URTICARIA (HIVES) Urticaria is a vascular reaction of the skin characterized by the appearance of wheals, generally surrounded by a red halo

or flare and associated with severe itching, stinging, or pricking sensations. These wheals are caused by localized edema. Clearing of the central region may occur and lesions may coalesce, producing an annular or polycyclic pattern (Fig. 7-14). Subcutaneous swellings (angioedema) may accompany the wheals. Angioedema may target the gastrointestinal and respiratory tracts, resulting in abdominal pain, coryza, asthma, and respiratory problems. Respiratory tract involvement can produce airway obstruction. Anaphylaxis and hypotension may also occur.

Classification Acute urticaria evolves over days to weeks, producing evanescent wheals that individually rarely last more than 12 h, with complete resolution of the urticaria within 6 weeks of onset. Daily episodes of urticaria and/or angioedema lasting more than 6 weeks is designated chronic urticaria. Chronic urticaria predominantly affects adults and is twice as common in women as in men. Nonimmunologic mechanisms can produce mast cell degranulation. Common triggers include opiates, polymyxin B, tubocurarine, radiocontrast dye, aspirin, other NSAIDs, tartrazine, and benzoate. More than 50% of chronic urticaria is idiopathic. Physical stimuli may produce urticarial reactions and represent 7% to 17% of cases of chronic urticaria. The physical urticarias include dermatographic, cold, heat, cholinergic, aquagenic, solar, vibratory, and exercise-induced cases. Physical urticaria commonly occurs in patients with chronic urticaria.

Etiologic Factors Drugs Drugs are probably the most frequent cause of acute urticaria. Penicillin and related antibiotics are the most frequent offenders (see Chapter 6). A frequently overlooked factor is that penicillin sensitivity may become so exquisite that reactions can occur from penicillin in dairy products. The incidence of aspirin-induced urticaria has fallen, most likely related to the availability of alternative antiinflammatory agents. Aspirin-sensitive persons tend to have cross-sensitivity with tartrazine, the yellow azo-benzone dye, and other azo dyes, natural

salicylates, and benzoic acid and its derivatives. These are common food additives and preservatives. Aspirin exacerbates chronic urticaria in at least 30% of patients. Patients may have allergic rhinitis or asthma, nasal polyps, and food-induced anaphylaxis. Mite-contaminated wheat flour has been implicated as an allergen. The nature of the association between aspirin intolerance and mite-induced respiratory allergies is unknown.

Food Foods are a frequent cause of acute urticaria whereas in chronic urticaria food is a less frequent factors. The most allergenic foods are chocolate, shellfish, nuts, peanuts, tomatoes, strawberries, melons, pork, cheese, garilic,onions, eggs, milk, and spices. Food allergens that may cross-react with latex include chestnuts, bananas, passion fruit,avocado and kiwi. Exposure to safely cooked fish and shelfish parasitized by Anisakis simplex can result in angiodema and urticaria, suggesting that some seafood allergies may be related to exposure to parasite antigens. If the urticaria is acute and recurrent, food alergi may be suggested by a food diary. Serum radioallergosorbent test (RASTs) can be used to detect specific IgE, and elimination diets can be of benefit in some patients. One such diet permits inclusion of the following: lamb, beef, rice, potatoes,carrots, string beans, peas, squash, apple sauce, tapioca,preserved pears, peaches, or cherries, Ry-Krisp crackers, butters, sugar, tea without milk or lemon, and coffee without cream. This diet is followed for 3 weeks. If urticaria does not occur then suspected foods are added one by one and reactions observed It should be noted that potatoes often contain sulphites, and that some patients may be allergic to the foods contained in the above diet. It is best tried only after a careful history The use of food challenges, and scratch and intradermal tests can be misleading. alsepositive food challenges are common and an offending food may give a negative prick or intradermal test. Moreover, food additives and preservatives may be responsible.

