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5 If underlying allergies are suspected, skin prick testing and specific IgE levels may help identify possible triggers. Cases of autoimmune chronic urticaria could be diagnosed through the use of autologous serum skin test and histamine release assay and through the assessment of CD63 levels that mark basophil activation.9�C11 Finally, in the absence of an identified trigger and the continuation of hives, the diagnosis of chronic spontaneous urticaria may be applied.9�C11 Differential diagnosis When diagnosing CU, it is important to rule out other possible causes of urticaria. These include viral-induced urticaria, allergic reactions (food, medications, bug bites) and other types of physical urticaria. Given the history of reactions, infectious and allergic triggers unlikely contribute to the patient��s symptoms. Physical urticarias (also referred to as inducible urticarias) include mechanical, cold, solar, heat, delayed pressure, aquagenic and vibrative urticarias.2 Once the trigger of cold is identified, the differential diagnosis of CU includes primary idiopathic, secondary, atypical and familial syndromes.4 12�C14 In the three cases described, the patients did not have symptoms of fever, joint involvement or hearing loss and the urticaria did not develop during early childhood. Hence, familial syndromes including rare cases of phospholipase C��-2 gene mutations15 and mutations in cold-induced auto-inflammatory syndrome-1 gene resulting in cryopyrin-associated periodic syndrome16 17 are unlikely. Treatment It is important to reassure patients on the usually benign course of the disease and to protect body surfaces when cold exposure is inevitable as well as to avoid rapid exposure to cold water. Patients are usually advised to keep an urticaria activity score diary18 to characterise cold triggers and control of disease activity. In severe cases, it is important to have an action plan in case of systemic reaction including the need to have an epinephrine Selleckchem Crizotinib autoinjector available and prompt use if necessary. Medication of choice is antihistamines, preferably second generation, which will control the hives and itchiness in most cases.5 19 In 2008, at the Third International Meeting on Urticaria, it was established that antihistamine dose could be safely increased up to fourfold if symptoms persist before switching to other therapies.20 21 Although studies suggest that cold tolerance induction may be an effective strategy to control symptoms, it is rarely used due to poor compliance.22 Outcome and follow-up All three cases were managed with low to high doses of antihistamines. The third patient was prescribed an epinephrine autoinjector, but had achieved control with the use of antihistamines and did not require the use of the autoinjector.