A common complaint among patients with cold agglutinin disease is painful fingers and toes with purplish discoloration associated with cold exposure. In chronic cold agglutinin disease, the patient is more symptomatic during the colder months.

Cold agglutinin mediated acrocyanosis differs from Raynaud phenomenon. In Raynaud phenomena, caused by vasospasm, a triphasic color change occurs, from white to blue to red, based on vasculature response. No evidence of such a response exists in cold agglutinin disease.

Other symptoms

- Respiratory symptoms: May be present in patients with "M pneumoniae" infection.

- Hemoglobinuria (the passage of dark urine that contains hemoglobin), A rare symptom that results from hemolysis, this may be reported following prolonged exposure to cold, hemoglobinuria is more commonly seen in paroxysmal cold hemoglobinuria.

- Chronic fatigue, Due to anemia.

Cold agglutinin disease is an autoimmune disease characterized by the presence of high concentrations of circulating antibodies, usually IgM, directed against red blood cells. It is a form of autoimmune hemolytic anemia, specifically one in which antibodies only bind red blood cells at low body temperatures, typically 28–31 °C.

Cold agglutinin disease was first described in 1957.

Cold autoimmune hemolytic anemia caused by cold-reacting autoantibodies. Autoantibodies that bind to the erythrocyte membrane leading to premature erythrocyte destruction (hemolysis) characterize autoimmune hemolytic anemia.

Cold agglutinin disease can be either primary (arising spontaneously) or secondary (a result of another pathology).

- The primary form is caused by excessive cell proliferation of B lymphocytes.

- Secondary cold agglutinin disease is a result of an underlying condition.

- In adults, this is typically due to a lymphoproliferative disease such as lymphoma and chronic lymphoid leukemia, or infection. Waldenström's macroglobulinemia may also be positive for cold agglutinins.

- In children, cold agglutinin disease is often secondary to an infection, such as "Mycoplasma" pneumonia, mononucleosis, and HIV.

Warm antibody autoimmune hemolytic anemia (WAIHA) is the most common form of autoimmune hemolytic anemia. About half of the cases are of unknown cause, with the other half attributable to a predisposing condition or medications being taken. Contrary to cold autoimmune hemolytic anemia (e.g., cold agglutinin disease and paroxysmal cold hemoglobinuria) which happens in cold temperature (28–31 °C), WAIHA happens at body temperature.

Acute PCH tends to be transient and self-limited, particularly in children. Chronic PCH associated with syphilis resolves after the syphilis is treated with appropriate antibiotics. Chronic idiopathic PCH is usually mild.

People with PCH, a polyclonal IgG anti-P autoantibody binds to red blood cell surface antigens in the cold. This can occur in a susceptible individual as blood passes through cold extremities in cold weather. When the blood returns to the warmer central circulation, the red blood cells are lysed with complement, causing intravascular hemolysis. Hemoglobinuria and anemia can then occur. The anemia may be mild or severe.

AIHA may be:

- Idiopathic, that is, without any known cause

- Secondary to another disease, such as an antecedent upper respiratory tract infection, systemic lupus erythematosus or a malignancy, such as chronic lymphocytic leukemia (CLL)

Autoimmune hemolytic anemia (or autoimmune haemolytic anaemia; AIHA) occurs when antibodies directed against the person's own red blood cells (RBCs) cause them to burst (lyse), leading to an insufficient number of oxygen-carrying red blood cells in the circulation. The lifetime of the RBCs is reduced from the normal 100–120 days to just a few days in serious cases. The intracellular components of the RBCs are released into the circulating blood and into tissues, leading to some of the characteristic symptoms of this condition. The antibodies are usually directed against high-incidence antigens, therefore they also commonly act on allogenic RBCs (RBCs originating from outside the person themselves, e.g. in the case of a blood transfusion). AIHA is a relatively rare condition, affecting one to three people per 100,000 per year.

The terminology used in this disease is somewhat ambiguous. Although MeSH uses the term "autoimmune hemolytic anemia", some sources prefer the term "immunohemolytic anemia" so drug reactions can be included in this category. The National Cancer Institute considers "immunohemolytic anemia", "autoimmune hemolytic anemia", and "immune complex hemolytic anemia" to all be synonyms.

AIHA is classified as either warm autoimmune hemolytic anemia or cold autoimmune hemolytic anemia, which includes cold agglutinin disease and paroxysmal cold hemoglobinuria. These classifications are based on the characteristics of the autoantibodies involved in the pathogenesis of the disease. Each has a different underlying cause, management, and prognosis, making classification important when treating a patient with AIHA.

Acquired hemolytic anemia can be divided into immune and non-immune mediated forms of hemolytic anemia.

Drug induced hemolysis has large clinical relevance. It occurs when drugs actively provoke red blood cell destruction. It can be divided in the following manner:

- Drug-induced autoimmune hemolytic anemia

- Drug-induced nonautoimmune hemolytic anemia

A total of four mechanisms are usually described, but there is some evidence that these mechanisms may overlap.

The signs and symptoms in the increasingly rare cases of cryoglobulinemic disease that cannot be attributed to an underlying disease generally resemble those of patients suffering Type II and III (i.e. mixed) cryoglobulinemic disease.

