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Cold urticaria

Cold urticaria
Author:
Marcus Maurer, MD
Section Editors:
Sarbjit Saini, MD
Jeffrey Callen, MD, FACP, FAAD
Deputy Editor:
Anna M Feldweg, MD
Literature review current through: Nov 2022. | This topic last updated: Aug 23, 2022.

INTRODUCTION — Cold urticaria, or cold contact urticaria, is a subtype of physical urticaria (table 1) [1-3]. The physical urticarias are forms of inducible urticaria, in which there is a specific and definite stimulus that triggers the development of symptoms. Cold urticaria is characterized by pruritic wheals (hives) and/or angioedema due to cutaneous mast cell degranulation and release of proinflammatory mediators after cold exposure of the skin. Triggers include skin contact with cold objects, cold liquids, and cold air. The underlying pathophysiology is largely unknown but is likely to involve immunoglobulin E (IgE)-mediated mast cell activation [4,5].

Cold urticaria is reviewed here. Other urticaria disorders, including acute and chronic spontaneous urticaria and other forms of inducible urticaria, including physical urticaria, are discussed separately. (See "Physical (inducible) forms of urticaria" and "New-onset urticaria" and "Chronic spontaneous urticaria: Standard management and patient education" and "Chronic spontaneous urticaria: Clinical manifestations, diagnosis, pathogenesis, and natural history".)

EPIDEMIOLOGY — Cold urticaria most frequently affects young adults [6,7]. Both sexes are affected with similar frequency in most studies [6,8-10], although one study reported that females were affected twice as often as males [7]. Up to one-half of patients with cold urticaria are atopic, and one-fourth have other types of inducible urticaria, most commonly symptomatic dermographism and cholinergic urticaria [8,10,11].

The incidence of cold urticaria was estimated to be 0.05 percent in Central Europe [8]. The frequency of cold urticaria among physical urticaria subtypes varies between 5 and 34 percent, partly depending on the geographic region (ie, higher incidences are found in regions with colder climates and lower rates are seen in regions with a warmer climate) [6,8,12,13].

Natural history — Cold urticaria is a self-limited disorder in many patients. Remission, or at least improvement of symptoms, occurs in 50 percent of patients within five to six years [3,6-8,14]. The mean time to resolution in one study was 5.6±3.5 years [6]. Recurrence of cold urticaria after remission is rare. However, some patients have the disorder for many years, and there are variant forms that appear to be lifelong (eg, familial atypical cold urticaria). (See 'Variant forms' below.)

PATHOGENESIS — Cold urticaria symptoms result from the activation of mast cells, their degranulation, and subsequent release of histamine and other proinflammatory mediators. Following a cold stimulation test (CST), cutaneous mast cells in patients with cold urticaria show signs of degranulation, and serum levels of mast cell mediators are increased [15-17]. This results in pruritus, burning, and erythema from activation of skin nerves and vasodilation of skin vessels with extravasation causing wheals and angioedema. On skin biopsy, cold urticaria lacks a late-phase cellular infiltrate, similar to most other forms of physical urticaria (except delayed pressure urticaria) [18].

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-immunoglobulin E (IgE) antibodies [19].

Associations noted in case reports include cryoglobulinemia, cold agglutinins, anti-lamin-B antibodies, reduced levels of C1 esterase inhibitor and C4 and increased levels of platelet-activating factor and platelet factor 4 [20-24].

Associated disorders — A number of diseases have been anecdotally associated with cold urticaria, largely in case reports. The causal relationship between these various disorders and cold urticaria is unknown.

Associations have been reported with various infections, including viral, parasitic, and bacterial infections. Specific disorders include Lyme disease, hepatitis, infectious mononucleosis, acute toxoplasmosis, Helicobacter pylori colonization, and human immunodeficiency virus (HIV) infection [25-29].

Cold urticaria has been associated with antecedent Hymenoptera stings, food and drug intolerance [30], and hematologic, lymphatic, or neoplastic conditions [31,32].

CLINICAL MANIFESTATIONS — The clinical manifestations of the most common form of cold urticaria consist of cutaneous wheals and/or angioedema, which form after cold exposure of the skin. A subset of patients develops systemic reactions. Variant forms have specific characteristic features that can be elicited by a careful clinical history and provocation testing.

Cutaneous signs and symptoms — Cold urticaria is characterized by the development of wheal-and-flare skin reactions and/or angioedema after the skin is exposed to cold air, liquids, or objects (picture 1) [14]. Wheals and angioedema typically develop minutes after exposure and are usually limited to cold-exposed skin areas. Exposure to cold weather is one of the most common triggers for symptoms, with variables that include temperature, humidity, and wind chill factor.

Systemic reactions — Extensive cold contact, such as swimming in cold water, may result in systemic reactions, ranging from generalized urticaria to anaphylaxis, with symptoms involving the respiratory, gastrointestinal, and/or cardiovascular systems [9]. In a series of 30 children with cold urticaria seen in a tertiary referral center, one-third had a history of cold-induced anaphylaxis [11]. 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 approximately one-half of patients reported milder cutaneous systemic reactions [6]. In these two studies, almost all patients reported either cutaneous or systemic symptoms 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 [7,9,33]. 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.

