pain) based on the segment affected. The lumbar area ...
*
Diarrhea
Diarrhea (American English), also spelled diarrhoea or diarrhœa (British English), is the condition of having at least three loose, liquid, or watery bowel movements in a day. It often lasts for a few days and can result in dehydration d ...
*
Headache
A headache, also known as cephalalgia, is the symptom of pain in the face, head, or neck. It can occur as a migraine, tension-type headache, or cluster headache. There is an increased risk of Depression (mood), depression in those with severe ...
*
Hepatomegaly
Hepatomegaly is enlargement of the liver. It is a non-specific sign (medicine), medical sign, having many causes, which can broadly be broken down into infection, hepatic tumours, and metabolic disorder. Often, hepatomegaly presents as an abdomin ...
*
Lymphadenopathy
Lymphadenopathy or adenopathy is a disease of the lymph nodes, in which they are abnormal in size or consistency. Lymphadenopathy of an inflammatory type (the most common type) is lymphadenitis, producing swollen or enlarged lymph nodes. In c ...
*
Nausea
Nausea is a diffuse sensation of unease and discomfort, sometimes perceived as an urge to vomit. It can be a debilitating symptom if prolonged and has been described as placing discomfort on the chest, abdomen, or back of the throat.
Over 30 d ...
and
vomiting
Vomiting (also known as emesis, puking and throwing up) is the forceful expulsion of the contents of one's stomach through the mouth and sometimes the nose.
Vomiting can be the result of ailments like food poisoning, gastroenteritis, pre ...
*
Splenomegaly
Splenomegaly is an enlargement of the spleen. The spleen usually lies in the left upper quadrant (LUQ) of the human abdomen. Splenomegaly is one of the four cardinal signs of ''hypersplenism'' which include: some reduction in number of circulat ...
Cause
Cold agglutinin disease can be either primary (unknown cause
) or secondary (a result of another pathology/ caused by an underlying condition
).
Primary cold agglutinin disease
The primary form is caused by excessive
cell proliferation
Cell proliferation is the process by which ''a cell grows and divides to produce two daughter cells''. Cell proliferation leads to an exponential increase in cell number and is therefore a rapid mechanism of tissue growth. Cell proliferation ...
of
B lymphocytes, characterized by clonal
lymphoproliferative disorder.
Primary cold agglutinin disease occurs after the fifth decade of life and peaks prevalence in a person's 70s and 80s.
Secondary cold agglutinin disease
Secondary cold agglutinin syndrome occurs when
autoantibodies
An autoantibody is an antibody (a type of protein) produced by the immune system that is directed against one or more of the individual's own proteins. Many autoimmune diseases (notably lupus erythematosus) are associated with such antibodies.
Pr ...
bind to
red blood cell
Red blood cells (RBCs), referred to as erythrocytes (, with -''cyte'' translated as 'cell' in modern usage) in academia and medical publishing, also known as red cells, erythroid cells, and rarely haematids, are the most common type of blood cel ...
s, rendering them subject to attack by the
complement system
The complement system, also known as complement cascade, is a part of the humoral, innate immune system and enhances (complements) the ability of antibodies and phagocytic cells to clear microbes and damaged cells from an organism, promote inf ...
.
It is a result of an underlying condition potentially associated with either
monoclonal cold-reacting autoantibodies or
polyclonal cold-reacting autoantibodies predominantly caused by infection or lymphoproliferative disorders.
In adults, this is typically due to:
*
Bacterial infections
Pathogenic bacteria are bacteria that can cause disease. This article focuses on the bacteria that are pathogenic to humans. Most species of bacteria are harmless and many are beneficial but others can cause infectious diseases. The number of t ...
such as
mycoplasma
''Mycoplasma'' is a genus of bacteria that, like the other members of the class ''Mollicutes'', lack a cell wall, and its peptidoglycan, around their cell membrane. The absence of peptidoglycan makes them naturally resistant to antibiotics ...