Food Additives Less than 10% of cases of chronic urticaria are caused by food additives. Natural food that may be implicated in urticaria include yeasts, salicylates, citric acid, egg, and fish albumin. Synthetic additives include azo dyes, benzoic acid derivatives, sulfite, and penicillin

Yeast is widely used in foods. When suspected as the causative agent, bread and breadstuffs, sausages, wine,bear, grapes, cheese, vinegar, pickled foods, catsup, a tablets should be avoided. Foods containing azo dyes and benzoic acid include candy soft drinks, jelly, marmalade, custards, puddings,various cake and pancake mixes, mayonnaise, ready-made salad dressings and sauces, packaged soups, anchovies colored toothpastes. With the

exception of sulphite and penicillin, most food additives can be avoided by eating only meat produce and dairy products. Packaged foods aire largely off limits.

Infections Acute urticaria may be associated with uperespiratory infections, especially streptococcal infections The incidence of streptococcal infection in pediattric cases of acute urticaria varies greatly in reported series. The possibility of localized infection in the tonsils, a tooth, the sinuses, gallbladder, prostate, bladder, or kidney should be considered as a possible cause in cases of acute or cronic urticaria. In some patients, treatment with antibiotics for Helicobacter pylori has led to resolution of the urticaria Chronic viral infections such as hepatitis B and C may cause urticaria. Acute infectious mononucleosis and psittacosis may also be triggering conditions. Helminths may cause urticaria. Among these are ascaris, ankylostoma, strongyloides, toxocara, and liver fluke. filaria, echinococcus, schistosoma, trichineella

Emotional Stress Persons under severe emotional stress may have more marked urticaria, no matter what the primary cause is. In cholinergic urticaria emotional stress is a Particularly well-documented inciting stimulus.

Menthol Rarely, menthol may cause urticaria. It is found in mentholated cigarettes, candy and mints, cough drops, aerosol sprays, and topical medications.

Neoplasms Urticaria has been associated with carcinomas and Hodgkin's disease. Cold urticaria with cryoglobulinemia has been reported associated with chronic lymphocytic leukemia.

Inhalants Grass pollens, house dust mites, feathers, formaldehyde, acrolein (produced when frying with lard or smoking cigarettes containing glycerin), castor bean or soybean dust,

cooked lentils, cottonseed, animal dander, cosmetics, aerosols, pyrethrum, and molds have been known to cause urticaria.

Alcohol Urticaria may be induced by the ingestion of alcohol. The mechanism of alcoholinduced indirect mast cell stimulation is unknown. Wines generally contain sulfites.

Pathogenesis/Histopathology Cappillary permeability results from the increased release of Histamine from the mast cells situated around the capillaries, The mast cell is the primary effector cell in urticarial reactions, other substances besides histamine may cause vasodilation id and capillary permeability, and thereby may possibly become mediators of urticaria and angioedema. These include serotonin, leukotrienes, prostaglandins, proteases, and kinins.The major basic protein of eosinophil granules is abnormally high in the blood of more than 40% of patients with chronic urticaria, even when peripheral blood eosino phil counts are normal, and there are extracellular deposits of it in the skin in about the same proportion of patients,. About one-third of patients with chronic idiopathic irticaria have circulating functional histamine-releasing IgG autoantibodies that bind to the high-affinity IgE receptor, Some patients have IgG that does not bind the IgE receptor, but causes mast-cell degranulation. Thyroid autoantibodies He are often present in women with chronic idiopathic urticaria, hit clinically-relevant thyroid disease is seldom present. Even in those with thyroid disease, treatment of the thyroid disorder generally does not affect the course of the urticaria. The histopathologic changes in acute urticaria include mild dermal edema and margination of neutrophils within post-capillary venules. Later, neutrophils migrate through tbe vessel wall into the interstitium, and eosinophils and lymphocytes are also noted in the infiltrate. Karyorrhexis and fibrin deposition within vessel walls are absent, helping to differentiate urticaria from vasculitis. A subset of patients have long-lasting, refractory lesions ltd this has been dubbed "neutrophilic urticaria." Lesions in these patients often persist for longer than 24 h, and biospies demonstrate a neutrophil-rich perivascular infiltrate thai wks karyorrhexis or fibrin deposition within vessels walls Eosinophils and mononuclear cells are noted in varying proportions. Patients with neutrophilic urticara may presen with acute urticaria, chronic urticaria or physical urticaria Lesional skin demonstrates increased expression of TNF-oc and IL-3, whereas IL-8 expression is only minor. As neutrophils are commonly present in

