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Cold Urticaria

      Cold urticaria is one form of urticaria that may be associated with other forms of physical urticarias. Frequency is generally estimated at two or three per 100. The triggering effect of cold is found at history taking in most of the cases. The urticaria is usually superficial, and more rarely associated with deep and/or mucosal urticaria. The diagnosis is based on history taking and the ice cube test. An exhaustive search for an etiologic factor is often unfruitful, and the presence of a cryopathy should lead to a complete work-up. Therapy of cold urticaria may prove to be difficult. In patients with secondary cold urticaria, underlying disease must be treated in order to resolve the skin symptoms. H1-antihistamines can be used but the clinical responses are highly variable. Short-time treatment with low concentration corticosteroids suppresses the symptoms only partially and temporarily. In patients who do not respond to previous treatments, induction of cold tolerance may be proposed but the procedure is difficult to carry out in daily life over an extended period.

      Keyword

      Cold urticaria (CU) is a distinct clinical entity characterized by redness, itching, wheals, and edema on the cold-exposed skin. The lesions can be strictly limited to the site of contact to cold or can be generalized with a risk of systemic symptoms such as headaches, chills, tachycardia, and diarrhea. Oral mucous membranes can also be involved (
      • Möller A.
      • Henz B.M.
      Cold urticaria.
      ). Different clinical manifestations of CU have been described, including cold-induced dermographic urticaria, localized CU, cold reflex urticaria, perifollicular CU, cholinergic CU, and autosomal dominant delayed familial CU (
      • Baxter D.L.
      • Utecht L.M.
      • Yeager J.K.
      • Cobb M.W.
      Localized, perifollicular cold urticaria.
      ;
      • Ormerod A.D.
      • Smart L.
      • Reid T.M.S.
      • Milford-Ward A.
      Familial cold urticaria. Investigation of a family and response to stanozolol.
      ). Delayed CU has a latency of 3–24 h after cold exposure and persists up to 24 h. In systemic familial CU, the rash is maculopapular, different from classical acute urticaria, and can be triggered by cold winds. The diagnosis can be ascertained by the ice cube test with the appearance of a wheal on rewarming. This test may become negative when CU symptoms have decreased. Ethyl chloride, cold water on the arm (15 min, 8°C), or cold air can also be tested (
      • Möller A.
      • Henz B.M.
      Cold urticaria.
      ).
      The cause of CU is unknown. Histamine has been suggested to be the main mediator but other inflammatory mediators such as prostaglandins, proteinases, and kinins are also released during the reaction (
      • Kaplan A.P.
      • Garofalo J.
      • Sigler R.
      • Hauber T.
      Idiopathic cold urticaria. in vitro demonstration of histamine release upon challenge of skin biopsies.
      ). A recent study suggests that histamine is not central to the pathogenesis of vascular changes in acquired CU (
      • Keahey T.M.
      • Greaves M.W.
      Cold urticaria. Dissociation of cold-evoked histamine release and urticaria following cold challenge.
      ). Vasculitis has been demonstrated in the skin of patients who have been repeatedly challenged by cold with the presence of IgM, C3, and fibrin in the blood vessel walls (
      • Ahmed A.R.
      • Moy R.
      Acquired cold urticaria.
      ).
      The frequency of CU varies between 5.2% and 33.8% (
      • Möller A.
      • Henz B.M.
      Cold urticaria.
      ), with a higher incidence in cold climates. CU can also be seen in tropical regions. The women/men ratio is 2/1 and the peak age incidence is between 20 and 30 y. The mean age of onset is 22 y for idiopathic CU and 49 y for secondary CU (
      • Möller A.
      • Henz B.M.
      Cold urticaria.
      ).
      Idiopathic CU is more frequent than secondary CU (
      • Neittaanmäki H.
      Cold urticaria. Clinical findings in 220 patients.
      ;
      • Wanderer A.A.
      • Grandel K.E.
      • Wasseman S.I.
      • Farr R.S.
      Clinical characteristics of cold-induced systemic reactions in acquired cold urticaria syndromes: recommandations for prevention of this complication and a proposal for a diagnostic classification of cold urticaria.
      ;
      • Henquet C.J.M.
      • Martens B.P.M.
      • Van Vloten W.A.
      Cold urticaria. A clinico-therapeutic study in 30 patients, with special emphasis on cold desensitization.
      ;
      • Husz S.
      • Toth-Kase I.
      • Kiss M.
      • Dobozy A.
      Treatment of cold urticaria.
      ;
      • Koeppel M.C.
      • Bertrand S.
      • Abitan R.
      • Signoret R.
      • Sayag J.
      Urticaire au froid. 104 cas.