,
Legionnaires' disease
Legionnaires' disease is a form of atypical pneumonia caused by any species of ''Legionella'' bacteria, quite often ''Legionella pneumophila''. Signs and symptoms include cough, shortness of breath, high fever, myalgia, muscle pains, and headach ...
,
syphilis
Syphilis () is a sexually transmitted infection caused by the bacterium ''Treponema pallidum'' subspecies ''pallidum''. The signs and symptoms depend on the stage it presents: primary, secondary, latent syphilis, latent or tertiary. The prim ...
,
listeriosis
Listeriosis is a bacterial infection most commonly caused by '' Listeria monocytogenes'', although '' L. ivanovii'' and '' L. grayi'' have been reported in certain cases. Listeriosis can cause severe illness, including severe sepsis, me ...
, or ''
E. coli
''Escherichia coli'' ( )Wells, J. C. (2000) Longman Pronunciation Dictionary. Harlow ngland Pearson Education Ltd. is a gram-negative, facultative anaerobic, rod-shaped, coliform bacterium of the genus ''Escherichia'' that is commonly foun ...
''.
*
Viral infection
A viral disease (or viral infection) occurs when an organism's body is invaded by pathogenic viruses, and infectious virus particles (virions) attach to and enter susceptible cells.
Examples include the common cold, gastroenteritis, COVID-19, t ...
s such
Epstein-Barr virus,
cytomegalovirus
''Cytomegalovirus'' (CMV) (from ''cyto-'' 'cell' via Greek - 'container' + 'big, megalo-' + -''virus'' via Latin 'poison') is a genus of viruses in the order '' Herpesvirales'', in the family '' Herpesviridae'', in the subfamily '' Betaherp ...
,
mumps
MUMPS ("Massachusetts General Hospital Utility Multi-Programming System"), or M, is an imperative, high-level programming language with an integrated transaction processing key–value database. It was originally developed at Massachusetts Gen ...
,
varicella,
rubella
Rubella, also known as German measles or three-day measles, is an infection caused by the rubella virus. This disease is often mild, with half of people not realizing that they are infected. A rash may start around two weeks after exposure and ...
,
adenovirus
Adenoviruses (members of the family ''Adenoviridae'') are medium-sized (90–100 nm), nonenveloped (without an outer lipid bilayer) viruses with an icosahedral nucleocapsid containing a double-stranded DNA genome. Their name derives from t ...
,
HIV
The human immunodeficiency viruses (HIV) are two species of '' Lentivirus'' (a subgroup of retrovirus) that infect humans. Over time, they cause acquired immunodeficiency syndrome (AIDS), a condition in which progressive failure of the im ...
,
influenza
Influenza, commonly known as the flu, is an infectious disease caused by influenza viruses. Symptoms range from mild to severe and often include fever, runny nose, sore throat, muscle pain, headache, coughing, and fatigue. These sympto ...
, or
hepatitis C
Hepatitis C is an infectious disease caused by the hepatitis C virus (HCV) that primarily affects the liver; it is a type of viral hepatitis. During the initial infection period, people often have mild or no symptoms. Early symptoms can include ...
.
*
Parasitic infections such as
malaria
Malaria is a Mosquito-borne disease, mosquito-borne infectious disease that affects vertebrates and ''Anopheles'' mosquitoes. Human malaria causes Signs and symptoms, symptoms that typically include fever, Fatigue (medical), fatigue, vomitin ...
or
trypanosomiasis
Trypanosomiasis or trypanosomosis is the name of several diseases in vertebrates caused by parasitic protozoan trypanosomes of the genus ''Trypanosoma''. In humans this includes African trypanosomiasis and Chagas disease. A number of other disea ...
.
* Other
autoimmune disease
An autoimmune disease is a condition that results from an anomalous response of the adaptive immune system, wherein it mistakenly targets and attacks healthy, functioning parts of the body as if they were foreign organisms. It is estimated tha ...
s such as
systemic lupus erythematosus
Lupus, formally called systemic lupus erythematosus (SLE), is an autoimmune disease in which the body's immune system mistakenly attacks healthy tissue in many parts of the body. Symptoms vary among people and may be mild to severe. Common ...