Cryoglobulinemia, cryoglobulinaemia, or cryoglobulinemic disease, is a medical condition in which the blood contains large amounts of cryoglobulins – proteins (mostly immunoglobulins themselves) that become insoluble at reduced temperatures. This should be contrasted with cold agglutinins, which cause agglutination of red blood cells.

Cryoglobulins typically precipitate at temperatures below normal body temperatureand will dissolve again if the blood is heated. The precipitated clump can block blood vessels and cause toes and fingers to become gangrenous. While this disease is commonly referred to as cryoglobulinemia in the medical literature, it is better termed cryoglobulinemic disease for two reasons: 1) cryoglobulinemia is also used to indicate the circulation of (usually low levels of) cryoglobulins in the absence of any symptoms or disease and 2) healthy individuals can develop transient asymptomatic cryoglobulinemia following certain infections.

In contrast to these benign instances of circulating cryoglobulins, cryoglobulinemic disease involves the signs and symptoms of precipitating cryoglobulins and is commonly associated with various pre-malignant, malignant, infectious, or autoimmune diseases that are the underlying cause for production of the cryoglobulins.

A broad range of autoimmune diseases have been reported to be associated with cryofibrinogenemia. These diseases include systemic lupus erythematosis, Sjorgren's syndrome, rheumatoid arthritis, mixed connective tissue disease, polymyositis, dermatomyositis, systemic sclerosis, antiphospholipid antibody syndrome, Hashimoto disease, Graves disease, sarcoidosis, pyoderma gangrenosum, spondyloarthropathy, Crohn disease, and ulcerative colitis.

Cryofibrinogenmic disease commonly begins in adults aged 40–50 years old with symptoms of the diseases occurring in the almost always affected organ, skin. Cutaneous symptoms include on or more of the following: cold contact-induced urticarial (which may be the first sign of the disease); painful episodes of finger and/or toe arterial spasms termed Ranaud phenomena; cyanosis, s palpable purpura termed Cryofibrinogenemic purpura), and a lace-like purplish discoloration termed livedo reticularis all of which occur primarily in the lower extremities but some of which may occur in the nose, ears, and buttocks; non-healing painful ulcerations and gangrene of the areas impacted by the cited symptoms. Patients also have a history of cold sensitivity (~25% of cases), arthralgia (14-58%), neuritis (7-19%), myalgia (0-14%); and overt thrombosis of arteries and veins (25-40%) which may on rare occasions involve major arteries such of those of the brain and kidney. Signs of renal involvement (proteinuria, hematuria, decreased glomerular filtration rate, and/or, rarely, renal failure) occur in 4-25% of cases. Compared to secondary cryofibrinogemia, primary crygofibrinogenemia has a higher incidence of cutaneous lesions, arthralgia, and cold sensitivity while having a far lower incidence of renal involvement. Patients with secondary cryofibrinogenemia also exhibit signs and symptoms specific to the infectious, malignant, premalignant vasculitis, and autoimmune disorders associated with their disease. While rare, individuals with cryofibrinogemic disease may experience pathological bleeding due to the consumption of blood clotting factors consequential to the formation of cryofibrinogen precipitates.

The typical symptoms of a cold include a cough, a runny nose, nasal congestion and a sore throat, sometimes accompanied by muscle ache, fatigue, headache, and loss of appetite. A sore throat is present in about 40% of cases and a cough in about 50%, while muscle ache occurs in about half. In adults, a fever is generally not present but it is common in infants and young children. The cough is usually mild compared to that accompanying influenza. While a cough and a fever indicate a higher likelihood of influenza in adults, a great deal of similarity exists between these two conditions. A number of the viruses that cause the common cold may also result in asymptomatic infections.

The color of the sputum or nasal secretion may vary from clear to yellow to green and does not indicate the class of agent causing the infection.

A cold usually begins with fatigue, a feeling of being chilled, sneezing, and a headache, followed in a couple of days by a runny nose and cough. Symptoms may begin within sixteen hours of exposure and typically peak two to four days after onset. They usually resolve in seven to ten days, but some can last for up to three weeks. The average duration of cough is eighteen days and in some cases people develop a post-viral cough which can linger after the infection is gone. In children, the cough lasts for more than ten days in 35–40% of cases and continues for more than 25 days in 10%.

Infectious mononucleosis mainly affects younger adults. When older adults do catch the disease, they less often have characteristic signs and symptoms such as the sore throat and lymphadenopathy. Instead, they may primarily experience prolonged fever, fatigue, malaise and body pains. They are more likely to have liver enlargement and jaundice. People over 40 years of age are more likely to develop serious illness. (See Prognosis.)

In adolescence and young adulthood, the disease presents with a characteristic triad:

- Fever – usually lasting 14 days; often mild

- Sore throat – usually severe for 3–5 days, before resolving in the next 7–10 days.

- Swollen glands – mobile; usually located around the back of the neck (posterior cervical lymph nodes) and sometimes throughout the body.