urticaria in general, it is likely that cases of neutrophilic urticaria represent urticaria with upregulation of some mast cell-derived cytokines.

Diagnosis Diagnosis of urticaria and angioedema is usually made on clinical grounds. Lesions in a fixed location for more than 24 h suggest the possibility of urticarial vasculitis, the urticarial phase of an immunobullous eruption, EM, granuloma annulare, sarcoidosis, or cutaneous Tcell lymphoma. If individual wheals last for longer than 24 h, a skin biopsy should be performed. Clinical Evaluation Laboratory evaluation should be driven by associated signs and symptoms. Random tests in the absence of a suggestive history or physical findings are rarely cost-effective. A practical evaluation is limited to a detailed history (foods, drugs, aspirin, physical causes) and physical examination. Angioedema in the absence of urticaria may be related to hereditary angioedema or an angiotensin-converting enzyme (ACE)-inhibitor. CI esterase deficiency does not cause hives, only angioedema. If there is a history of sinus difficulties, particularly if there is palpable tenderness over the maxillary or ethmoid sinuses, radiologic sinus evaluation is recommended. In areas where parasitic disease is common, a blood count to detect eosinophilia is an inexpensive screening test with a fair yield. The blood count may be unreliable if the patient has been on a systemic corticosteroid. In patients with chronic urticaria, a review of medications, including over-the-counter products, supplements, aspirin and other NSAIDs should be obtained. If the history suggests a physical urticaria, then the appropriate challenge test should be used to confirm the diagnosis. Lesions that burn rather than itch, resolve with purpura or last longer than 24 h should prompt a biopsy to exclude urticarial vasculitis. A directed history and physical examination should elicit signs or symptoms of thyroid disease, connective tissue disease, changes in bowel or bladder habits, vaginal or urethral discharge, other localized infection, jaundice, or risk factors for hepatitis or Lyme disease. Positive findings should prompt appropriate screening tests. Although sinus x-ray films, a Panorex dental film, a streptococcal throat culture, abdominal ultrasonography, and urinalysis with urine culture (in men, with prostatic massage) may reveal the most common occult infections triggering urticaria, positive cases are almost always associated with some signs or symptoms suggestive of the diagnosis. In patients with chronic angioedema, without

classic wheals or symptoms of pruritus, a careful drug history and evaluation of C4 level should be ordered. If C4 is low, an evaluation of CI esterase inhibitor is appropriate.

Anaphylaxis Anaphylaxis is an acute and often life-threatening immunologic reaction often heralded by scalp pruritus, diffuse erythema, urticaria, or angioedema. Bronchospasm, laryngeal edema, hyperperistalsis, hypotension, and cardiac arrhythmia may occur. Antibiotics, especially penicillins, other drugs, and radiographic contrast agents are the most common causes of serious anaphylactic reactions. Hymenoptera stings are the next most frequent cause, followed by ingestion of crustaceans and other food allergens. Atopic dermatitis is commonly associated with anaphylaxis regardless of origin. Causative agents can be identified in up to two-thirds of cases and recurrent attacks are the rule. Exerciseinduced anaphylaxis is often dependent on priming by prior ingestion of a specific food, or food in general.