.
* Certain types of cancers such as
lymphoma
Lymphoma is a group of blood and lymph tumors that develop from lymphocytes (a type of white blood cell). The name typically refers to just the cancerous versions rather than all such tumours. Signs and symptoms may include enlarged lymph node ...
,
chronic lymphocytic leukemia
Chronic lymphocytic leukemia (CLL) is a type of cancer that affects the blood and bone marrow. In CLL, the bone marrow makes too many lymphocytes, which are a type of white blood cell. In patients with CLL, B cell lymphocytes can begin to colle ...
,
Waldenström macroglobulinemia
Waldenström macroglobulinemia ( , ) is a type of cancer affecting two types of white blood cells: lymphoplasmacytoid cells and plasma cells (both B cells). It is characterized by having high levels of a circulating antibody, immunoglobulin M (I ...
,
multiple myeloma
Multiple myeloma (MM), also known as plasma cell myeloma and simply myeloma, is a cancer of plasma cells, a type of white blood cell that normally produces antibody, antibodies. Often, no symptoms are noticed initially. As it progresses, bone ...
, and
Kaposi sarcoma.
In children, cold agglutinin disease is often secondary to an infection, such as
''Mycoplasma'' pneumonia,
mononucleosis
Infectious mononucleosis (IM, mono), also known as glandular fever, is an infection usually caused by the Epstein–Barr virus (EBV). Most people are infected by the virus as children, when the disease produces few or no symptoms. In young adu ...
, and
HIV
The human immunodeficiency viruses (HIV) are two species of '' Lentivirus'' (a subgroup of retrovirus) that infect humans. Over time, they cause acquired immunodeficiency syndrome (AIDS), a condition in which progressive failure of the im ...
.
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. However, no disease-causing genes have been identified and no familial cases have been reported.
Pathophysiology
All individuals have circulating antibodies directed against red blood cells, but their concentrations are often too low to trigger disease (
titers under 64 at 4 °C). In individuals with cold agglutinin disease, these antibodies are in much higher concentrations (titers over 1000 at 4 °C).
At body temperatures of 28–31 °C, such as those encountered during winter months, and occasionally at body temperatures of 37 °C, antibodies (generally
IgM) bind to the
polysaccharide
Polysaccharides (), or polycarbohydrates, are the most abundant carbohydrates found in food. They are long-chain polymeric carbohydrates composed of monosaccharide units bound together by glycosidic linkages. This carbohydrate can react with wat ...
region of
glycoprotein
Glycoproteins are proteins which contain oligosaccharide (sugar) chains covalently attached to amino acid side-chains. The carbohydrate is attached to the protein in a cotranslational or posttranslational modification. This process is known a ...
s on the surface of red blood cells (typically the
I antigen or
Pr antigen).
Binding of antibodies to red blood cells activates the classical pathway of the
complement system
The complement system, also known as complement cascade, is a part of the humoral, innate immune system and enhances (complements) the ability of antibodies and phagocytic cells to clear microbes and damaged cells from an organism, promote inf ...
. If the complement response is sufficient, red blood cells are damaged by the
membrane attack complex, an effector of the complement cascade. In the formation of the membrane attack complex, several complement proteins are inserted into the red blood cell membrane, forming pores that lead to membrane instability and intravascular
hemolysis
Hemolysis or haemolysis (), also known by #Nomenclature, several other names, is the rupturing (lysis) of red blood cells (erythrocytes) and the release of their contents (cytoplasm) into surrounding fluid (e.g. blood plasma). Hemolysis may ...
(destruction of the red blood cell within the blood vessels).
