a frigore - Alergología e Inmunología Clínica

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Table III. Classification of cold urticaria based on the results of the cold contact challenge test Typical Atypical Idiopathic Systemic Secondary Localised Cold-induced cholinergic Reflex local Cold-induced dermographism than 20 minutes in the cold-stimulated area; the result is termed "atypical" when there is no response, when the response occurs in an area distant from the stimulated one, or when no immediate response occurs. Acquired cold urticarias with a positive cold contact challenge test ("typical" cold urticaria) constitute about 80-90% of all these urticaria types; they can be further subclassified into primary (or idiopathic) cold urticarias and cold urticarias secondary to a systemic disease. The familial form of cold urticaria is a rare condition with an autosomal dominant inheritance pattern, recently related by Hoffman et al. to a locus in chromosome 1 (1q44) 4 . This form usually has its onset during childhood and persists throughout life. It is clinically characterised by the development of erythematous and painful maculopapular lesions (the patients usually describe a burning sensation rather than pruritus) that begin to appear a few minutes after the exposure to cold and may persist for 48 hours. There is generally no mucosal involvement, and the ice-cube test is usually negative 5 . The immediate form is characterised by the onset of the lesions shortly after the exposure to cold and the frequent association of fever, chills, leukocytosis, arthro-myalgia and headache, which last for 4 to 6 hours. Histologically, the lesions show a polymorphonuclear cell infiltrate. In the delayed form the lesions appear 9 to 18 hours after the exposure to cold, and the biopsy samples evidence a mononuclear cell infiltrate. The primary (or idiopathic) acquired form of cold urticaria is the most frequent form of urticaria a frigore. Although it may debut at any age, it is more frequent in young adults and, in some cases, a past history may be found of upper airway viral infection, infectious mononucleosis, syphilis, viral hepatitis, erythema nodosum, insect stings, thyroid disease or drug administration (penicillin, oral contraceptives, griseofulvin) 6 . The lesions may appear a few minutes to one hour after the exposure to the cold stimulus, and both cold Urticaria a frigore winds and cold, rainy days are important triggering factors. After the ingestion of cold foods, the patients may develop angioedema in the oral cavity or the pharynx, which may be occasionally associated to systemic symptoms such as stifling, palpitations, headache, wheezing or even loss of consciousness upon bathing in cold water. Cold urticaria has been associated to pressure urticaria, cholinergic urticaria and dermographism. Although its course is unpredictable, the mean duration of the complaint is usually about six years 2,7 . Wanderer et al. 5 have described a number of clinical patterns of primary acquired cold urticaria: type I (30% of the cases) is characterised by the onset of urticaria and/or localised angioedema; type II (32%) includes the presence of one or more episodes of urticaria and/or generalised angioedema without symptoms of hypotension (mild systemic reaction), and type III (38%) involves severe systemic reactions with one or more episodes of urticaria and/or generalised angioedema, hypotension or shock. Furthermore, a correlation has been observed between the time required for the cold challenge test to induce a positive response and the degree or type of clinical manifestations the patient may evidence upon "natural" exposure to cold: the earlier the response is, the greater the risk will be of developing systemic manifestations and thus hypotension or anaphylactic shock. Thus, cold-induced hypotension and systemic reactions occur more frequently in patients with a cold contact challenge test that produces a positive response in 3 minutes or less 5 . The secondary acquired form of cold urticaria is a very rare form of urticaria a frigore (0.5% of all cases) 7 . The clinical manifestations include whealing, Raynaud’s phenomenon, purpura, or skin necrosis. This condition has been associated to a number of disorders characterised by the existence of abnormal immunoglobulins that evidence some form of cold-dependent properties. The presence of cryoglobulins may be idiopathic or occur in the context of connective tissue disease, chronic lymphoid leukaemia, multiple myeloma, Waldenström’s disease, secondary syphilis (which may feature paroxysmal cold haemoglobinuria due to Donath-Landsteiner antibodies) or hepatitis C 2,8,9 . Atypical cold urticaria encompasses a number of forms of generalised or localised urticaria (Table III) appearing upon exposure to a cold stimulus, even though the cold challenge test is negative. The systemic form is a rare disorder characterised by generalised urticarial lesions that are not restricted to the areas exposed to cold; it may be associated to severe and life-threatening anaphylactoid re- 221