      ) (Table I). CU secondary to serum cryoproteins is rare (1%), whereas CU occurs in only 3% of people with cryoglobulinemia (
      • Neittaanmäki H.
      Cold urticaria. Clinical findings in 220 patients.
      ;
      • Wanderer A.A.
      • Grandel K.E.
      • Wasseman S.I.
      • Farr R.S.
      Clinical characteristics of cold-induced systemic reactions in acquired cold urticaria syndromes: recommandations for prevention of this complication and a proposal for a diagnostic classification of cold urticaria.
      ;
      • Henquet C.J.M.
      • Martens B.P.M.
      • Van Vloten W.A.
      Cold urticaria. A clinico-therapeutic study in 30 patients, with special emphasis on cold desensitization.
      ;
      • Husz S.
      • Toth-Kase I.
      • Kiss M.
      • Dobozy A.
      Treatment of cold urticaria.
      ;
      • Koeppel M.C.
      • Bertrand S.
      • Abitan R.
      • Signoret R.
      • Sayag J.
      Urticaire au froid. 104 cas.
      ) (Table II). CU may precede the presence of cryoglobulins or myeloma by many years and may disappear after reduction of cryoglobulins. CU has been described in association with infectious mononucleosis, hepatitis, measles, HIV, borreliosis, syphilis, and bacterial infections (
      • Lemanske R.F.
      • Bush R.K.
      Cold urticaria in infectious mononucleosis.
      ;
      • Neittaanmäki H.
      Cold urticaria. Clinical findings in 220 patients.
      ;
      • Wanderer A.A.
      • Grandel K.E.
      • Wasseman S.I.
      • Farr R.S.
      Clinical characteristics of cold-induced systemic reactions in acquired cold urticaria syndromes: recommandations for prevention of this complication and a proposal for a diagnostic classification of cold urticaria.
      ;
      • Henquet C.J.M.
      • Martens B.P.M.
      • Van Vloten W.A.
      Cold urticaria. A clinico-therapeutic study in 30 patients, with special emphasis on cold desensitization.
      ;
      • Husz S.
      • Toth-Kase I.
      • Kiss M.
      • Dobozy A.
      Treatment of cold urticaria.
      ;
      • Yu R.C.
      • Evans B.
      • Cream J.J.
      Cold urticaria, raised IgE and HIV infection.
      ;
      • Koeppel M.C.
      • Bertrand S.
      • Abitan R.
      • Signoret R.
      • Sayag J.
      Urticaire au froid. 104 cas.
      ) (Table III). The incidence of atopy seems to be higher than in control groups (
      • Möller A.
      • Henz B.M.
      Cold urticaria.
      ).
      Table IIdiopathic cold urticaria
      • Neittaanmäki H.
      Cold urticaria. Clinical findings in 220 patients.
      168/220 (31%)
      • Wanderer A.A.
      • Grandel K.E.
      • Wasseman S.I.
      • Farr R.S.
      Clinical characteristics of cold-induced systemic reactions in acquired cold urticaria syndromes: recommandations for prevention of this complication and a proposal for a diagnostic classification of cold urticaria.
      ,
      • Henquet C.J.M.
      • Martens B.P.M.
      • Van Vloten W.A.
      Cold urticaria. A clinico-therapeutic study in 30 patients, with special emphasis on cold desensitization.
      ,
      • Husz S.
      • Toth-Kase I.
      • Kiss M.
      • Dobozy A.
      Treatment of cold urticaria.
      46/50 (92%) 26/30 (87%) 37/42 (88%)
      • Koeppel M.C.
      • Bertrand S.
      • Abitan R.
      • Signoret R.
      • Sayag J.
      Urticaire au froid. 104 cas.
      99/104 (95%)
      Table IICryoglobulinemia and cold urticaria
      • Neittaanmäki H.
      Cold urticaria. Clinical findings in 220 patients.
      2/220 (0.01%)
      • Wanderer A.A.
      • Grandel K.E.
      • Wasseman S.I.
      • Farr R.S.
      Clinical characteristics of cold-induced systemic reactions in acquired cold urticaria syndromes: recommandations for prevention of this complication and a proposal for a diagnostic classification of cold urticaria.
      ,
      • Henquet C.J.M.
      • Martens B.P.M.
      • Van Vloten W.A.
      Cold urticaria. A clinico-therapeutic study in 30 patients, with special emphasis on cold desensitization.
      ,
      • Husz S.
      • Toth-Kase I.
      • Kiss M.
      • Dobozy A.
      Treatment of cold urticaria.
      2/50 (0.04%) 0/30 (0%) 0/42 (0%)
      • Koeppel M.C.
      • Bertrand S.