If the complement response is insufficient to form membrane attack complexes, then extravascular lysis will be favored over intravascular red blood cell lysis. In lieu of the membrane attack complex, complement proteins (particularly C3b and C4b) are deposited on red blood cells. This
opsonization
Opsonins are extracellular proteins that, when bound to substances or cells, induce phagocytes to phagocytose the substances or cells with the opsonins bound. Thus, opsonins act as tags to label things in the body that should be phagocytosed (i.e. ...
enhances the clearance of red blood cell by
phagocyte
Phagocytes are cells that protect the body by ingesting harmful foreign particles, bacteria, and dead or dying cells. Their name comes from the Greek ', "to eat" or "devour", and "-cyte", the suffix in biology denoting "cell", from the Greek ...
s in the
liver
The liver is a major metabolic organ (anatomy), organ exclusively found in vertebrates, which performs many essential biological Function (biology), functions such as detoxification of the organism, and the Protein biosynthesis, synthesis of var ...
,
spleen
The spleen (, from Ancient Greek '' σπλήν'', splḗn) is an organ (biology), organ found in almost all vertebrates. Similar in structure to a large lymph node, it acts primarily as a blood filter.
The spleen plays important roles in reg ...
, and
lungs
The lungs are the primary organs of the respiratory system in many animals, including humans. In mammals and most other tetrapods, two lungs are located near the backbone on either side of the heart. Their function in the respiratory syste ...
, a process termed extravascular hemolysis.
Individuals with cold agglutinin disease present with signs and symptoms of
hemolytic anemia
Hemolytic anemia or haemolytic anaemia is a form of anemia due to hemolysis, the abnormal breakdown of red blood cells (RBCs), either in the blood vessels (intravascular hemolysis) or elsewhere in the human body (extravascular). This most commonl ...
. Those with secondary agglutinin disease may also present with an underlying disease, often autoimmune.
Diagnosis
Detection of antibodies (cold or warm) and /or complement system on RBC from the patient is a direct
Coombs antiglobulin test. Detection of antibodies in serum of the patient (still circulating in the blood, that have not yet formed any complexes with RBC) is an
indirect Coombs antiglobulin test.
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
A complete blood count (CBC), also known as a full blood count (FBC) or full haemogram (FHG), is a set of medical laboratory tests that provide cytometry, information about the cells in a person's blood. The CBC indicates the counts of white blo ...
(CBC) detects abnormal clumping (
agglutination
In linguistics, agglutination is a morphology (linguistics), morphological process in which words are formed by stringing together morphemes (word parts), each of which corresponds to a single Syntax, syntactic feature. Languages that use agglu ...
) of the red blood cells. In most cases, the diagnosis is based on evidence of
hemolytic anemia
Hemolytic anemia or haemolytic anaemia is a form of anemia due to hemolysis, the abnormal breakdown of red blood cells (RBCs), either in the blood vessels (intravascular hemolysis) or elsewhere in the human body (extravascular). This most commonl ...
(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
The direct and indirect Coombs tests, also known as antiglobulin test (AGT), are blood tests used in immunohematology. The direct Coombs test detects antibodies that are stuck to the surface of the red blood cells. Since these antibodies sometimes ...
) may be performed to determine the presence of a specific type of
antibody
An antibody (Ab) or immunoglobulin (Ig) is a large, Y-shaped protein belonging to the immunoglobulin superfamily which is used by the immune system to identify and neutralize antigens such as pathogenic bacteria, bacteria and viruses, includin ...
. In people with cold agglutinin disease, the Coombs test is almost always positive for
immunoglobulin M
Immunoglobulin M (IgM) is the largest of several isotypes of antibodies (also known as immunoglobulin) that are produced by vertebrates. IgM is the first antibody to appear in the response to initial exposure to an antigen;
causing it to also ...
(
IgM).
Treatment
* Avoid cold weather.
* Treat the underlying lymphoma.
* No cold drinks; all drinks should be at room temperature (or above).
* Requires heater to maintain temperature in cold places.