Risk factors for systemic reactions — Some risk factors or predictors of systemic reactions have been identified, although this area requires further study [34]:

In the pediatric study described above, the only risk factor identified was a history of a previous cold-induced systemic reaction [11].

In another study, patients with a history of cold-induced oropharyngeal angioedema were at greater risk of a systemic reaction triggered by swimming, compared with those with a history of only a few hives after swimming [33].

Severe systemic reactions may be more frequent in patients <30 years old at disease onset [6].

Physical variables associated with systemic reactions include a greater surface area of skin exposed, exposure to lower temperatures, and longer duration of cold exposure. Exposure to cold water or solid objects that are cold is more likely to elicit symptoms than exposure to cold air. We also advise patients to pay attention to the wind chill factor during cold months, as symptoms will be more easily triggered on days when the wind chill is significant.

Variant forms — There are several variant forms of cold urticaria (atypical cold urticarias). In a retrospective review of 74 patients referred to a specialty center, nearly 30 percent of cold urticaria patients had atypical cold urticaria [35]. In all of these disorders, the standard cold stimulation test (CST) is negative. Each involves urticarial lesions, although the specific triggers, timing, or location of the lesions are different from classic cold urticaria. Some are acquired and others are hereditary [17,36]. Modified types of CST are needed to elicit the signs and symptoms. (See 'Cold stimulation test' below.)

Delayed cold urticaria – There are both acquired and hereditary forms of delayed cold urticaria, all of which are rare. In these disorders, the wheal-and-flare reaction occurs up to 24 hours after cold exposure [37,38]. Patients have no immediate response to CST but will develop a wheal-and-flare response at the test site, usually 18 to 24 hours later. In the familial form, hyperpigmentation typically develops at the site of lesions following resolution.

Familial atypical cold urticaria – In this disorder, symptoms begin in early childhood and are life-long [39]. 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. CSTs were negative in the small number of patients described.

A syndrome of familial cold urticaria related to deletions in the gene for phospholipase C (PLC)-gamma-2 was described in 2012 [40]. Affected individuals have cold urticaria from childhood, although symptoms are elicited by evaporative cooling (eg, exposure to cold air or wind), rather than touching cold objects or water, and autoimmunity and immunodeficiency are each present in about one-half of patients. Investigators suggested the condition be called PLC-gamma-2-associated antibody deficiency and immune dysregulation, or PLAID.

Cold-dependent dermographism – In this variant, the skin becomes dermographic when cooled [41,42]. To reproduce this, the skin should be stroked firmly while cool and then rewarmed.

Cold-induced cholinergic urticaria – Patients with this variant develop hives only when exercising in cold environments [43]. The diagnosis is often made by clinical history alone and would be confirmed by exercise challenge in a cold room.

Systemic cold urticaria – In this form of cold urticaria, generalized urticaria is seen after systemic cold exposure. This form is not associated with exercise [44]. CST is negative, and the diagnosis is usually based on clinical history and confirmed by cold exposure in a cold room.

Localized cold urticaria – Patients with localized cold urticaria develop hives following cold exposure but only at defined skin sites, such as the face [45,46]. Thus, the CST is positive only if performed at these sites.

Food-dependent cold urticaria – Hives develop at the site of the ice cube challenge, but only after the intake of food [47].

EVALUATION — In a patient with a suggestive clinical history, evaluation consists of a cold stimulation test (CST) [17,48,49]. Modified types of testing are often needed for variant forms. Laboratory testing is not needed in routine cases of cold-induced urticaria in children or adults, although it is appropriate if the patient's symptoms are not typical for cold-induced urticaria or suggest the presence of systemic disease or an associated condition. (See 'Associated disorders' above and 'Differential diagnosis' below.)

Cold stimulation test — A CST can be performed by several different methods. All methods involve the application of a cold object to the skin and then removing the stimulus and allowing the skin to rewarm. The test is considered positive if the test site shows a palpable and clearly visible wheal-and-flare skin reaction upon rewarming. The affected site is pruritic 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.

Ice cube test — The ice cube test, which requires no special equipment, involves placing an ice cube and a small amount of water in a thin plastic bag, allowing a few minutes for the ice and water temperatures to equilibrate and then placing the bag against the skin (usually of the volar forearm) for 5 minutes [33]. The bag is then removed and response is assessed 10 minutes after removal (picture 2). This method is readily performed in most offices and has a sensitivity of 83 to 90 percent and a specificity of 100 percent [7,48]. Longer periods of exposure are rarely needed.

If no wheal has developed, we revisit the history. Sometimes, a variant form of cold urticaria is present. As an example, we might ask the patient again if there are only certain areas of the body on which cold-induced wheals and/or angioedema have formed in the past (suggesting localized cold urticaria). Modified testing can sometimes elicit a positive test. (See 'Variant forms' above.)

