PHYSICAL URTICARIAS INTRODUCTION Physical urticarias are disorders in which urticaria (ie, hives or wheals) are induced by environmental

l stimuli, such as heat, cold, pressure applied to the skin, exercise, water, vibration, and sunlight. These conditions probably result from heightened sensitivity by the mast cell to environmental conditions, although the exact pathogenesis is unknown. An urticarial lesion is an intensely pruritic, circumscribed, raised, erythematous plaque, which can range in diameter from a few millimeters to many centimeters (picture 1 and picture 2). Urticaria may enlarge, sometimes developing central pallor, and coalesce with other adjacent lesions. They usually appear in crops and are typically short-lived, expanding and then resolving over a few hours without leaving residual marks on the skin (unless there is trauma from scratching). Physical urticarias will be discussed in this topic review. Other disorders of acute and chronic urticaria are reviewed separately. (See "New onset urticaria: Epidemiology, clinical manifestations, and etiologies" and "Chronic urticaria: Diagnosis, theories of pathogenesis, and natural history" and "Chronic urticaria: Standard management and patient education".) GENERAL POINTS ABOUT PHYSICAL URTICARIAS Before discussing individual syndromes, it is helpful to review some observations about the physical urticaria disorders as a group. Physical urticarias are considered subtypes of chronic urticaria (CU). In some patients, a specific physical stimulus is the only trigger for hives, whereas in others, a physical stimulus is an identifiable factor in a case of otherwise idiopathic urticaria. A minority of patients have hives triggered by multiple physical stimuli. Prevalence Considered together, the physical urticarias are present in approximately 20 to 30 percent of adults with chronic urticaria, a disorder that afflicts approximately 1 percent of adults. Physical urticarias may be more common in children [1]. The prevalence of these disorders in the general population is not well defined, and many cases may be mild and easily managed in the primary care setting. In contrast, most published reports are based upon patient populations referred to specialty centers, and so may overestimate the severity and persistence of these disorders. Classification There are differences among experts concerning the best manner of classifying the physical urticarias. Guidelines for classification and diagnosis have been published by a European expert panel [2]; the material in this topic review is similar, although not identical. Variations in clinical presentation and severity Physical urticarias vary widely in severity. The symptoms of each syndrome can range from mild to disabling, with some patients experiencing potentially dangerous systemic symptoms. Testing Specific testing procedures are presented in the discussions of each disorder below and summarized in the table (table 1) [3]. However, there are some general points to consider in performing challenge procedures for physical urticarias. Precautions Physical challenges are not always needed for diagnosis, although they are sometime invaluable in clarifying or confirming the diagnosis. These challenges are usually performed by allergy specialists with training in the management of the systemic allergic reactions that could conceivably

result in anaphylaxis. Proper access to the staff and equipment necessary to treat a potentially lifethreatening allergic reaction is essential. This is especially true if the patient has experienced systemic symptoms in the past (eg, bronchospasm or hypotension). During these challenges, physical stimuli are applied to the skin for a specified amount of time, usually a few minutes, and then removed. Urticaria typically develops AFTER removal of the stimulus. Leaving the stimulus in contact with the skin until hives actually appear can result in excessive exposure and systemic symptoms. Similarly, exposure time may need to be reduced in patients who describe unusual levels of sensitivity. When to refer Patients suspected of having a syndrome of physical urticaria should be referred to an allergy or dermatology specialist with experience in these disorders in the following situations: The diagnosis is not apparent, orThe condition does not respond adequately to initial therapy As mentioned previously, referral is usually appropriate if a challenge procedure is being considered. Patients with past systemic reactions/anaphylaxis should be referred to allergists specifically, because of the potential risk involved in challenging such patients. OVERVIEW OF TREATMENT APPROACH The treatment of physical urticarias should be approached in a stepwise manner. Avoidance of the physical stimuli that induce symptoms should always be considered initially, although complete avoidance may not be possible or practical. Pharmacologic therapy is often required but variably successful. Certain types of physical urticaria (eg, dermographism) are responsive to antihistamines, while other forms (eg, local heat urticaria) are typically resistant. However, therapy must be individualized in each case, often by trial and error. In addition, most studies of therapy in these disorders were performed with first-generation, sedating H1 antihistamines, and the relative effectiveness of the newer second- and third-generation drugs has not been evaluated. In most patients with a physical urticaria disorder who cannot avoid the stimulus, a trial of antihistamines is warranted. The approach outlined here is opinion-based, since trials comparing different regimens are lacking. We usually begin with a second or third generation H1 antihistamine at standard doses, but quickly increase to double the standard dose (eg, cetirizine 10 mg twice daily, fexofenadine 180 mg twice daily, or loratadine 10 mg twice daily) if needed.If symptoms are not controlled, we add an H2 antihistamine at standard dose. If there is no detectable improvement, the H2 antihistamine can be discontinued.If the response is still not adequate, we usually change the second generation H1 antihistamine to a first generation agent, and increase the dose as tolerated (eg, hydroxyzine, beginning with 25 mg at bedtime, and increasing gradually to an upper limit of 100 to 200 mg daily, divided among four doses). When symptoms of physical urticaria cannot be controlled with combinations of antihistamines, oral glucocorticoids may be used for short-term treatment and are usually very effective. We typically continue antihistamines and begin glucocorticoid therapy with prednisone, 0.5 to 1.0 mg per kg daily. Symptoms usually improve within days. The dose can then be tapered gradually over two to four weeks to discontinuation, or at least to <10 mg per day. If the prednisone cannot be reduced to <10 mg per day after two to four weeks or stopped entirely within two to three months, then an alternate, steroid-

sparing agent should be considered, as the long-term side effects of glucocorticoids make chronic therapy undesirable. (See "Major side effects of systemic glucocorticoids".) Agents that have been found to be useful for particular physical urticaria syndromes are discussed in the sections below, as are alternate therapies for refractory disease. The treatment of chronic idiopathic urticaria is reviewed in detail separately. (See "Chronic urticaria: Standard management and patient education".) DERMOGRAPHISM Dermographism (also called dermatographism) literally means to ''write on the skin.'' Patients with this condition develop the rapid onset of a wheal and flare reaction after firm stroking, scratching, or the application of pressure to the skin. Dermographism is the most common of the physical urticarias and is often an incidental finding in the evaluation of other skin conditions, most commonly atopic dermatitis, chronic idiopathic urticaria, and the other physical urticarias discussed in this article. There are several forms of dermographism. Most individuals have simple dermographism, which is asymptomatic (non-pruritic) other than the raised urticarial welts that form on the skin with scratching, etc. (picture 3 and picture 4). The other forms of dermographism are symptomatic and vary in their clinical appearances. Epidemiology Simple dermographism is the most common form and is thought to occur in approximately 2 to 5 percent of the general population [4,5]. The symptomatic forms of dermographism are much less common and usually occur sporadically, although there is a single case report of familial dermographism [6]. Clinical features In simple dermographism, a wheal is provoked by stroking the skin with a firm object. The wheal typically appears within 6 to 7 minutes and begins to fade 15 to 30 minutes later [4]. Symptomatic dermographism is only slightly different, with lesions appearing in less than 5 minutes and lasting 30 minutes [2]. In addition to classic wheals, variants of symptomatic dermographism have been described in which the reactions are follicular [7] or inflamed and swollen (red dermographism) [8]. Although a purposeful stroking of the skin is the most common way to elicit symptoms, patients often are unaware of the inciting action. Occasionally, idiopathic pruritus or pruritus caused by dry skin can be the event that elicits scratching and subsequent dermographism. In this setting, the wheals are typically linear. Simple actions such as scratching, leaning against a solid object, or irritation from clothes or bed sheets may provoke whealing. In one case series, dermographism could be exacerbated by hot water, emotion, exercise, or cold exposure [9]. Dermographism is typically idiopathic and begins without a clear inciting event. However, inflammatory perturbations may occasionally precede onset, as cases have been described in which symptomatic dermographism appeared to be triggered by infections with bacteria, fungi, and scabies [10,11] or after receiving penicillin [12] or famotidine [13]. Pathogenesis The cause of dermographism is unknown. The release of vasoactive mediators from cutaneous mast cells is assumed to be involved, and elevated levels of serum histamine have been demonstrated after a whealing episode [14]. Experiments in which serum from a dermatographic