Treatment Acute Urticans The mainstay of treatment of acute urticaria is administration of antihistamines. In adults, nonsedating antihistamines pose a lower risk of psychomotor impairment. If the cause of the acute episode can be identified, avoiding that uigger should be stressed. In patients with acute urticaria that does not respond to antihistamines, systemic corticosteroids are generally effective. Less rebound is seen with a 3-week tapered course of systemic corticosteroid therapy as compared with shorter courses. For severe reactions, including anaphylaxis, respiratory and cardiovascular support is essential. A 0.3 mL dose of a 1:1000 dilution of epinephrine is administered every 10 to 20 min as needed. In young children, a half-strength dilution is used. In rapidly progressive cases, intubation or tracheotomy may be required. Adjunctive therapy includes intramuscular antihistamines (25-50 mg hydroxyzine or diphenhydramine every 6 h as needed) and systemic corticosteroids (250 mg hydrocortisone or 50 mg methyiprednisolone intravenously every 6 h for two to four doses).

Chronic Urticaria The mainstay for treating chronic urticaria is, again, administration of antihistamines. These should be taken on a daily basis; they should not be prescribed to be taken as needed. The patient should be warned about driving an automobile when firstgeneration antihistamines are used.

Second-generation Hj antihistamines (cetirizine, famotidine, loratadine, acrivastine, and azelastine) are large, lipophilic molecules with charged side chains that bind extensively to proteins, preventing the drugs from crossing the blood-brain barrier; thus they produce less sedation in most patients. Long-acting forms are available, and the long half-life of these antihistamines and reduced sedation result in improved compliance and efficacy. Cetirizine (Zyrtec) and some of the other second-generation antihistamines can cause drowsiness in some individuals, particularly in higher doses or when combined with other antihistamines. Doxepin, a tricyclic antidepressant with potent H1 antihistaminic activity, may be useful and can be added to the existing antihistamine. Doxepin is frequently dosed at bedtime, so much of the drowsiness and dry mouth are gone by morning. In stubborn cases, dosages of antihistamines that exceed drug labeling are sometimes required. Even second-generation antihistamines may become sedating at higher doses. Fexofenadine is generally well tolerated, even at doses that exceed product labeling. The combination of H1 and H2 antihistamines, such as hydroxyzine and cimetidine or ranitidine, may be effective in some cases. Cimetidine or ranitidine should not be used alone for treatment of urticaria, as they may interfere with feedback inhibition of histamine release. Other second-line treatments include phototherapy, calcium-channel antagonists (nifedipine), antimalarial medications, dapsone, gold, azathioprine, lowdose Cyclosporine terbutaline, and methotrexate. Unfortunately, HP systemic corticosteroids are effective in suppressing most cases ofchronic urticaria, their long-term side effects make their extended use impractical. As soon as the corticosteroid is stopped, hives recur. In addition, if an infection is a trigger, this could be exacerbated by long-term steroid therapy. Topical corticosteroids, topical antihistasmines and topical anesthetics have no role in the management of chronic urticaria.

For local treatment, tepid or cold tub baths or showers may be freely advocated. Topical camphor and menthol can provide symptomatic relief. Sarna lotion contains menthols phenol, and camphor. In about one-third of cases of chronic idiopathic urticaria, patients have autoantibodies that bind to high-affinity IgE receptors. Such patients may require more aggressive management to include chronic immunosuppressive therapy, plasmapheresis, or intravenous immunoglobulin (IVIG).