Another major symptom is feeling tired. Headaches are common, and abdominal pains with nausea or vomiting sometimes also occur. Symptoms most often disappear after about 2–4 weeks. However, fatigue and a general feeling of being unwell (malaise) may sometimes last for months. Fatigue lasts more than one month in an estimated 28% of cases. Mild fever, swollen neck glands and body aches may also persist beyond 4 weeks. Most people are able to resume their usual activities within 2–3 months.

The most prominent sign of the disease is often the pharyngitis, which is frequently accompanied by enlarged tonsils with pus—an exudate similar to that seen in cases of strep throat. In about 50% of cases, small reddish-purple spots called petechiae can be seen on the roof of the mouth. Palatal enanthem can also occur, but is relatively uncommon.

Spleen enlargement is common in the second and third weeks, although this may not be apparent on physical examination. Rarely the spleen may rupture. There may also be some enlargement of the liver. Jaundice occurs only occasionally.

A small minority of people spontaneously present a rash, usually on the arms or trunk, which can be macular (morbilliform) or papular. Almost all people given amoxicillin or ampicillin eventually develop a generalized, itchy maculopapular rash, which however does not imply that the person will have adverse reactions to penicillins again in the future. Occasional cases of erythema nodosum and erythema multiforme have been reported.

In general, signs of anemia (pallor, fatigue, shortness of breath, and potential for heart failure) are present. In small children, failure to thrive may occur in any form of anemia. Certain aspects of the medical history can suggest a cause for hemolysis, such as drugs, consumption of fava beans due to Favism, the presence of prosthetic heart valve, or other medical illness.

Chronic hemolysis leads to an increased excretion of bilirubin into the biliary tract, which in turn may lead to gallstones. The continuous release of free hemoglobin has been linked with the development of pulmonary hypertension (increased pressure over the pulmonary artery); this, in turn, leads to episodes of syncope (fainting), chest pain, and progressive breathlessness. Pulmonary hypertension eventually causes right ventricular heart failure, the symptoms of which are peripheral edema (fluid accumulation in the skin of the legs) and ascites (fluid accumulation in the abdominal cavity).

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, but usually in the spleen). It has numerous possible consequences, ranging from relatively harmless to life-threatening. The general classification of hemolytic anemia is either inherited or acquired. Treatment depends on the cause and nature of the breakdown.

Symptoms of hemolytic anemia are similar to other forms of anemia (fatigue and shortness of breath), but in addition, the breakdown of red cells leads to jaundice and increases the risk of particular long-term complications, such as gallstones and pulmonary hypertension.

The syndromes within CAPS overlap clinically, and patients may have features of more than one disorder. In a retrospective cohort of 136 CAPS patients from 16 countries, the most prevalent clinical features were fever (84% of cases, often with concurrent constitutional symptoms such as fatigue, malaise, mood disorders or failure to thrive), skin rash (either urticarial or maculopapular rash; 97% of cases) especially after cold exposure, and musculoskeletal involvement (myalgia, arthralgia, and/or arthritis, or less commonly joint contracture, patellar overgrowth, bone deformity, bone erosion and/or osteolytic lesion; 86% of cases). Less common features included ophthalmological involvement (conjunctivitis and/or uveitis, or less commonly optic nerve atrophy, cataract, glaucoma or impaired vision; 71% of cases), neurosensory hearing loss (42% of cases), neurological involvement (morning headache, papilloedema, and/or meningitis, or less commonly seizure, hydrocephalus or mental retardation; 40% of cases), and AA amyloidosis (4% of cases). Age of onset is typically in infancy or early childhood. In 57% of cases, CAPS had a chronic phenotype with symptoms present almost daily, whereas the remaining 43% of patients experienced only acute episodes. Up to 56% of patients reported a family history of CAPS. Previous studies confirm these symptoms, although the exact reported rates vary.

Cryopyrin-associated periodic syndrome (CAPS) is a group of rare, heterogeneous autoinflammatory disease characterized by interleukin 1β-mediated systemic inflammation and clinical symptoms involving skin, joints, central nervous system, and eyes. It encompasses a spectrum of three clinically overlapping autoinflammatory syndromes including familial cold autoinflammatory syndrome (FCAS, formerly termed familial cold-induced urticaria), the Muckle–Wells syndrome (MWS), and neonatal-onset multisystem inflammatory disease (NOMID, also called chronic infantile neurologic cutaneous and articular syndrome or CINCA) that were originally thought to be distinct entities, but in fact share a single genetic mutation and pathogenic pathway.

Autoimmunity is the system of immune responses of an organism against its own healthy cells and tissues. Any disease that results from such an aberrant immune response is termed an "autoimmune disease". Prominent examples include celiac disease, diabetes mellitus type 1, sarcoidosis, systemic lupus erythematosus (SLE), Sjögren's syndrome, eosinophilic granulomatosis with polyangiitis, Hashimoto's thyroiditis, Graves' disease, idiopathic thrombocytopenic purpura, Addison's disease, rheumatoid arthritis (RA), ankylosing spondylitis, polymyositis (PM), dermatomyositis (DM) and multiple sclerosis (MS). Autoimmune diseases are very often treated with steroids.