patient injected intradermally into a monkey transferred dermographism suggest that the reaction may be IgE-mediated, although no allergen has been identified [14,15]. Diagnostic testing Patients with dermographism can be diagnosed in an office setting by stroking the skin with a firm (clean) object, such as a tongue blade (table 1). This action provokes a typical whealand-flare response within a few minutes, as described earlier. The patient should refrain from taking antihistamines for several days before the test. Treatment Simple dermographism that is non-pruritic requires no therapy, and treatment involves avoidance of inciting triggers. If the skin appears dry, emollients (such as hydrated petrolatum applied daily, immediately after bathing) can be helpful. H1 antihistamines have been shown to be effective for treatment of pruritus and reduction of whealing, and are the initial drug of choice. Both first-generation antihistamines, such as hydroxyzine, and secondgeneration H1 antihistamines, such as cetirizine, have demonstrated benefit, although studies comparing different antihistamine regimens are lacking [8,16-18]. It is our practice to initiate therapy for symptomatic dermographism with non-sedating secondgeneration H1 antihistamines, as described above. (See 'Overview of treatment approach' above.)The addition of an H2 antihistamine was beneficial in several studies [17,19,20], although not all concluded that there was an additive effect [14]. A trial of combination therapy with an H1 and H2 antihistamine is warranted if the response to H1 antihistamines alone is inadequate.Some patients report that sun exposure improves the condition, and one uncontrolled study of 43 patients reported that 39 improved or cleared with ultraviolet B (UVB) light treatment [21]. Such aggressive therapy could be considered in a patient refractory to standard medications and with a severe decrease in quality of life (eg, poor sleep, poor performance at work or school, negative effect on social life).Case reports describe successful treatment with omalizumab [22], although this application is not approved by the US Food and Drug Administration. DELAYED PRESSURE URTICARIA/ANGIOEDEMA Delayed-pressure urticaria/angioedema (which is sometimes classified as a delayed form of symptomatic dermographism) presents most commonly as an erythematous swelling of the skin that develops four to six hours after pressure has been applied to the area. Clinical manifestations The leading presentation is erythematous swelling of the skin four to six hours after the application of pressure. Less often, patients develop urticaria with prominent swelling. The amount of pressure that is needed to induce symptoms varies among different individuals. Patients often describe burning and pain instead of or in addition to pruritus, and the swelling can last several hours to several days [2]. There may be accompanying arthralgias [10]. Activities that typically induce symptoms in patients with delayed-pressure angioedema include wearing tight clothing (affecting areas of constriction), sitting for prolonged periods of time on a hard surface (affecting the buttocks), an extended period of walking (affecting the soles and feet), or carrying heavy bags of groceries (affecting the palms and hands). Some patients will wake up with facial swelling on the side of the face that was compressed against the pillow. Diagnosis Delayed pressure urticaria/angioedema can often be accurately diagnosed based upon historical features alone. Devices called dermographometers have been used in research protocols in

the past, but are not widely available [23,24]. Alternatively, a sling attached to a 10 pound weight may be placed over the patient's arm for 20 minutes [25], after which the patient is instructed to observe the compressed skin for symptoms over the next 24 hours (table 1). The patient should refrain from taking antihistamines for several days before the test. Treatment The approach to treatment of delayed-pressure urticaria/angioedema is similar to that of symptomatic dermographism, although antileukotriene agents have also shown utility [26-28]. In a randomized trial of 36 patients with delayed pressure urticaria confirmed by challenge with a dermographometer (18 of whom had concomitant chronic idiopathic urticaria), patients were assigned to one of three treatment groups [28]: Oral desloratadine (5 mg once daily) plus oral placeboOral desloratadine (5 mg once daily) plus montelukast (10 mg once daily)Oral placebo alone Subjects were rechallenged after two weeks of therapy. Patients in both active treatment groups showed a significant reduction in the mean diameter of the induced wheals compared to placebo, and patients in the group receiving montelukast were significantly better than those receiving desloratadine alone, with fewer episodes and reduced symptoms. The use of other antihistamines in combination with montelukast has not been studied, although different agents are probably also effective. A few case reports describe successful treatment with omalizumab [29,30], although this application is not approved by the US Food and Drug Administration. CHOLINERGIC URTICARIA Cholinergic urticaria (sometimes called generalized heat urticaria) describes hives that are precipitated by an increase in core body temperature. Common triggers include exercise, strong emotions, and bathing in hot water [31]. Epidemiology Cholinergic urticaria is believed to account for approximately 30 percent of all cases of physical urticaria and approximately 5 percent of all cases of chronic urticaria [32]. Cholinergic urticaria typically has its onset during the second or third decade of life [33-35]. Whereas one study noted a predominance in male patients [33], others have found that both sexes are affected equally [34,35]. Familial cases are rare but have been reported (in which all affected individuals were male) [36]. Clinical features The classic initial appearance of cholinergic urticaria is that of numerous small (1 to 3 mm), punctate wheals surrounded by large flares (picture 5). Many patients note a tingling, itching, or burning sensation of the skin before the appearance of the hives [33]. As the response progresses, the flares may coalesce to form large areas of erythema. The wheals typically begin on the trunk and neck and spread distally to involve the face and extremities, although lesions may begin anywhere on the body. In rare cases, cholinergic urticaria has been reported to progress to include systemic symptoms such as hypotension, angioedema, and bronchospasm [33,37,38]. As mentioned earlier, any trigger that results in an elevation of core body temperature may provoke the onset of cholinergic urticaria. Exercise is one of the most common triggers, and cholinergic urticaria may be confused with exercise-induced urticaria if other triggers are not considered. However, the two conditions can usually be distinguished, because a variety of triggers precipitate cholinergic urticaria,

while exercise or exertion is usually the sole trigger for exercise-induced urticaria. (See 'Exercise-induced urticaria' below.) Other typical inciting factors for cholinergic urticaria include hot baths or showers, strong emotional feelings, and ingestion of spicy or hot foods [33,34]. In one study, a patient with preexisting cholinergic urticaria experienced a flare of his condition while undergoing dialysis treatments [39]. A decrease in the patient's dialysate temperature by 1.5C led to resolution of his symptoms, and rechallenge with fluid at a higher temperature reproduced his urticaria. Pathogenesis As with many of the other physical urticarias, a variety of pathogenetic mechanisms have been postulated in cholinergic urticaria, and there may be different mechanisms at work in different patients. Elevated levels of histamine have been detected in the serum during an attack [38]. One theory of pathogenesis proposed that urticaria in this condition was caused by the cholinergic nervous system [37]. In some patients, the injection of methacholine intradermally induces urticaria, which can be reversed by administration of atropine [33,40,41]. Patients with cholinergic urticaria have been shown to have an increased number of muscarinic receptors on cutaneous mast cells in areas that demonstrate hives [42].The presence of a more typical antigen-antibody reaction or a transferable serum factor has been investigated in a series of passive transfer experiments using sera from patients with cholinergic urticaria that were injected into the skin of a primate [43]. When the monkey subsequently was injected with acetylcholine, a cutaneous reaction was observed with 7 of 16 patient sera. (See 'Diagnosis and testing' below.)Many of the triggers for cholinergic urticaria also lead to increased sweating, and a subgroup of patients with symptoms suggestive of cholinergic urticaria have urticaria only in response to sweating. Several studies have suggested that cholinergic urticaria might be caused by an IgE-mediated allergy to some component of human sweat [44-47]. Some patients demonstrate immediate reactions to skin testing with their own diluted sweat [44,47,48]. An IgE-mediated mechanism was also implicated in a case report of a patient successfully treated with anti-IgE therapy [46]. Another found that a group of 18 patients with cholinergic urticaria appeared to have two separate mechanisms for their condition [45]. One subset reacted when skin tested to their own sweat, and had a positive acetylcholine skin test. The rest of the patients had a negative acetylcholine test and were skin test negative to sweat. There have been several reports of patients with cholinergic urticaria that was associated with hypohidrosis [49,50]. An explanation was proposed that occlusion of the pores of the stratum corneum could cause hypohidrosis and subsequent abnormal leakage of inflammatory sweat materials into the upper dermis, resulting in a whealing reaction [50]. Diagnostic testing The presentation of the lesions of classic cholinergic urticaria in the context of typical inciting triggers is often sufficient to make the diagnosis, and a clinical diagnosis is usually all that is required in routine practice. However, several methods of provocation testing have been proposed, which are largely used in research settings (table 1): An intradermal injection of 0.01 mg of methacholine in 0.1 mL saline that produces a local area of hives is diagnostic. However, only about one-third of patients with cholinergic urticaria demonstrate a positive test, so this procedure cannot be used to exclude the diagnosis [33,40]. In addition, there are currently no injectable forms of methacholine commercially available in the United States.Another diagnostic strategy used in research protocols involves non-exertional elevation of the patient's core body

