**5. Cold contact urticaria (CCU)**

Cold contact urticaria (CCU) is characterized by the appearance of wheals and angioedema after exposure to cold. Lesions occur a few minutes following the cold contact. Lesions usually do not spread beyond the contact area [28]. This form of PU can be fatal in some cases. After extensive cold contact, severe angioedema or shock can be seen, mostly following swimming in cold water [29]. CCU is mostly seen in young adults and can continue for 5–8 years [2].

There are some rare variants of CCU. In some cases, CCU lesions develop 24–48 h after cold exposure. In this case, it is called *delayed CCU*. In *cold‐ dependent dermatographism,* the lesions are seen in cold‐exposed and mechanically stimulated areas. *Cold‐ induced cholinergic urticaria* is the case that happens after physical exercise in cold air [30]. Familial cold auto‐inflamma‐ tory syndrome (FCAS) is a rare autosomal dominant condition in which wheals appear within 2 h of systemic cold exposure. The lesions in this syndrome cannot be brought out by localized cold exposure. In FCAS, CIAS1/NLRP3 mutation leads to the activation of NLRP3 inflamma‐ some complex, and finally, interleukin‐1β is released from the mast cells. That is why FCAS responds dramatically to interleukin‐1 antagonists [31].

CCU lesions and symptoms arise as a result of the release of some mediators such as hista‐ mine, prostaglandin D2, platelet‐activating factor, and leukotrienes. Yet, it is not known why cold exposure causes the release of these mediators [32]. Half of the CCU patients are positive for antibodies against immunoglobulin E (IgE). IgE binding of some possible, unproven cold‐ depended skin antigens can be the reason of mast cell degradation [33]. It is also shown that CCU patients have circulating histamine‐releasing factors and positive autologous serum skin test (ASST) [34].

Suspecting CCU or angioedema, one should perform cold stimulation test since fatality has been reported in several cases. In this test, the volar aspect of the forearm is exposed to ice cube in a thin plastic bag for 5 min. Ten minutes after the removal of the bag, the response should be assessed. If a well‐demarcated, palpable wheal with a pruritic and burning sensation is present, the test is considered as positive. Ice cube should be in a thin bag in order to avoid any confusion with aquagenic urticaria [35]. Further critical temperature threshold tests with sophisticated devices can enable the patients to avoid situations that cause whealing [28]. More accurate testing is possible with computer‐aided thermoelectric Peltier device. This device can also be used for the evaluation of the success of the treatments. In most of the studies, the criti‐ cal temperature threshold is about 15–20°C [36]. The avoidance of below threshold tempera‐ tures is hard to manage in daily life. Even so, the patients should be warned to avoid contact with subthreshold temperatures.

The essential of the treatment of CCU is to avoid cold exposure. Non‐sedating H1 antihista‐ mines are accepted as the first‐line therapy by the current European Academy of Allergy and Clinical Immunology (EAACI)/Global Allergy and Asthma European Network (GA2 LEN)/ European Dermatology Forum (EDF)/World Allergy Organization (WAO) guidelines [5]. Usually high doses of H1 antihistamines are necessary to control CCU. Siebenhaar et al. claimed that high dose of desloratadine is better in controlling CCU when compared with the standard dose [37]. Likewise, Magerl et al. reported that H1 antihistamine up‐dosing increases the success rate in the treatment of CCU [38].

In case of failure of therapy with H1 antihistamines, there is lack of well‐studied alternative treatment options. Boyce JA reported successful treatment of cold‐induced urticaria/anaphy‐ laxis with omalizumab (anti‐IgE) [39]. In 2011, Gualdi et al. claimed that a patient who had CCU healed with the use of etanercept for the treatment of co‐existing psoriasis vulgaris. It was the first case report regarding the efficacy of etanercept in CCU [40]. Interleukin‐1 receptor antagonist (anakinra) was shown to be effective in controlling severe idiopathic cold urticaria [41]. But more controlled studies are necessary to show the effects of omalizumab, etanercept, and anakinra in CCU.

Cold tolerance induction and maintenance therapy can also be tried with precaution due to the risk of anaphylaxis. In this procedure, the patient starts daily showers, first with water temper‐ atures above the threshold and in time, the temperature of the water is decreased gradually. Acquired tolerance is maintained with daily cold showers for a long time [42].