C. Carrasquer Moya, et al actions. The localised form involves the onset of urticaria and/or angioedema in localised areas of the body surface; there have been some reports of cases in association to insect stings, to skin tests with allergens, to the administration of immunotherapy or to tetanus vaccination 5,10 . In cold-induced cholinergic urticaria the typical lesions, small pruritic papules 1-7 mm in diameter, appear after total body exposure to cold or after physical exertion in a cold environment; thus, physical exercise performed at low environmental temperatures triggers the apparition of the lesion, while they do not occur if the physical exercise is performed in a warm environment. The ice-cube and acetylcholine tests are negative, a useful detail for the differential diagnosis to cholinergic urticaria in which the acetylcholine test is positive. In local reflex cold urticaria, the ice-cube test triggers the apparition of urticarial lesions distant from the area of cold application. In the case of cold-dependent dermographism, wheals describing the pressure-stimulated area occur only upon cold exposure; this condition may occur with exclusively cutaneous manifestations or in association to systemic symptoms such as abdominal pain, vomiting or diarrhoea. Cold-dependent dermographism should be differentiated from typical cold urticaria, which is sometimes associated to dermographism. AETIOLOGY A review of the various reported series of patients with cold urticaria shows that most cases are idiopathic. This type of urticaria has been related to a number of clinical contexts (Table IV), among them the presence of cryoproteins, infections (such as infectious mononucleosis, Table IV. Aetiologic implications 222 rubella or syphilis) and the administration of various drugs (penicillin, oral contraceptives and griseofulvin) 5 . PATHOGENESIS The pathogenesis of cold urticaria is not well known although, as in other types of urticaria, the mast cell is the fundamental cell type involved. Increased levels of different mediators released in the course of mast cell degranulation, such as histamine, prostaglandin D 2, platelet activation factor and tumour necrosis factor alpha (TNF-α) have been detected in the skin and in the blood of these patients. Increased expression of TNF-α and of interleukin 3 (IL-3) in the endothelial cells of healthy and affected skin have been reported in patients with different types of urticaria, including urticaria a frigore 6 . The involvement of immunologic mechanisms in which immunoglobulins (in some cases, the sera of these patients can induce a response to cold in the form of urticarial phenomena when transfused to healthy individuals; this phenomenon is mediated by IgE-type immunoglobulins, although there have also been descriptions of IgM and IgA mediation), neuropeptides such as substance, chemotactic factors and cytokines participate has also been postulated 7,8 . DIAGNOSIS The diagnostic procedure for a patient with cold urticaria should encompass in the first place a detailed anamnesis for orientation of the suspicion diagnosis. In patients with a suggestive history, the cold challenge test should be performed and a number of complementary explorations and analyses should be requested. Author(s) Year No. of cases Idiopathic Cryoproteins Infectious disease Neittaanmäki13 1985 220 168 2 cryoglobulinaemias 11 viral airway disease (1 of them with lymphoma) 4 pneumonia, 3 rubella Wanderer5 1986 50 46 2 cryoglobulins (1 with CLL) 1 infectious mononucleosis Henquet14 1992 30 26 1 cryofibrinogen No Huszl et al15 1994 42 37 No 5 odontologic infections Koeppel et al8 1996 104 99 4 cryoglobulins 1 cryofibrinogen 1 HIV Mathelier-Fusade et al3 1998 35 32 No No CLL = chronic lymphoid leukaemia; HIV = human immune deficiency virus.
Page 1 and 2: Alergol Inmunol Clin 2001; 16: 218-
Page 3: C. Carrasquer Moya, et al Table II.
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a frigore - Alergología e Inmunología Clínica

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