temperature. Patients may have one or both arms submerged in a 40C hot water bath until the core body temperature has increased at least 0.7C [51]. The appearance of generalized urticaria confirms the diagnosis of cholinergic urticaria. Treatment Identification and avoidance of known triggers are the first steps in controlling cholinergic urticaria. Bathing in hot water and performing strenuous exercise during hot weather are to be avoided. Medical therapy consists predominantly of oral H1 antihistamines. Typically these are taken daily, although as needed administration is possible if triggers are easy to identify in advance.We usually initiate therapy with a second generation antihistamine, as described previously. (See 'Overview of treatment approach' above.) Cetirizine, a less sedating metabolite of hydroxyzine, has shown efficacy at doses twice normal (10 mg twice daily) [52].If cetirizine at twice normal dose is not effective, we typically change to the first generation antihistamine hydroxyzine, which has been used successfully for decades [5,34]. This agent is highly sedating for some patients. Therapy should be initiated with a low dose which is increased gradually until the urticaria is controlled, which typically occurs at doses of 100 to 200 mg divided over 24 hours. Studies comparing the hydroxyzine to cetirizine have not been performed, but clinical experience suggests that some patients who do not respond to cetirizine do respond to hydroxyzine.Ketotifen (not available in the United States) has also shown efficacy in treating cholinergic urticaria at doses of 3 to 8 mg daily [53,54]. This agent is highly sedating for some patients.The anabolic steroid danazol can be effective [55,56]. This agent is postulated to correct the low blood levels of protease inhibitors that occur in some patients with cholinergic urticaria [57]. Given its potential for adverse effects, however, this medication should be reserved only for severe cases refractory to antihistamines.Omalizumab has been used successfully in the treatment of cholinergic urticaria [46,48], although failures are also reported [58].Desensitization may be possible as patients will sometimes experience a period of latency after an episode of cholinergic urticaria. In most cases, these relatively symptom-free periods lasted only a few hours but could last more than 24 hours if the initial episode was severe. One study described two patients who treated themselves on a nightly basis using a dose of antihistamine that was followed three hours later by a hot bath [34].Oral anticholinergic agents have NOT been shown to be effective [34]. Prognosis The prognosis for cholinergic urticaria is generally favorable. One study reported only 31 percent of patients with a persistence of symptoms greater than 10 years [33]. Another estimated that the average duration of symptoms is 7.5 years (range, 3 to 16 years) [59]. LOCAL HEAT URTICARIA Local heat urticaria describes a rare disorder in which a warm stimulus must come into direct contact with the skin and results in the formation of a wheal at the heated site within minutes [25]. The pathogenesis involves histamine release, implicating the mast cell in the cause of this condition [60]. Passive transfer experiments, however, have been negative. There is one case report of a familial, delayed-type variant of local heat urticaria [61]. Diagnostic testing is conducted by the application of a test tube containing water at 44C to the arm for four to five minutes [25]. Other authors recommend using a cylinder heated to 50C to 55C [51] (table 1). A localized hive should develop within a few minutes after removal of the heated object. The patient should refrain from taking antihistamines for several days before the test. Occasionally, positive test can only be obtained on specific areas of skin that have displayed symptoms in the past [62].

Therapy using antihistamines and oral cromolyn has not been effective for local heat urticaria [25]. Desensitization using daily hot baths was successful in one patient but carries some risk for a systemic reaction [63]. EXERCISE-INDUCED URTICARIA Urticaria with exercise has been shown to occur in two distinct situations. Cholinergic urticaria Patients with cholinergic urticaria develop hives after exercising or after experiencing any other trigger that elevates core body temperature. Systemic symptoms are uncommon, but can occur. (See 'Cholinergic urticaria' above.)Exercise-induced anaphylaxis Urticaria with exercise may also be an early manifestation of exercise-induced anaphylaxis. Unlike in cholinergic urticaria, exercise is the only trigger in exercise-induced anaphylaxis, and passively raising the core body temperature is not sufficient to induce symptoms. This disorder is reviewed in detail elsewhere. (See "Exercise-induced anaphylaxis: Clinical manifestations, epidemiology, and diagnosis".) The hives of exercise-induced anaphylaxis are typically larger in size than those of cholinergic urticaria, although cases of exercise-induced anaphylaxis presenting with punctate lesions have been reported. AQUAGENIC URTICARIA Aquagenic urticaria is a rare condition in which urticaria develop as a result of direct skin contact with water. Epidemiology There are fewer than 50 cases of aquagenic urticaria reported in the medical literature [2,64-68]. Women seem to have a slightly higher incidence than men, and in most cases, the age of onset is during or slightly after puberty. Familial occurrences have been reported on several occasions [65-67]; in one report the condition existed across three generations of a single family [65]. Clinical features The lesions of aquagenic urticaria are characteristically small, punctuate (1 to 3 mm), perifollicular wheals that may occur on all parts of the body, although generally not on the palms and soles. In appearance, they are indistinguishable from the wheals of cholinergic urticaria. However, in aquagenic urticaria, hives appear rapidly after direct contact with various sources of water (ie, distilled, tap, or saline). In some patients, salinity appears to be important. One patient experienced urticaria after exposure to tap water, snow, and sweat but did not develop symptoms after exposure to sea water [69]. Another developed hives on exposure to sea water, but not fresh water, although over time she also because sensitive to tap water as well [70]. Hive formation is not influenced by the temperature or pH of the water [68]. Alcohol and other liquid organic solvents applied to the skin do not lead to wheal formation [67,68]; however, they can potentiate the reaction to water, likely by enhancing the permeability of the skin [71]. Wheals appear rapidly within 20 to 30 minutes following exposure to water; once the water source is removed from the skin, the wheals generally fade within 30 to 60 minutes [2]. Systemic symptoms are rare, but have been reported [66,72]. A refractory period lasting several hours has been demonstrated after an attack [73]. Repeated, short, purposeful exposures to water can lead to exhaustion of the wheal response [71].