Other Uriticarial Variants Angioedema Angioedema is an acute, evanescent circumscribed edema that usually affects the most distensible tissues, such as the eyelids, lips, lobes of the ears and external genitalia, or the mucous membranes of the mounth tongue, or larynx.The swelling occurs in the deeper parts of the skin or in the subcutaneous tissues and as a rule is only, slightly tender, with the overlying skin unaltered, edematous, or, rarely, ecchymotic. There may be a diffuse swelling on the hands, forearms, feet, and ankles. Frequently the condition begins during the night and is found on awakening. There are two distinct subsets of angioedema. The First is, considered a deep form of urticaria and may be observed as solitary or multiple sites of angioedema alone or in combination with urticaria. The action of histamine or Similar substances creates vasomotor lability, and pruritus may be a significant feature. The second, angioedema associated with C1 esterase inhibitor deficiency, is not associated witht hives and there is no pruritus. Symptoms of pain predominate Angioedema may be related to ACE inhibitors.

Hereditary Angioedema Also known as Quinckeedema, hereditary angioedema (HAE) was originally described and named by Osier in 1888. HAE charactheristically appears in the second to fourth decade. Sudden attacks of angioedema occur as frequently as every 2 weeks throught out the patient's life, lasting for 2 to 5 days. Swelling is typically asymmetrical, and urticaria or itching does not occur The presentation may overlap with that of the autoinflamatory syndromes. Patients may experience local swelling in subcutaneous tissues (face, hands, arms, legs, genitals, and buttock) abdominal organs (stomach, intestines, bladder) mimicking surgical emergencies; and the upper airway (larynx) that can be life-threatening. There is little response to antihistamine epinephrine, or steroids.The mortality rate is high, with death often caused by laryngeal edema. Gastrointestinal edema is manifested by nausea, vomiting, and severe colic, and it may simulate appendicitis so closely, that appendectomy is mistakenly performed. The factors that trigger attacks are minor trauma, surgery, sudden changes of temperature, or sudden emotional stress. Inherited in an autosomal-dominant fashion, HAE is estimated to occur in 1 in 50,000 to 150,000 persons, There are three phenotypic forms of the disease. Type I is characterized by low antigenic and functional plasma levels Riormal CI esterase inhibitor protein (Cl-EI). Type II is fccterized by the presence of normal or elevated anti-Klevels of a dysfunctional protein. Type III demonstrates Bmal Cl-EI function and normal complement. It has been

described only in female members of affected families. Criteria for type III include a long history of recurrent fccks of skin swelling, abdominal pain or upper airway Obstruction; absence of urticaria; familial occurrence; normal h-El and C4 concentrations; and failure of treatment with anthistamines, corticosteroids, and Cl-EI concentrate. The screening resi of choice for types I and II is a C4 level. C4 will be low (< 40% of normal) as a result of continuous activation and consumption. In addition to depressed C4 levels, patients with types I and II also have low CI, Clq, Vtnd C2 levels. If the clinical picture and screening tests are positive, a titer of Cl-EI should be ordered. Cl-EI is a labile protein and sample decay is common. A low Cl-EI in the presence of normal C4 levels should raise the suspicion of sample decay, rather than true HAE. The treatment of choice for acute HAE types I and II is replacement therapy with concentrates or fresh frozen plasma. Short-term prophylaxis (e.g. for patients undergoing dental care, endoscopy, or intubation for surgery) can be obtained from stanozolol, an attenuated androgen. Estrogens in oral contraceptives, in contrast, may precipitate attacks, Antibrinolytic tranexamic acid, a drug related to e-aminocaproic acid, has been used to treat acute and chronic disease.Type 111 does not respond to Cl-EI replacement, but may respond to danazol.

Acquired C1 Esterase Inhibitor Deficiency Some (patients present with symptoms indistinguishable from HAE, : tut with onset after the fourth decade of life and lacking a tamily history. As in HAE. there is no associated pruritus wurticaria.This condition is subdivided into acquired angio-edema-I and -II, and an idiopathic form. Acquired angioedema-H.a rare disorder associated with lymphoproliferative diseases. These associations include lymphomas (usually keif), chronic lymphocytic leukemia, monoclonal gammo-pathy,myeloma, myelofibrosis. Waldenstrom macroglobulin-[oriia,and breast