Treatment with
rituximab
Rituximab, sold under the brand name Rituxan among others, is a monoclonal antibody medication used to treat certain autoimmune diseases and types of cancer. It is used for non-Hodgkin lymphoma, chronic lymphocytic leukemia (in children and ad ...
has been described.
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
An autoimmune disease is a condition that results from an anomalous response of the adaptive immune system, wherein it mistakenly targets and attacks healthy, functioning parts of the body as if they were foreign organisms. It is estimated tha ...
. 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.
In severe cases of
hemolysis
Hemolysis or haemolysis (), also known by #Nomenclature, several other names, is the rupturing (lysis) of red blood cells (erythrocytes) and the release of their contents (cytoplasm) into surrounding fluid (e.g. blood plasma). Hemolysis may ...
, medical interventions may be necessary.
Rituximab
Rituximab, sold under the brand name Rituxan among others, is a monoclonal antibody medication used to treat certain autoimmune diseases and types of cancer. It is used for non-Hodgkin lymphoma, chronic lymphocytic leukemia (in children and ad ...
(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
Plasmapheresis (from the Greek language, Greek πλάσμα, ''plasma'', something molded, and ἀφαίρεσις ''aphairesis'', taking away) is the removal, treatment, and return or exchange of blood plasma or components thereof from and to the ...
, which involves filtering blood to remove antibodies, may be useful in acute hemolytic crisis and before surgery requiring
hypothermia
Hypothermia is defined as a body core temperature below in humans. Symptoms depend on the temperature. In mild hypothermia, there is shivering and mental confusion. In moderate hypothermia, shivering stops and confusion increases. In severe ...
, however its effect is only short term. Removing the spleen is not recommended for cold agglutinin disease. In addition, because severe cold agglutinin disease requires very high doses of
corticosteroids
Corticosteroids are a class of steroid hormones that are produced in the adrenal cortex of vertebrates, as well as the synthetic analogues of these hormones. Two main classes of corticosteroids, glucocorticoids and mineralocorticoids, are invol ...
(levels not considered safe), corticosteroid treatment is no longer a recommended treatment in severe cases.
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.
However more studies need to be performed before the safety and effectiveness of these therapies can be determined.
Sutimlimab (Enjaymo) was approved for medical use in the United States in February 2022.
[ ]
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
Cold is the presence of low temperature, especially in the atmosphere. In common usage, cold is often a subjectivity, subjective perception. A lower bound to temperature is absolute zero, defined as 0.00K on the Kelvin scale, an absolute t ...
is avoided. Those with cold agglutinin disease caused by
HIV infection
The human immunodeficiency virus (HIV) is a retrovirus that attacks the immune system. Without treatment, it can lead to a spectrum of conditions including acquired immunodeficiency syndrome (AIDS). It is a preventable disease. It can ...
or certain types of
cancer
Cancer is a group of diseases involving Cell growth#Disorders, abnormal cell growth with the potential to Invasion (cancer), invade or Metastasis, spread to other parts of the body. These contrast with benign tumors, which do not spread. Po ...
generally have a poor prognosis due to the nature of the underlying condition.
Epidemiology
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
Infectious mononucleosis (IM, mono), also known as glandular fever, is an infection usually caused by the Epstein–Barr virus (EBV). Most people are infected by the virus as children, when the disease produces few or no symptoms. In young adu ...
,
lymphoproliferative diseases, or
mycoplasma pneumonia are more susceptible to this condition.
Cold agglutinin disease represents an estimated 16–32% of
autoimmune hemolytic anemia
Autoimmune hemolytic anemia (AIHA) occurs when a person's immune system produces antibodies directed against their own red blood cells (RBCs). These antibodies attach to red cells, causing them to break down ( lyse), and reducing the number of ox ...
, whose annual incidence is estimated to be between 1/35,000-1/80,000 in
North America
North America is a continent in the Northern Hemisphere, Northern and Western Hemisphere, Western hemispheres. North America is bordered to the north by the Arctic Ocean, to the east by the Atlantic Ocean, to the southeast by South Ameri ...
and
Western Europe
Western Europe is the western region of Europe. The region's extent varies depending on context.