Aquagenic urticaria is occasionally associated with other forms of physical urticaria. Case reports describe patients with aquagenic urticaria and coexisting dermographism [66,74], cholinergic urticaria [67,73,74], or cold urticaria [75]. Pathogenesis The pathogenesis of this condition is poorly understood and may not be the same in all patients. Several theories have been proposed based upon studies in small numbers of subjects. Serum histamine levels are variable from patient to patient, as is the response to pretreatment with oral antihistamines. The following mechanisms have been postulated: Several researchers have proposed that water is primarily acting as a solvent in aquagenic urticaria, solubilizing an antigen that then permeates the skin and activates dermal mast cells. Water may interact with sebum (the oily substance produced by sebaceous glands in the skin) to form a substance capable of acting as a direct mast cell degranulator, resulting in histamine release [64]. One study demonstrated that patch testing with a patient's sweat produced only erythema, whereas testing with sweat and sebum produced marked urticaria [68]. Others have proposed that the causative antigen(s) normally reside at the epidermal layer of the skin and solubilization in water allowing these antigens to diffuse more deeply into the skin [67]. It is possible that different antigens in different skin layers are involved. In another study, removal of the stratum corneum layer of the skin enhanced reactivity upon contact with water [71]. Similarly, pretreatment of the skin with organic solvents enhanced wheal formation to water. These investigators concluded that enhancing the ability of water to penetrate the stratum corneum layer of the skin increases the wheal-provoking effects of water in these patients.Another theory suggested that activation of the cholinergic pathway was essential for the formation of aquagenic urticaria, based upon the ability of the acetylcholine antagonist scopolamine to suppress wheal formation when applied to the skin before water exposure in two patients [71]. However, other studies did not find evidence for a cholinergic mechanism, as pretreatment with atropine did not suppress subsequent wheal formation [67]. In addition, methacholine injection testing, often positive in cholinergic urticaria, was negative in a series of patients with aquagenic urticaria [68]. The studies reviewed above were performed before the publication of those implicating hypersensitivity to sweat allergens in cholinergic urticaria, and comparative mechanistic studies of the two conditions have not been undertaken. (See 'Cholinergic urticaria' above.) Diagnostic testing The standard test for aquagenic urticaria is the application of a compress of 35C water to the upper body for 30 minutes (table 1). Although water of any temperature can provoke aquagenic urticaria, using ambient-temperature water avoids confusion with cold-induced or local heat urticaria. The upper body is chosen as the preferred site, because other areas, such as the extremities, are affected less commonly in aquagenic urticaria [76]. The patient should refrain from taking antihistamines for several days before the test. In some case reports, rinsing specific areas of the body with water or performing direct bath and shower challenges has been attempted. Use of these approaches may be required when localized testing using a small water compress is negative, although it should be avoided in patients with a history of significant systemic symptoms.

Differential diagnosis Aquagenic pruritus, cholinergic urticaria, cold-induced urticaria, and local heat urticaria may have inciting factors that can be confused with those of aquagenic urticaria. Aquagenic pruritus is itching of the skin upon contact with water, without the development of actual hives or other objective findings.Cholinergic urticaria can be elicited by sweating, exercise, heat, and strong emotions, whereas aquagenic urticaria requires the skin to be in direct contact with water.Coldinduced urticaria can be differentiated from aquagenic urticaria by the history of reactions upon exposure to cold air and tolerance of warm or hot water.Local heat urticaria can be distinguished from aquagenic pruritus by reactions to warm but dry triggers (heating pad or test tube filled with warm water). Treatment A trial of H1 antihistamines is warranted in all patients as an initial intervention, although the success of these agents is variable [71,77]. Barrier creams were reported to be effective in a small number of patients, although this may only be practical in very specific circumstances [71,76]. In cases in which antihistamines failed to provide symptomatic benefit, other measures have been attempted. UVB light treatments twice a week in a child with coexisting aquagenic urticaria, cholinergic urticaria, and dermographism resulted in improvement by 20 weeks [74]. Two reports have documented the benefits of PUVA therapy [78,79]. Stanozolol was effective in a patient with HIV infection, hepatitis C virus infection, and aquagenic urticaria, who had failed therapy with oral antihistamines [72]. Symptoms recurred when stanozolol was stopped. SOLAR URTICARIA Solar urticaria involves the induction of urticaria, most commonly following direct exposure of the skin to sunlight [80]. The number of patients affected by this condition is small, and most data are case reports and small series [81-84]. The largest series included 87 cases confirmed by phototesting [85]. Epidemiology Retrospective reviews of patients with urticaria found that only approximately 0.5 percent were classified as solar urticaria [81,82]. There is a higher incidence in women [83,85]. Patient age at onset, atopic history, and the wavelength of light responsible for the reaction varies significantly among patients. Geographic and racial differences have not been described. Clinical features Solar urticaria generally presents with classic-appearing urticarial lesions developing within minutes after exposure to direct sunlight, and occurring on skin that was uncovered (picture 6). However, in the series of 87 cases, 76 and 83 percent developed symptoms through thin clothing and glass, respectively [85]. Limited exposures provoke only itching or burning erythema, while more prolonged exposures lead to typical wheals. A more delayed onset of symptoms (several hours after light exposure) has been reported in a few patients [86,87]. The severity of the symptoms generally increases with the intensity of the sun exposure. Areas of skin that frequently are exposed to sunlight are less sensitive than areas that are usually covered [88]. The exact mechanism of this "hardening" phenomenon remains unknown [89]. A more severe reaction may be provoked by purposeful sunbathing rather than by normal daily sunlight exposure. Systemic, anaphylactic reactions are possible if the exposed body surface area is large enough [5].

When the patient is removed from the sun exposure, symptoms usually fade rapidly. Most patients note disappearance of the urticaria within 24 hours. Pathogenesis It has been hypothesized that solar urticaria is dependent on the presence in the skin of a precursor molecule that is activated by exposure to a particular wavelength of light and becomes a photoallergen. This antigen can be activated in vivo or in vitro by irradiating a sample of the patient's serum [83]. The origin of the precursor molecule has not been determined yet. The fact that passive transfer is not always successful could indicate that there are different photoallergens at work in different patients. One group has suggested that the disorder be divided into two subtypes: type I solar urticaria, due to IgE antibodies directed against an abnormal photoallergen present only in affected patients, and type II solar urticaria, due to circulating IgE antibodies against a normal photoallergen present in most people [90]. Diagnosis and testing Clinical history may be sufficient to differentiate solar urticaria from other conditions. If there is clinical uncertainty, the diagnosis can be established using phototesting (table 1). The patient should refrain from taking antihistamines for several days before the test. A simple form of testing may be performed by exposing a small area of the patient's skin to natural sunlight, which induces erythema or urticaria. The reaction generally fades quickly after the test is halted. However, patients with cholinergic or local heat urticaria might react to this type of testing as well. More formal evaluation is performed with a visible light source, or using instruments that generate UVA or UVB. The patient's skin is exposed to varying wavelengths using a monochromatic light source. Most patients demonstrate a threshold wavelength at which symptoms develop, which is referred to as the action spectrum. In some patients, testing with monochromatic light failed to provoke urticaria, although exposure to other light sources, such as natural sunlight, high-intensity ultraviolet light, or slide-projector light, did cause symptoms [84]. Some patients exhibit an inhibition spectrum, which when applied to the skin during or immediately after the action spectrum, inhibits the development of the wheal reaction [91]. However, application of the inhibition spectrum before the action spectrum does not prevent symptoms [83], so this phenomenon has no immediate clinical utility. Differential diagnosis A variety of photosensitive disorders have been described. Two that can present with symptoms similar to solar urticaria are polymorphous light eruption and erythropoietic protoporphyria. (See "Approach to the patient with macular skin lesions", section on 'Photodistributed macular eruptions'.) The symptoms of solar urticaria could initially be mistaken for common sunburn, however, the lesions of solar urticaria develop within minutes of sun exposure. Polymorphous light eruption In this idiopathic condition, which is far more common than solar urticaria, papular and papular-vesicular lesions appear on sun-exposed areas, although there is less of a predilection for the face (picture 7 and picture 8). The lesions of polymorphous light eruption tend to last two to six days, which usually allows differentiation from solar urticaria, in which lesions resolve within 24 hours. (See "Polymorphous light eruption".)Erythropoietic protoporphyria This condition can demonstrate urticaria on sun-exposed areas, although the lesions are typically painful rather than pruritic. Erythropoietic protoporphyria usually presents in early childhood, and there is a family history