carcinoma. Some patients have detectable autoantibodies to Cl-El. Acquired angioedema-!I is an extremely rare disease defined by the presence of autoantibodies to Cl-EI. It is important to realize that autoantibodies directed against Cl-El may also be found in acquired angioedema-I, particularly inpatients with B-cell lymphomas, so the diagnosis of acquired angioedema-ll is made only when no such [mderlying condition exists. The pathophysiology of acquired angioedema-I is unknown but may be related to increased catabolism of Cl-EI, since many patients with the disorder have been shown to produce normal amounts of Cl-EI. In acquired angioedema-Hepatocytes and monocytes are

able to synthesize normal C1-EI; however, a subpopulation of B-cells secretes autoantibodies to the functional region of the Cl-EI molecule. Management of acute attacks in acquired angioedema-I is directed toward replacement of Cl-EI with concentrates or fresh-frozen plasma. Some patients develop progressive resistance to the infusions. Antifibrinolytic agents such as aminocaproic acid or tranexamic acid may be beneficial, and are more effective than antiandrogen therapy. Synthetic androgens, such as danazol, may be helpful in angioedema-I; however, androgens are ineffective in treating patients with acquired angioedema-II, stressing the importance of identifying these patients. Immunosuppressive therapy has been shown to be effective in the treatment of acquired angioedema-II by decreasing autoantibody production. Systemic corticosteroids may be temporarily effective. Plasmapheresis is another consideration.

Episodic Angioedema with Eosinophilia Episodic angioedema or isolated facial edema may occur with fever, weight gain, eosinophilia, and elevated eosinophil major basic protein. The disorder is not uncommon, and there is no underlying disease. Increased levels of IL-5 have been documented during periods of attack. Treatment options include administration of systemic steroidal medications, antihistamines, and IVIG.

Schnitzler Syndrome The rare disorder Schnitzler syndrome is a combination of chronic, non-pruritic urticaria, fever of unknown origin, disabling bone pain, hyperostosis, increased erythrocyte sedimentation rate, and monoclonal IgM gammopathy. Pruritus is not generally a feature. The age of onset ranges from 29 to 77 years, without gender predilection. In some cases the IgM gammopathy progresses to neoplasia, especially Waldenstrom

macroblobulinemia. Effective therapy has not been determined, although the bone pain and urticarial lesions respond to systemic corticosteroids in some patients.

Physical Urticarias Specific physical stimuli are the cause of approximately 20% of all urticarias. They occur most frequently in persons between the ages of 17 and 40. The most common form is dermatographism followed by cholinergic and cold urticaria. Several forms of physical urticaria may occur in the same patient. Physical urticarias, particularly dermatographism, delayed pressure, cholinergic, and cold urticaria, are frequently found in patients with chronic idiopathic urticaria.

Dermatographism Dermatographism is a sharply localized edema or wheal with a surrounding erythematous flare occurring within seconds to minutes after the skin has been stroked (Fig. 7-15). It affects 2% to 5% of the population. Dermatographism may arise spontaneously after drug-induced urticaria and persist for months. It has also been reported to be associated with the use of the H2 blocker famotidine. It may occur in hypo-and hyper-thyroidism, infectious diseases, diabetes mellitus, and during onset of menopause. It may be a cause of localized or generalized pruritus. Antihistamines suppress this reaction. The addition of an H, antihistamine may be of benefit. Cholinergic Urticaria Cholinergic urticaria, produced'by the action of acetylcholine on the mast cell, is characterized by minute, highly pruritic, punctate wheals or papules 1 to 3 mm in diameter and surrounded by areas of erythema (Fig. 7-16). These lesions occur primarily on the trunk and face. The condition spares the palms and soles. Lesions persist for 30 to 90 min and are followed by a refractory period of up to 24 h. Bronchospasm may occur. Familial cases have been reported. The lesions may be induced in the susceptible patient by exercise, emotional stress, increased environmental temperature, or intradermal injection of nicotine picrate or methacholine. Sometimes an attack may be aborted by rapid cooling of the body, as by taking a cold shower. A refractory period with no lesions occurs for approximately 24 h after an attack. Cholinergic dermatographism is noted in some patients. Treatment with antihistamines is often effective if dosage is adequate. Attenuated androgens, such as danazol, may be of benefit in refractory cases. Provocative tests include exercise, a warm bath to raise core temperature by 0.7 to 1.0 C (1.2 to 1.8 F), or a methacholine skin test.