The concept of "the West" appeared in Europe in juxtaposition to "the East" and originally applied to the Western half of the ancient Mediterranean ...
.
In patients with infectious
mononucleosis
Infectious mononucleosis (IM, mono), also known as glandular fever, is an infection usually caused by the Epstein–Barr virus (EBV). Most people are infected by the virus as children, when the disease produces few or no symptoms. In young adu ...
, more than 60% of whom develop cold agglutinins disease.
Primary cold agglutinin disease
In single-center series, primary CAD has been found to account for 13–15% of the cases of
AIHA.
[Dacie J. The auto-immune haemolytic anaemias: Introduction. In: Dacie J, editor. The haemolytic anaemias. vol. 3. London: Churchill Livingstone; 1992. pp. 1–5.] In a population-based clinical study of primary CAD in Norway, the prevalence was found to be 16 per million in habitants and the incidence rate 1 per million inhabitants per year.
Little is known about possible geographic variations. Median age of CAD patients was 76 years and median age at onset of symptoms was approximately 67 years.
The male/female ratio has been reported to be 0.5–0.6 which is not very different from a male/female ratio of 0.72 in an age-matched general population. The frequency of auto-immune disorders other than CAD does probably not differ from what is to be expected in an elderly population with some female predominance.
as about 12.5 years from diagnosis and median age at death was 82 years, which implies a life expectancy in these patients similar to that of an age-matched general population.
More than 90% of patients with primary CAD have Cold-induced circulatory symptoms ranging from moderate acrocyanosis to severe Raynaud phenomena precipitated even by very slight cold exposure.
History
Cold hemagglutination was first reported by Landsteiner in 1903
[Landsteiner K. Über Beziehungen zwischen dem Blutserum und den Körperzellen. Münchener medizinische Wochenschrift. 1903;50:1812–1814.] and found to occur in human beings in 1918.
[Clough MC, Richter IM. A study of an auto-agglutinin occurring in human serum. Johns Hopkins Hosp Bull. 1918;29:86–93.] The association of cold hemagglutination with hemolysis was described in 1937 by Rosenthal and Corten.
[Rosenthal F, Corten M. Über das Phänomen der Auto-hämagglutination und über die Eigenscaften der Kältehämagglutinine. Folia Haematol (Leipzig) 1937;58:64–90.] During the 1960s, Dacie
and Schubothe
published systematic descriptions of 16 CAD patients each. The auto antibodies responsible for hemagglutination at low temperatures, cold agglutinins (CA), may be found in the sera of healthy subjects as well as in patients with AIHA of the cold reactive types.
CA bind to erythrocyte surface antigens at a temperature optimum of 0–4 °C.
In contrast to polyclonal CA in healthy individuals, monoclonal CA often have a high-thermal amplitude, which contributes to their pathogenicity at temperatures approaching 37 °C.
Binding of CA causes agglutination of erythrocytes
and the antigen–antibody complex induces complement (C) activation and hemolysis.
Essential clinical manifestations of primary CAD are hemolytic anemia and cold-induced circulatory symptoms.
Exact estimates of the severity of anemia and the frequency of cold-induced symptoms, however, have not been provided until recent years.
See also
*
Cold shock response
*
Donath–Landsteiner hemolytic anemia
*
List of hematologic conditions
*
Paroxysmal cold hemoglobinuria
Paroxysmal cold hemoglobinuria (PCH) or Donath–Landsteiner hemolytic anemia (DLHA) is an autoimmune hemolytic anemia featured by complement-mediated intravascular hemolysis after cold exposure. It can present as an acute non-recurrent postinfec ...
*
Warm antibody autoimmune hemolytic anemia
References
External links
{{Authority control
Autoimmune diseases
Acquired hemolytic anemia
Cold autoimmune hemolytic anemia