of the disorder. The cutaneous lesions of erythropoietic protoporphyria can develop within minutes of sun exposure, and diffuse edema of the skin in sun-exposed areas may resemble angioedema. Petechiae and purpuric lesions may be seen. With time, the skin may become lichenified and leathery, with labial grooving and nail changes (picture 9). This disorder is reviewed separately. (See "Erythropoietic protoporphyria".) Treatment and prognosis H1 antihistamines provide symptomatic treatment and can be used orally or topically. These medications are effective in reducing pruritus and wheal formation but may not eliminate the erythema. In most of the initial studies, terfenadine was used, and higher-than-standard doses often were required to achieve symptom relief [92]. Whether this finding is true for all antihistamines, including some of the newer agents, remains to be determined. Topical and systemic steroids can be used if antihistamines are insufficient. (See 'Overview of treatment approach' above.) Desensitization may be useful in some cases. It has been demonstrated that skin that is regularly exposed to sunlight becomes less reactive than that which is usually covered [88]. Patients may be repeatedly exposed to ultraviolet light sources, although the desensitized state typically lasts only a few days. The use of psoralen plus ultraviolet A radiation (PUVA) has been shown to induce a longer-lasting effect, although the potential long-term adverse effects are greater [92]. At least one instance of the successful use of cyclosporine (4.5 mg per kg per day) for refractory solar urticaria has been reported [93]. A small number of case reports describe resolution or improvement with omalizumab treatment [30,94,95]. Plasmapheresis has been used alone and in conjunction with PUVA therapy [96-98]. This modality has been reported to improve symptoms in the few patients included in these studies. One study failed to demonstrate a lasting benefit with plasmapheresis [99]. The effectiveness of this therapy may depend on the characteristics of the specific photoallergen at work (ie, circulating antigen versus cutaneous antigen). The long-term outlook for patients with solar urticaria has been uncertain because of the small number of cases. A review of 87 patients found that 25 percent of 60 subjects who were available for follow-up reported complete resolution of their conditions [85]. An additional 32 percent reported improvement, whereas 35 percent were unchanged, and 8 percent believed that their conditions had worsened. Most of the original case reports indicated that the condition was persistent, and although many experienced overall improvement in symptoms, few patients experienced complete resolution. VIBRATORY ANGIOEDEMA Vibratory angioedema refers to the development of pruritus and swelling after the application of a vibratory stimulus to the skin. Hives are usually not observed in this syndrome. Epidemiology Reports of vibratory angioedema are rare. The condition was initially described in four members of one family, in which there was an autosomal dominant inheritance pattern [100]. This was followed by another familial report [101], and the condition was given the name hereditary vibratory angioedema. Other case reports of patients with vibratory angioedema have been sporadic and generally related to the subject's occupation.

Clinical features Common triggers for vibratory angioedema include mowing the lawn, riding a motorcycle, horseback riding, or mountain biking. At risk occupations include jackhammer operator, machinist [102], carpenter [102], and metal grinder [103]. Patients generally complain of local pruritus, erythema, and swelling arising within a few minutes after exposure to vibration and affecting the area that was most exposed to the stimulus (often the hands). There are rare cases of delayed onset symptoms beginning one to two hours after exposure [104]. Symptoms peak in severity at four to six hours and typically resolve by 24 hours. In some episodes, the symptoms may persist for several days. The severity and duration of the symptoms may vary and seem to be proportional to the intensity and duration of the applied vibratory stimulus and to the area of exposed body surface. Patterson's initial report described systemic symptoms of headache and generalized erythema [100]. One patient developed carpal tunnel syndrome, and slowed median nerve conduction was documented only during episodes of edema [103]. Pathogenesis The pathogenesis of vibratory angioedema has not been satisfactorily elucidated yet. Elevated levels of serum histamine and mast cell degranulation have been documented during symptomatic episodes [102,104,105]. Most investigators favor a nonimmunologic reaction (eg, direct mast cell stimulation from the vibration causes degranulation and local release of histamine) and passive transfer experiments have been negative [100,105]. In a study of vibration exercise in 37 healthy subjects, approximately one-half developed a pruritic erythematous eruption [106]. Diagnostic testing Several methods for reproducing the vibratory stimulus and classifying the reaction have been used in the literature [2]. The patient should refrain from taking antihistamines for several days before the test. The subject's arm is held on a level plane, and a vortex mixer is placed in contact with the skin (table 1). The vibratory stimulus is applied for five minutes, and the site is observed for five to six hours. The test is considered positive if the area becomes erythematous, pruritic, and edematous around the full circumference of the arm, although one study found that this test also induced a positive response in 7 of 20 normal volunteers [107], suggesting that this response may not be entirely abnormal, as mentioned previously. Dermographism and pressure urticaria should be excluded using the appropriate tests. Treatment Patient avoidance of specific vibratory stimuli is the first line of therapy, although this may not be possible in occupational cases. H1 antihistamines have been used successfully [108]. (See 'Overview of treatment approach' above.) A state of tolerance was achieved in one patient by using twice-daily vibration challenges until symptoms were delayed in onset and reduced in duration [105]. The patient eventually attained complete control of her symptoms by using a five-minute desensitization protocol every five to seven days. However, a state of tolerance could not be induced in another case report [108]. INFORMATION FOR PATIENTS Educational materials on this topic are available for patients. (See "Patient information: Hives (urticaria)".) We encourage you to print or e-mail this topic review, or to refer patients to our public web site, www.uptodate.com/patients, which includes this and other topics. SUMMARY AND RECOMMENDATIONS

Clinical manifestations Physical urticarias are forms of chronic urticaria in which hives (sometimes with angioedema) are induced by environmental stimuli. Physical urticarias vary in severity from mild to disabling. Some forms can escalate to systemic reactions and anaphylaxis. (See 'Introduction' above and 'Prevalence' above.) The more common physical urticaria syndromes include dermographism, cholinergic urticaria, and delayed pressure urticaria/angioedema.Rare disorders include urticaria/angioedema following exposure to heat, exercise, water, vibration, or sunlight. (See sections on specific disorders above). Diagnosis and treatment Physical urticarias can often be diagnosed based upon history and physical examination. In some cases, physical challenge procedures are needed to clarify or confirm the responsible trigger (table 1). These challenges are usually performed by allergy or dermatology specialists with experience with these techniques, as overly aggressive challenges can induce systemic reactions. Patients with past systemic reactions should only be challenged by an allergist in a medical setting equipped to manage anaphylaxis. (See 'When to refer' above.) The management of physical urticaria begins with accurate identification and avoidance of the triggering stimulus.For initial pharmacotherapy, we suggest a less-sedating, second generation antihistamine (Grade 2C). Options include cetirizine (10 mg daily), loratadine (10 mg daily) or fexofenadine (180 mg daily). Many patients will require a doubling of the standard dose to impact symptoms significantly (eg, cetirizine, 10 mg twice daily). (See 'Overview of treatment approach' above.)Subsequent management proceeds in a stepwise manner and includes H2 antihistamines, first generation H1 antihistamines, and in some cases, limited courses of systemic glucocorticoids. (See 'Overview of treatment approach' above.)Specific physical urticarias are more or less responsive to pharmacotherapy, and others agents have shown utility in certain disorders (eg, antileukotriene agents in delayed pressure angioedema). (See sections on specific disorders above).Steroid-sparing therapies should be considered for patients requiring systemic glucocorticoids beyond two to three months. Depending on the disorder, options include phototherapy, physical desensitization protocols, and immunomodulatory agents. (See sections on specific disorders above). Use of UpToDate is subject to the Subscription and License Agreement REFERENCES 1. Khakoo G, Sofianou-Katsoulis A, Perkin MR, Lack G. Clinical features and natural history of physical urticaria in children. Pediatr Allergy Immunol 2008; 19:363. 2. Kontou-Fili K, Borici-Mazi R, Kapp A, et al. Physical urticaria: classification and diagnostic guidelines. An EAACI position paper. Allergy 1997; 52:504. 3. Magerl M, Borzova E, Gimnez-Arnau A, et al. The definition and diagnostic testing of physical and cholinergic urticarias--EAACI/GA2LEN/EDF/UNEV consensus panel recommendations. Allergy 2009; 64:1715. 4. Kirby JD, Matthews CN, James J, et al. The incidence and other aspects of factitious wealing (dermographism). Br J Dermatol 1971; 85:331. 5. Orfan NA, Kolski GB. Physical urticarias. Ann Allergy 1993; 71:205. 6. Jedele KB, Michels VV. Familial dermographism. Am J Med Genet 1991; 39:201. 7. Shelley WB, Shelley ED. Follicular dermographism. Cutis 1983; 32:244. 8. Warin RP. Factitious urticaria: red dermographism. Br J Dermatol 1981; 104:285. 9. Matthews CN, Kirby JD, James J, Warin RP. Dermographism: reduction in weal size by chlorpheniramine and hydroxyzine. Br J Dermatol 1973; 88:279. 10. Greaves M. Chronic urticaria. J Allergy Clin Immunol 2000; 105:664.