      • Abitan R.
      • Signoret R.
      • Sayag J.
      Urticaire au froid. 104 cas.
      4/104 (0.04%)
      Table IIIInfections and cold urticaria
      • Neittaanmäki H.
      Cold urticaria. Clinical findings in 220 patients.
      220 cases
      11 viral respiratory infections
      10 streptococcal throat infections
      4 bacterial pneumonias
      3 sinusitis
      3 rubellas
      • Wanderer A.A.
      • Grandel K.E.
      • Wasseman S.I.
      • Farr R.S.
      Clinical characteristics of cold-induced systemic reactions in acquired cold urticaria syndromes: recommandations for prevention of this complication and a proposal for a diagnostic classification of cold urticaria.
      50 cases
      1 infectious mononucleosis
      • Henquet C.J.M.
      • Martens B.P.M.
      • Van Vloten W.A.
      Cold urticaria. A clinico-therapeutic study in 30 patients, with special emphasis on cold desensitization.
      30 cases
      0 infection
      • Husz S.
      • Toth-Kase I.
      • Kiss M.
      • Dobozy A.
      Treatment of cold urticaria.
      42 cases
      5 dental infections
      • Koeppel M.C.
      • Bertrand S.
      • Abitan R.
      • Signoret R.
      • Sayag J.
      Urticaire au froid. 104 cas.
      104 cases
      1 VIH infection
      Routine laboratory investigations may include serology for syphilis, borreliosis, HIV, EBV, search for cryoglobulins, cold agglutinins, cryofibrinogens, and a complete blood cell count.
      Treatment consists of avoiding cold exposure (ice cream, cold beverages, cold water). Suspected drugs should be discontinued. In patients with secondary CU, underlying disease must be treated in order to resolve the skin symptoms.
      • Möller A.
      • Henz B.M.
      Cold urticaria.
      state that up to 50% of patients respond to a 2-wk treatment with penicillin or tetracyclin and propose to use such a treatment in each case. Nonsedating H1-antihistamines can be used but the clinical responses are highly variable (
      • Villas-Martinez F.
      • Contreras J.M.
      • Lopez-Cazana J.M.
      • Lopez-Serrano M.C.
      • Martinez-Alzamora F.
      A comparison of new nonsedating and classical antihistamines in the treatment of primary acquired cold urticaria.
      ). Doxepin, a potent H1-blocker, hydroxyzine, and cinnarizine have been shown to be more effective than placebo (
      • Neittaanmäki H.
      • Myöhänen T.
      • Fräki J.E.
      Comparison of cinnarizine, cyproheptadine, doxepin and hydroxyzine in treatment of idiopathic cold urticaria: usefulness of doxepin.
      ). Short-time treatment with low concentration of corticosteroids partially and only temporarily suppresses the symptoms of CU (
      • Kobza-Black A.
      • Keahey T.M.
      • Eady R.A.J.
      • Greaves M.W.
      Dissociation of histamine release and clinical improvement following treatment of acquired cold urticaria by prednisone.
      ). Stanazolol may be useful for the rare forms of familial CU (
      • Ormerod A.D.
      • Smart L.
      • Reid T.M.S.
      • Milford-Ward A.
      Familial cold urticaria. Investigation of a family and response to stanozolol.
      ). A combination of β-sympathomimetic and aminophyllin has been reported to be efficient on the wheals and itching (
      • Husz S.
      • Toth-Kase I.
      • Kiss M.
      • Dobozy A.
      Treatment of cold urticaria.
      ). Other drugs such as cyproheptadine, ketotifen, oral cromoglycate, H2-blockers, and IFNα are not effective (
      • Möller A.
      • Henz B.M.
      Cold urticaria.
      ). In patients with CU who do not respond to the previous treatments, induction of cold tolerance has been proposed. The patients must be hospitalized and treated with antihistamines. Cold water is applied several times daily on increasing body surface and with decreasing temperature. The initial temperature of the cold water must be 5°C above provocation. Risks of anaphylactic symptoms are always present. Cold desensitization is difficult to carry out in daily life over an extended period.
      In conclusion, further investigations are needed for a better understanding of the patho-physiologic mechanisms of CU and for a better management of the patients.

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        Familial cold urticaria. Investigation of a family and response to stanozolol.
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        • Contreras J.M.
        • Lopez-Cazana J.M.
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        • Martinez-Alzamora F.
        A comparison of new nonsedating and classical antihistamines in the treatment of primary acquired cold urticaria.
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        Clinical characteristics of cold-induced systemic reactions in acquired cold urticaria syndromes: recommandations for prevention of this complication and a proposal for a diagnostic classification of cold urticaria.
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