Adrenergic Urticaria Urticaria may be attributable to norepinephrine. The eruption consists of small (1-5 mm) red macules and papules with a pale halo, appearing within 10 to 15 min a tional upset, coffee or chocolate. Serum catecholam epinephrine, dopamine, and epinephrine may rise during attacks, whereas histamine and seroton remain normal. Propranolol in a dosage of 10 mg fi a day is effective; atenolol has been ineffective. A tive test consists of intradermal administration of 3 of norepinephrine.

Cold Urticaria Exposure to cold may result in edema and whealin| exposed areas, usually the face and hands. The i does not develop during chilling, but on rewarmi. heterogenous group of disorders is classified into primary (essential), secondary, and familial cold urticaria. Primary (essential) cold urticaria is not associatf underlying systemic diseases or cold reactive p: Symptoms are usually localized to the areas of cold eksposure. although respiratory and cardiovascular compromis develop. Fatal shock may occur when these persi swimming in cold water or take cold showers. Thi of cold urticaria usually begins in adulthood. It is i ice-cube test positive (Fig. 7-17). The treatment of primary cold urticaria is with dox< doses from 25 mg at bedtime to 50 mg twice a day, or heptadine 4 mg three times a day. Good therapeutic res[ to the secondgeneration antihistamines acrivastine am rizine have been reported, and these agents are less lik result in sedation. Cetirizine and zafirlukast in combir are more effective than either drug given alone. Keti may also be effective. Although this drug is not marl in the US, patients in southern states have been kill obtain it in Mexico. Corticosteroid medications are ineffective. Desensitization by repeated, increased exposures ta has been effective in some cases. In one report, succesful desensitization was induced in an 18-year-old patient severe cold urticaria. Tolerance in a small area of the occurred by repeated applications of an ice cube at 30 intervals for 7 h, followed by forearm immersion in water hourly for 4 h. The other limbs were then treated one at a time, and finally the trunk. After a week, the patient wasable to tolerate whole-body immersion in cold water for 5 min without urticaria. He maintained this "desensitization" with a 5-min cold shower every 12 h. He was free from urticaria for 6 months, continuing his daily cold showers, this short of regimen is only suitable in rare cases. There is udency for cold urticaria to disappear after months, although about 50% of patients have symptomatic disease. As a provocative test, a plastic-wrapped ice cube is applied [to the skin for 5 to 20 min. If no wheal develops, the area should be fanned for an additional 10 min. The use of a combination of cold and moving air is, in some cases, more effective in reproducing lesions than is cold alone.The provocative is not performed if secondary cold urticaria is Being considered Secondary cold urticaria is associated with an underlying systemic disease, such as cryoglobulinemia. Other associations include cryofibrinogenemia, multiple myeloma, secondary syphilis, hepatitis, and infectious mononucleosis. Patients may have headache, hypotension, laryngeal edema, and pcope. An ice-cube test is not recommended, since it can

jrecipitate vascular occlusion and tissue ischemia. Familial cold urticaria is grouped with the other autoInflamatory syndromes. The lesions produce a burning ensation rather than itching. They may have cyanotic centers nd surrounding white halos, and last for 24 to 48 h. They lay be accompanied by fever, chills, headache, arthralgia, ivalgia, and abdominal pain. A prominent feature is leukocytosis, which is the first observable response to cold, imilial cold urticaria will yield a negative result to an ice-ibe test. Stanozolol therapy has been shown to be effective treating three of eight patients.