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87. Ghigliotti G, Brusati C, Guarrera M, Nigro A. Persistent solar urticaria. A case report. Photodermatol Photoimmunol Photomed 1999; 15:140. 88. Blum HF, West RJ. STUDIES OF AN URTICARIAL RESPONSE TO BLUE AND VIOLET LIGHT IN MAN. J Clin Invest 1937; 16:261. 89. Leenutaphong V, Hlzle E, Plewig G. Solar urticaria: studies on mechanisms of tolerance. Br J Dermatol 1990; 122:601. 90. Botto NC, Warshaw EM. Solar urticaria. J Am Acad Dermatol 2008; 59:909. 91. Hasei K, Ichihashi M. Solar urticaria. Determinations of action and inhibition spectra. Arch Dermatol 1982; 118:346. 92. Rajatanavin N, Bernhard JD. Solar urticaria: treatment with terfenadine. J Am Acad Dermatol 1988; 18:574. 93. Edstrm DW, Ros AM. Cyclosporin A therapy for severe solar urticaria. Photodermatol Photoimmunol Photomed 1997; 13:61. 94. Gzelbey O, Ardelean E, Magerl M, et al. Successful treatment of solar urticaria with antiimmunoglobulin E therapy. Allergy 2008; 63:1563. 95. Waibel KH, Reese DA, Hamilton RG, Devillez RL. Partial improvement of solar urticaria after omalizumab. J Allergy Clin Immunol 2010; 125:490. 96. Duschet P, Leyen P, Schwarz T, et al. Solar urticaria--effective treatment by plasmapheresis. Clin Exp Dermatol 1987; 12:185. 97. Leenutaphong V, Hlzle E, Plewig G, et al. Plasmapheresis in solar urticaria. Dermatologica 1991; 182:35. 98. Hudson-Peacock MJ, Farr PM, Diffey BL, Goodship TH. Combined treatment of solar urticaria with plasmapheresis and PUVA. Br J Dermatol 1993; 128:440. 99. Collins P, Ahamat R, Green C, Ferguson J. Plasma exchange therapy for solar urticaria. Br J Dermatol 1996; 134:1093. 100. Patterson R, Mellies CJ, Blankenship ML, Pruzansky JJ. Vibratory angioedema: a hereditary type of physical hypersensitivity. J Allergy Clin Immunol 1972; 50:174. 101. Epstein PA, Kidd KK. Dermo-distortive urticaria: an autosomal dominant dermatologic disorder. Am J Med Genet 1981; 9:307. 102. Keahey TM, Indrisano J, Lavker RM, Kaliner MA. Delayed vibratory angioedema: insights into pathophysiologic mechanisms. J Allergy Clin Immunol 1987; 80:831. 103. Wener MH, Metzger WJ, Simon RA. Occupationally acquired vibratory angioedema with secondary carpal tunnel syndrome. Ann Intern Med 1983; 98:44. 104. Metzger WJ, Kaplan AP, Beaven MA, et al. Hereditary vibratory angioedema: confirmation of histamine release in a type of physical hypersensitivity. J Allergy Clin Immunol 1976; 57:605. 105. Ting S, Reimann BE, Rauls DO, Mansfield LE. Nonfamilial, vibration-induced angioedema. J Allergy Clin Immunol 1983; 71:546. 106. Rittweger J, Beller G, Felsenberg D. Acute physiological effects of exhaustive whole-body vibration exercise in man. Clin Physiol 2000; 20:134. 107. Mathelier-Fusade P, Vermeulen C, Leynadier F. [Vibratory angioedema]. Ann Dermatol Venereol 2001; 128:750. 108. Lawlor F, Black AK, Breathnach AS, Greaves MW. Vibratory angioedema: lesion induction, clinical features, laboratory and ultrastructural findings and response to therapy. Br J Dermatol 1989; 120:93.

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COLD URTICARIA INTRODUCTION Cold urticaria, or cold contact urticaria, is a subtype of physical urticaria (table 1). It is characterized by itchy wheals (hives) and/or angioedema due to cutaneous mast cell activation and release of proinflammatory mediators after cold exposure. The underlying causes are largely unknown. Cold urticaria is reviewed here. Other urticaria disorders, including acute and chronic spontaneous urticaria are discussed separately. (See "Physical urticarias" and "New onset urticaria: Epidemiology, clinical manifestations, and etiologies" and "Chronic urticaria: Standard management and patient education" and "Chronic urticaria: Diagnosis, theories of pathogenesis, and natural history".) EPIDEMIOLOGY The incidence of cold urticaria was estimated to be 0.05 percent in Central Europe [1]. The frequency of cold urticaria among physical urticaria subtypes varies between 5 and 34 percent, partly depending upon the geographic region (ie, higher incidences are found in regions with colder climates and lower rates are seen in regions with a warmer climate) [1-4]. Cold urticaria most frequently affects young adults [3,5]. Both sexes are affected with similar frequency in most studies [1,3,6], although one study reported that females were affected twice as often as males [5]. Up to half of patients with cold urticaria are atopic and one-fourth have other types of inducible urticaria, most commonly symptomatic dermographism and cholinergic urticaria [1,7]. PATHOGENESIS Cold urticaria symptoms are brought about by the activation of mast cells and subsequent release of histamine and other proinflammatory mediators. Following a cold stimulation test, cutaneous mast cells in patients with cold urticaria show signs of degranulation, and serum levels of mast cell mediators are increased [8]. This results in pruritus, burning and erythema from activation of skin nerves, and vasodilation of skin vessels with extravasation causing wheals and angioedema. The underlying etiology of cold urticaria remains unclear, since the mechanisms and signals for mast cell activation have not been identified. Consequently, about 95 percent of cold urticaria cases are idiopathic (essential) [5,9]. Most of the remaining cases are secondary to cryoglobulinemia. (See 'Differential diagnosis' below.) Further systematic studies are needed to identify and characterize the underlying cause(s) of cold urticaria. A number of diseases have been associated with essential cold urticaria, largely in case reports. Associations have been reported with viral, parasitic, and bacterial infections, including Lyme disease, hepatitis, infectious mononucleosis, acute toxoplasmosis, Helicobacter pylori colonization, and HIV infection [10-14]. In addition, cold urticaria has been associated with Hymenoptera stings, food and drug intolerance, and hematologic, lymphatic, or neoplastic conditions [15,16]. It is not clear why these infectious or immune events are associated with cold urticaria. A variety of laboratory abnormalities have been found in patients with cold urticaria, including the following: In a small series, the majority of patients with cold urticaria exhibited mast cell-activating anti-IgE antibodies [17].Associations noted in case reports include cryoglobulinemia, anti-lamin-B antibodies, reduced levels of C1-esterase inhibitor and C4, and increased levels of platelet-activating factor and platelet factor 4 [18-22].

