Acquired Cold Urticaria: Pathogenesis and Management

Introduction:

Urticaria, frequently called hives, is an allergic skin rash triggered by certain foods, medication, stress, and irritants. Chronic urticaria (urticaria for more than six weeks) is divided into chronic inducible urticaria (CIndU) and chronic spontaneous urticaria (CSU). Cold urticaria (CU) is the most prevalent (common) type of CIndU caused by exposure to intense cold. The symptoms include erythema (abnormal reddish skin discoloration), hives, and itching. There are two forms of CU: acquired cold urticaria and hereditary cold urticaria.

What Is the Disease Mechanism of Acquired Cold Urticaria?

Acquired cold urticaria is a type I hypersensitivity reaction involving IgE antibodies (a protein released in response to allergy), mast cells (an immune cell), and inflammatory mediators release (essential components of allergic inflammation). Although several theories exist regarding the disease mechanism of acquired cold urticaria, none is proven. Various studies support the autoimmune theory. Weals (a raised red mark on the skin) and angioedema (tissue swelling) in acquired cold urticaria involve mast cell degranulation (which releases histamine, a chemical involved in allergic immune response and cytokines; immune mediators) with the generation of inflammatory mediators.

These mediators induce vasodilatation (dilation of blood vessels), increased vessel permeability, and nerve endings stimulation. As a result, it leads to swelling, redness, and skin itching. The redness and itching can also be accompanied by fever, headache, tiredness, arthralgia (joint pain), and leukocytosis (increased circulating white blood cells). A weal is characterized by edema, mast cell degranulation, and an inflammatory infiltrate of cells (lymphocytes, monocytes, neutrophils, eosinophils, and basophils).

What Is the Clinical Presentation of Acquired Cold Urticaria?

• The symptoms of acquired cold urticaria appear two to five minutes after exposure to cold. On the other hand, it takes about one to two days for familial cold urticaria symptoms to appear. Also, symptoms last longer with the familial form (one to two days), whereas acquired cold urticaria symptoms last for one to two hours.
• Acquired cold urticaria comprises sub-categories such as primary acquired cold urticaria, delayed cold urticaria, localized cold urticaria, reflex cold urticaria, and secondary cold urticaria.
• Primary acquired cold urticaria can happen five to 30 minutes after cold exposure. The reaction occurs more often during the rewarming phase after the exposure. Itching and reddening of the skin may occur, followed by a burning sensation. Hives usually last about 30 minutes. The affected person may also have headaches, palpitations (feeling of a fast-beating heart), wheezing, or fainting. Delayed cold urticaria can appear several hours after a cold contact.
• Localized cold urticaria is reported to occur after cold exposure at the sites of previous allergies.
• Reflex cold urticaria is characterized by extensive rash due to a drop in body temperature after localized exposure to cold applications (for example, an ice pack). Secondary cold urticaria can occur secondary to blood disorders associated with viral infections such as infectious mononucleosis (caused by Epstein-Barr virus; EBV) and chickenpox. Other disorders are chronic lymphocytic leukemia (CLL, a type of blood cancer), cryoglobulinemia (a blood disorder in reaction to cold), lymphosarcoma (lymphatic system cancer), and syphilis (a sexually transmitted disease).

How Is Acquired Cold Urticaria Diagnosed?

There are different potential cold triggers of acquired cold urticaria. Hence, a detailed history and confirmatory tests can establish the diagnosis.

• The cold stimulation test (CST, also known as the ice cube test) can diagnose the condition. It is done by placing a cold stimulus (zero to four degree Celsius) on the skin of the subject's forearm for about five minutes. A positive result is indicated by a 'hive' in the shape of the stimulus (for example, an ice cube) after rewarming for five to ten minutes following stimulus removal. The two-step process suggests that hive formation occurs after the rise of the skin temperature following cold exposure.
• It can be followed by a cold stimulation time test (CSTT). It is the repetition of the CST at shorter intervals to establish the minimum time required for weal induction. A negative test is defined by the absence of weal after five to ten minutes. However, a negative result does not rule out hereditary cold urticaria. It is because it may require cold exposure for a longer time to bring out the characteristic response in some cases. One must note that underdiagnoses or misdiagnosis of acquired cold urticaria can affect the patient's quality of life (QoL).

What Are the Management Options for Acquired Cold Urticaria?

Management consists of patient education, stimulus avoidance, and medication. It is important to reassure patients of the benign disease course. Treatment of cold urticaria includes:

1. Cold Avoidance: An essential aspect of the treatment for acquired cold urticaria is avoiding cold triggers. Avoiding cold baths and swimming in cold water is recommended. Patients can keep an urticaria activity score diary to note cold triggers and control disease activity.

2. Desensitization: Desensitization involves slowly exposing the body to increasingly cold temperatures. Desensitization can help the body adjust and control its response to cold. However, one must consult a healthcare provider before desensitization. Further, such cold exposure requires a well-motivated patient. Studies show that tolerance by repeated cold exposure has variable results.

3. Antihistamines: Histamine is the principal mediator of acquired cold urticaria, and antihistamines are effective for the same. Various studies show an adequate response rate following their use. However, the drug (which acts as an anti-allergic) must be taken daily to get consistent results. Chlorpheniramine, Hydroxyzine, and Diphenhydramine are the classic (sedating) antihistamines. Newer generation (non-sedating) antihistamines are Loratadine, Cetirizine, Terfenadine, and Mizolastine. Further, Desloratadine, Levocetirizine, and Fexofenadine are useful. One must note that antihistamines are the first choice for acquired cold urticaria.

4. Adrenaline Injection: Intramuscular injection of Adrenaline (Epinephrine) is reserved for life-threatening anaphylaxis (a severe life-threatening allergic reaction) or throat swelling (hampers breathing). A quick Adrenaline injection can slow a severe allergic reaction. However, it should only be administered in a doctor’s office or hospital. Patients can also carry an adrenaline auto injector for emergencies.

5. Newer Options: The treatment of acquired cold urticaria is revolutionized with Omalizumab (an artificially synthesized antibody). Omalizumab binds IgE and rapidly reduces its levels by more than 90 percent. It also reduces mast cell degranulation. Both these mechanisms contribute to the efficacy of Omalizumab in this condition. Furthermore, Omalizumab is effective in the most complex and resistant cases. Other newer treatment options are antibiotics and Cyclosporine (an immunosuppressant).

Conclusion:

Acquired cold urticaria can be hard to diagnose and manage. Cold triggers such as aquatic activities and ingestion of cold substances can trigger the symptoms. While most cold urticaria cases are acquired, diagnosticians must rule out secondary forms and familial conditions. Hence, future research can determine its exact pathophysiology and preferred management. Further, it is crucial to develop guidelines and educational programs to increase awareness of this condition.