Heat Urticaria Within 5 min after the skin has been exposed to heat above43 C (109.4 F), the exposed area begins to burn and sting and becomes red, swollen, and indurated. This rare type of urticaria may also be generalized and is accompanied by cramps, weakness, flushing, salivation, and collapse. Heat desensitization may be effective. As a provocative test, apply a heated cylinder, 50 to 55 C (122-131 F), to a small area of skin of the upper body for 30 min. Solar Urticaria Solar urticaria appears soon after unshielded skin is exposed to sunlight. It is classified by the wavelengths of light that precipitate the reaction. Visible light can trigger solar urticaria, and sunblocks may not prevent it. Treatment is sun avoidance, sunscreens, antihistamines, repetitive phototherapy, and PUVA. (Solar urticaria is reviewed more ekstensively in Chapter 3.)

Presure Urticaria (Delayed Pressure Urticaria) Presure urticaria is characterized by the development of swelling with pain that occurs 3 to 12 h after local pressure has been applied. It occurs most frequently on the feet after walking and on the buttocks after sitting. It is unique in that there may be a latent period of as much as 24 h before lesions develop. Arthralgias, fever, chills, and leukocytosis can occur. The pain and swelling last for 8 to 24 h. Pressure urticaria may be seen in combination with other physical urticarias. As a provocative test, a 15-lb weight is applied to the skin for 20 min and the area inspected after 4 to 8 h. The combination of montclukast and an antihistamine has been used effectively. Systemic corticosteroids are often therapeutic, but are generally unsuitable for long-term use. High-dose IVIG is effective in some cases refractory to other treatment.

Exercise-Induced Urticaria Although both cholinergic urticaria and exercise urticaria are precipitated by exercise, they are distinct entities. Raising the body temperature passively will not induce exercise urticaria, and the lesions of exercise urticaria are larger than the tiny wheals of cholinergic urticaria. Urticarial lesions appear 5 to 30 min after the start of exercise. Anaphylaxis may be associated. Atopy is common in these patients and some have documented food allergy. Avoiding these allergens may improve symptoms. Therapy with H1 and H2 antihistamines may be partially effective. Self-injectable epinephrine kits are recommended for those rare patients with episodes of anaphylaxis manifesting respiratory symptoms. Exercise is a provocative test.

Vibratory Angioedema Vibratory angioedema, a form of physical urticaria, may be an inherited autosomaldominant trait, or it may be acquired after prolonged occupational vibration exposure. Dermato-graphism, pressure urticaria, and cholinergic urticaria may occur in affected patients. Plasma histamine levels are elevated during attacks. The appearance of the angioedema is usually not delayed. The treatment is antihistamines. As a provocative test, laboratory vortex vibration is applied to the forearm for 5 min.

Aquagenic Urticaria This rare condition is elicited by water or seawater at any temperature. Pruritic wheals develop immediately or within minutes at the sites of contact of the skin with water, irrespective of temperature or source, and clear within 30 to 60 min. Sweat, saliva, and even tears can precipitate a reaction. Aquagenic urticaria may be familial in some cases or associated with atopy or cholinergic urticaria. Systemic symptoms have been reported to include wheezing, dysphagia, and respiratory distress. The pathogenesis is unknown but may be associated with water-soluble antigens that diffuse into the dermis and cause histamine release from sensitized mast cells. Whealing may be prevented by pretreatment of the skin with petrolatum. Many antihistamines have been effective. PUVA appears to prevent skin lesions but may not prevent the symptoms of pruritus. The provocative test is to apply water compresses (35 C [95 F]) to the skin of the upper body for 30 min.

Galvanic Urticaria Galvanic urticaria has been described after exposure to a galvanic device used to treat hyperhidrosis. The relationship of this condition to other forms of physical urticaria remains to be established.