CLINICAL MANIFESTATIONS Cold urticaria is characterized by the development of wheal-and-flare skin reactions (picture 1) and/or angioedema after the skin is exposed to cold air, liquids, or objects [23]. Wheals and angioedema typically develop minutes after exposure. Cold urticaria symptoms are usually limited to cold-exposed skin areas. However, extensive cold contact may result in systemic reactions, ranging from generalized urticaria to anaphylaxis, with symptoms involving the respiratory, gastrointestinal, and/or cardiovascular systems [6]. In a series of 30 pediatric patients with cold urticaria seen in a tertiary referral center, one-third had a history of cold-induced anaphylaxis [7]. In another series of mostly adult patients, also from a tertiary referral clinic, nearly one-third experienced at least one severe systemic reaction with hypotension and/or respiratory compromise, and almost half of patients reported milder cutaneous systemic reactions [3]. Almost all patients in these two studies reported reactions triggered by aquatic activities, whereas only 30 percent experienced symptoms after touching a cold object. Patients with cold urticaria who participate in aquatic activities (eg, swimming in cold water) are at risk of death both directly from anaphylaxis and indirectly from drowning during a reaction [5,6,24]. Patients with cold urticaria are also at risk of suffocation due to oropharyngeal angioedema after consuming cold foods or beverages, although it is unclear how commonly this occurs. There are few identified risk factors or predictors of systemic reactions. Patients with a history of coldinduced oropharyngeal angioedema are at greater risk of a systemic reaction triggered by swimming, whereas those with a history of only a few hives after swimming appear to be at lower risk [24]. In the pediatric study described above, the only risk factor identified was a history of a previous cold-induced systemic reaction [7]. In another study, severe systemic reactions were more frequent in patients <30 years old at disease onset [3]. Factors associated with systemic reactions include a greater surface area of skin exposed, exposure to lower temperatures, and longer duration of cold exposure. DIAGNOSIS Cold urticaria is diagnosed in patients with a history of cold-induced urticaria and a positive reaction to a cold stimulation test (CST) [8,25,26]. A CST is considered positive when the patient develops urticarial skin lesions at the site of the cold challenge. CSTs are performed using ice cubes, cold packs, cold water baths, or TempTest: The ice cube test has a sensitivity of 83 to 90 percent and a specificity of 100 percent (picture 2) [5,25]. The ice cube should be melting and contained in a thin plastic bag to avoid cold damage of the skin [24]. Cold stimulation time thresholds can be determined using the ice cube test [6,9,27]. This method is readily performed in most offices, although it is not suitable for critical temperature threshold testing.Cold provocation testing using cold packs or cold water baths is not recommended as first-line screening tests, because these methods may induce systemic reactions [6,8]. Cold provocation tests using cold packs or cold water baths may be helpful in confirming the diagnosis of cold urticaria in patients who have a negative ice cube test.TempTest (Emo systems GmbH, Berlin, Germany) is a Peltier element-based cold provocation device that performs cold stimulation tests at multiple different temperatures simultaneously [25]. Its sensitivity and specificity (93 and 100 percent, respectively) are similar to the ice cube test. This method is suitable for assessing temperature thresholds (picture 3) and stimulation time thresholds (picture 4). Cold stimulation tests are performed for five minutes and test responses are assessed 10 minutes after the end of provocation testing. The test is considered positive if the test site shows a palpable and clearly visible wheal-and-flare skin reaction (picture 2). This reaction is itchy and/or associated with a

burning sensation in most cases. The test is considered negative if there is no reaction, or erythema or pruritus/burning only. Patients who show a negative test reaction to standard cold stimulation tests should be reevaluated and subjected to further testing if the history strongly suggests cold urticaria. Further testing is performed using larger areas for provocation (eg, cold pack or cold water bath) or using triggers that induced urticarial reactions in the past (eg, cold wind, cold water). Atypical cold urticarias should be considered if the additional stimulation tests are also negative (see 'Differential diagnosis' below).

The author's approach in patients who show a positive test reaction is to test their critical temperature threshold (highest temperature sufficient to induce a positive test reaction) and/or their cold stimulation time threshold (shortest duration of cold exposure required to induce a positive test reaction) [28]. Threshold testing, especially for temperature, can help patients avoid risky situations, and it allows physicians to gauge disease severity and to monitor treatment responses [27,29]. However, there are no data indicating that threshold levels are the same whether the area of exposure is localized, such as with the ice cube test or TempTest, versus a large area, such as submersion in cold water. Additional diagnostic measures should be limited to the exclusion of major underlying diseases and identification of associated diseases where suggested by the patients' history. Screening laboratory studies may include a complete blood count with differential. Underlying causes can only be identified in a minority of patients with cold urticaria, even if comprehensive testing is performed. (See 'Pathogenesis' above and 'Differential diagnosis' below.) VARIANT FORMS Most cold urticaria is readily distinguished from other types of urticaria by the patient history and a cold stimulation test (CST). The immediate CST is negative in rare subforms of cold urticaria (atypical cold urticarias) that can be either acquired or hereditary [8,15,28,30]: In delayed cold urticaria, which has both acquired and hereditary forms, the wheal-and-flare reaction occurs up to 24 hours after cold exposure. Hyperpigmentation typically develops at the site of lesions as they resolve in the familial form.In familial atypical cold urticaria, symptoms are lifelong and begin in early childhood. Localized urticaria typically develops on areas exposed to cold air, water, or objects. Symptoms triggered by cold food and beverages are also common. Systemic inflammatory symptoms are absent.In cold-dependent dermographism, urticaria is seen only after stroking precooled skin.In cold-induced cholinergic urticaria, generalized hives only develop when exercising in cold environments.In systemic cold urticaria, generalized urticaria is seen after systemic cold exposure. This form is not associated with exercise.In localized cold urticaria, hives only develop at defined skin sites, such as the face. Thus, the CST is only positive if performed at these sites.In localized cold reflex urticaria, hives develop near, but not directly where, the ice cube was applied. DIFFERENTIAL DIAGNOSIS The differential diagnosis of essential cold urticaria includes familial cold autoinflammatory syndrome and cold urticaria associated with abnormal serum proteins. Patients with familial cold autoinflammatory syndrome present within the first few months of life. The development of a papular rash after cold exposure is often delayed by one to two hours. This form is associated with systemic inflammatory symptoms, including fever and conjunctival injection. (See "Cryopyrin-associated periodic syndromes and related disorders", section on 'Familial cold autoinflammatory syndrome'.)Cold urticaria is associated with several diseases that have abnormal cold-

dependent immunoglobulins, including cryoglobulinemia, cryofibrinogenemia, cold agglutinin disease, and paroxysmal cold hemoglobinuria. (See "Overview of cryoglobulins and cryoglobulinemia" and "Clinical manifestations and diagnosis of essential mixed cryoglobulinemia" and "Cryofibrinogenemia" and "Clinical features and treatment of autoimmune hemolytic anemia: Cold agglutinins" and "Paroxysmal cold hemoglobinuria".) MANAGEMENT Cold avoidance Avoidance of cold is recommended, since it prevents the development of cold urticaria symptoms, including serious life-threatening events. However, avoidance is not always possible. Knowledge of their temperature threshold can help patients to recognize and avoid critical cold exposure in their daily lives (eg, swimming in water of subthreshold temperature) [25]. A study of 45 patients with cold urticaria found a mean + SEM critical temperature threshold of 17 + 6 degrees Celsius or approximately 63 + 11 degrees Fahrenheit (range 4 to 27 degrees Celsius or approximately 39 to 81 degrees Fahrenheit) [31]. Patients who chose to continue to participate in aquatic activities should avoid subthreshold temperature exposures. A water temperature above 77 degrees Fahrenheit (25 degrees Celsius) is sufficient for most patients [7]. Pretreatment with an antihistamine prior to cold exposure is often recommended, because clinical experience suggests that antihistamine pretreatment prevents skin reactions and systemic reactions. In addition, patients of all ages at increased risk of systemic reactions should have an epinephrine autoinjector readily available and should be accompanied by an adult who is trained in its use. (See 'Clinical manifestations' above and 'Emergency medication' below and 'Antihistamine therapy' below.) Antihistamine therapy Nonsedating H1 antihistamines are the treatment of choice for cold urticaria for symptomatic therapy, as with other forms of urticaria [32-35]. Antihistamines are also used as prophylactic therapy, both to prevent hives and to prevent systemic reactions, although there are no data to support the indication for the latter. (See "Chronic urticaria: Standard management and patient education", section on 'H1 antihistamines'.) A higher than usual dose of antihistamine (eg, up to four times the daily recommended dose) is required for sufficient protection from urticarial symptoms in many patients with cold urticaria [33,36,37]. Patients with cold urticaria who are incompletely treated with usual doses may suffer from severe and avoidable impairment in their quality of life. In addition, insufficiently treated patients with severe cold urticaria may be at greater risk of developing life-threatening reactions upon cold exposure. In a randomized, three-way crossover trial, 30 patients with cold urticaria received 5 or 20 mg of desloratadine or placebo daily, each for 7 days separated by 14-day washout periods [36]. Response to therapy was assessed by cold stimulation testing using TempTest. Both antihistamine doses decreased wheal volume 15 and 90 minutes after cold provocation testing, raised the critical temperature threshold, and increased the critical stimulation time compared with placebo, but there was a stronger response to the 20-mg dose compared with the 5-mg dose for all of these outcomes. Nonsedating second-generation H1 antihistamines are preferred for chronic treatment, although some of these medications may be sedating at higher doses. Some of these H1 antihistamines have been tested and shown to be effective in randomized controlled trials in patients with cold urticaria (eg, loratadine, cetirizine, desloratadine, ebastine, and rupatadine; the last two are not available in the

United States), whereas others have not (eg, levocetirizine and fexofenadine) [34,36-38]. The author starts with the standard daily dose and increases it up to four times that dose if the patient continues to experience symptoms. For patients who have been completely protected from cold-induced symptoms for at least six weeks on a higher than standard dose, the dose is then decreased over several months to the lowest level that provides complete protection. Patients are continued on a prophylactic antihistamine until they go into remission. The author typically discontinues the medication after three to six months to determine if remission has been achieved. Patients who participate in aquatic activities in the summer usually require year-round treatment, whereas other may need protection only during the winter months. Other pharmacotherapy Other therapies that were successful in case reports of patients with severe cold urticaria with a high risk of life-threatening reactions and/or an insufficient response to antihistamines include the concomitant use of leukotriene antagonists [39], cyclosporine [40], glucocorticoids [41], and anti-IgE [42,43]. Emergency medication Patients with cold urticaria are at potential risk of oropharyngeal edema caused by consumption of cold foods or beverages or anaphylaxis due to extensive cold exposure. Epinephrine is effective treatment for anaphylaxis caused by other triggers, and it appears to be effective in this setting as well, based upon clinical experience and case reports [44,45]. We recommend that patients with cold urticaria who have a history of anaphylaxis, systemic symptoms, frequent and unavoidable cold exposure, and/or a high temperature threshold be prescribed and carry an epinephrine autoinjector and be taught how and when to use this device. (See "Prescribing epinephrine for anaphylaxis self-treatment" and "Anaphylaxis: Rapid recognition and treatment" and "Long-term risk reduction in anaphylaxis" and "Patient information: Use of an epinephrine autoinjector".) The author also suggests patients carry oral glucocorticoids, for use in treating systemic symptoms that do not require therapy with epinephrine (eg, extensive urticaria and/or angioedema not involving the airway that does not respond to antihistamines). Additional treatment options Further treatment options include cold desensitization, topical capsaicin, and antibiotic therapy. Cold desensitization Several case series suggest that desensitization to cold (cold "tolerance" induction or hardening) by full-body baths/showers in cold water can protect patients with cold urticaria from cold-induced symptoms [46,47]. Patients are desensitized to the cold by repeatedly exposing increasingly larger skin areas to incrementally colder water, starting with above-threshold temperatures. This therapy decreases the critical temperature threshold. Cold tolerance induction needs to be initiated with great caution and under a physician's supervision because of the risk of severe systemic reactions. While the term "tolerance" is used, "desensitization" is more appropriate, since discontinuation for as little as a few days results in a complete loss of protection. Patients need to be informed that daily cold showers/baths are required to maintain the desensitized state. Most patients do not continue this therapy for more than a few weeks to months. Topical capsaicin Treatment with topical capsaicin, the pungent product of chili peppers, prevented cold urticaria symptoms for four to seven days in a small case series [48]. Capsaicin treatment results in the depletion of neuropeptides from sensory nerve fibers that may contribute to the induction of cold urticaria skin reactions. Its use is limited because it causes local irritation at the site of application.

Antibiotic therapy Antibiotic therapy was reported to be effective for some patients with cold urticaria in two observational studies [1,49]. In one of these series, 46 percent (13/28) of patients treated with high dose oral penicillin or tetracycline for two to four weeks went into remission and an additional 29 percent noted attenuated symptoms [1]. However, the rationale for its effectiveness is unclear, since this approach appeared to induce remission or decrease symptoms even when no underlying infection could be detected. Randomized controlled trials are needed to assess the efficacy of this treatment. PROGNOSIS Remission, or at least improvement of symptoms, occurs in 50 percent of patients within five to six years [1,3,5,23]. The mean time to resolution in one study was 5.6 3.5 years [3]. There are no reports of cold urticaria recurring after remission is achieved. SUMMARY AND RECOMMENDATIONS Cold urticaria is a subtype of physical urticaria characterized by itchy wheals and/or angioedema due to skin mast cell activation and the release of proinflammatory mediators after cold exposure (picture 1). The underlying causes are largely unknown. (See 'Introduction' above and 'Epidemiology' above and 'Pathogenesis' above.)Cold urticaria symptoms are usually limited to cold-exposed skin areas and develop within minutes of cold exposure. However, extensive cold contact may result in systemic reactions. Occurrence of severe anaphylactic reactions or suffocation due to oropharyngeal edema is possible. (See 'Clinical manifestations' above.)A cold stimulation test confirms the diagnosis in most patients (picture 2). (See 'Diagnosis' above.)Avoidance of cold exposure is the best prophylaxis. However, complete avoidance is difficult for most patients. (See 'Management' above.)We suggest the use of non-sedating H1 antihistamines for patients with cold urticaria who are unable to sufficiently avoid cold exposure and have frequent symptoms (Grade 2B). We typically use a second-generation H1 antihistamine, starting at the standard dose and increasing up to four times the standard dose as needed to control symptoms. (See 'Management' above and 'Antihistamine therapy' above and "Chronic urticaria: Standard management and patient education", section on 'H1 antihistamines'.)We recommend treating cold-induced anaphylaxis with epinephrine (Grade 1A). (See 'Emergency medication' above.)Patients should be informed about the possibility of a systemic reaction and supplied with emergency medication, including epinephrine for self-injection. (See 'Management' above.) Use of UpToDate is subject to the Subscription and License Agreement REFERENCES 1. Mller A, Henning M, Zuberbier T, Czarnetzki-Henz BM. [Epidemiology and clinical aspects of cold urticaria]. Hautarzt 1996; 47:510. 2. Moller, A, Henz, BM. Cold urticaria. In: Urticaria: Clinical, diagnostic, and therapeutic aspects, Henz, BM, Zuberbier, T, Grabbe, J, Monroe, E (Eds), Springer, Berlin p.1998. 3. Katsarou-Katsari A, Makris M, Lagogianni E, et al. Clinical features and natural history of acquired cold urticaria in a tertiary referral hospital: a 10-year prospective study. J Eur Acad Dermatol Venereol 2008; 22:1405. 4. Moreno JN, Harfi HA. Cold urticaria in Saudi Arabia. Ann Allergy 1989; 63:331. 5. Neittaanmki H. Cold urticaria. Clinical findings in 220 patients. J Am Acad Dermatol 1985; 13:636. 6. Wanderer AA, Grandel KE, Wasserman SI, Farr RS. Clinical characteristics of cold-induced systemic reactions in acquired cold urticaria syndromes: recommendations for prevention of this complication and a proposal for a diagnostic classification of cold urticaria. J Allergy Clin Immunol 1986; 78:417.

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