Testing methods that are not recommended — Cold provocation testing using cold packs or cold water baths is not recommended for first-line screening, because these methods expose larger areas of skin to cold and may induce systemic reactions [9,17]. Rather, they are usually used to evaluate patients in whom the ice cube or TempTest method was negative.

Natural exposure testing — In some situations, the most logical way to diagnose a cold-induced disorder is to ask the patient to re-expose himself/herself to the conditions (eg, cold wind, cold water) that elicited the signs and symptoms in the first place, if safe and feasible.

Specialized testing devices — TempTest 4.0 is a thermoelectric device that was developed, validated, and licensed as a commercially available medical product. TempTest 4.0 allows for CSTs, including threshold measurements, with a continuous gradient of temperatures ranging from 4 to 44°C (39 to 111°F) (picture 3). (See 'Threshold testing' below.)

Threshold testing — The author's approach in patients who show a positive initial test reaction is to further define a temperature threshold for the individual patient using the TempTest 4.0 device. The critical temperature threshold is the highest temperature sufficient to induce a positive test reaction (picture 4) [36]. Threshold testing is not necessary for the diagnosis, although the information can help patients avoid risky situations by knowing what temperatures are likely to elicit symptoms. It can also be used to monitor treatment responses without repeatedly exposing the patient to situations that induce symptoms [50,51].

A study of 45 patients with cold urticaria found a mean (+ standard error of the mean) critical temperature threshold of 17 (+ 6°C) or approximately 63 (+ 11°F) (range 4 to 27°C or approximately 39 to 81°F) [52]. Thus, patients' thresholds may vary significantly. Patients with higher threshold temperatures are considered to have more severe disease, although disease severity does not appear to predict response to antihistamine therapy. (See 'Dose' below.)

One important caveat about threshold determinations is the following. There are no data indicating that threshold levels are the same whether the area of exposure is localized, such as exposure of the face to a cold wind, versus a large area, such as submersion in cold water. We advise patients that if they are faced with a situation in which symptoms might occur (such as swimming in a pool), they can expose a limited area of the body first (eg, submerge a hand) and then wait to see if symptoms appear before exposing the rest of the body.

DIAGNOSIS — In a patient with an appropriate clinical history, the diagnosis of cold urticaria is confirmed by the presence of a positive cold stimulation test (CST). (See 'Cold stimulation test' above.)

DIFFERENTIAL DIAGNOSIS — Other disorders in which symptoms are induced by cold exposure include familial cold autoinflammatory syndrome (FCAS), disorders caused by cold-induced abnormal serum proteins, and cold-induced urticarial vasculitis (rare) [53]. Cold stimulation tests (CSTs) would be negative if performed in patients with these disorders. Patients do not develop typical urticaria, distinguishing these disorders from typical or variant forms of cold urticaria. (See "Autoinflammatory diseases mediated by miscellaneous mechanisms", section on 'PLAID/APLAID'.)  

Patients with FCAS present within the first few months of life. The development of a papular rash after cold exposure is often delayed by up to several hours. This form is associated with systemic inflammatory symptoms, including fever, conjunctival injection, and arthralgias. The presence of systemic symptoms distinguishes this disorder from simple cold urticaria. FCAS is considered a hereditary periodic fever syndrome. (See "Cryopyrin-associated periodic syndromes and related disorders", section on 'Familial cold autoinflammatory syndrome'.)

Several other diseases involve abnormal cold-dependent immunoglobulins, including cryoglobulinemia, cryofibrinogenemia, cold agglutinin disease, and paroxysmal cold hemoglobinuria. Patients with these disorders do not present with cold urticaria but rather with signs and symptoms of cutaneous (ie, purpura) or systemic vasculitis, renal disease, or other organ system manifestations. (See "Overview of cryoglobulins and cryoglobulinemia" and "Mixed cryoglobulinemia syndrome: Clinical manifestations and diagnosis" and "Cold agglutinin disease" and "Paroxysmal cold hemoglobinuria" and "Disorders of fibrinogen", section on 'Cryofibrinogenemia'.)

REFERRAL — Straightforward cases of cold urticaria may be diagnosed and managed by generalists. We suggest referral to an allergy/immunology expert if the clinician is not comfortable performing diagnostic testing and in cases involving systemic symptoms or atypical symptoms or if symptoms prove difficult to manage. Patients with cold-induced symptoms that are suggestive of an autoinflammatory or vasculitis disorder should be referred to a specialist.

MANAGEMENT — The management of cold urticaria consists of the following elements:

Education about the risks of systemic reactions

Preparation for treatment of acute symptoms

Practical advice to avoid cold exposure

Antihistamine therapy for prophylaxis

Several other adjunctive therapies may also be helpful. (See 'Other pharmacotherapy' below.)

Successful desensitization protocols have been described, but this approach requires daily cold exposure to maintain the desensitized state and is impractical for most patients. (See 'Cold desensitization' below.)

Education about high-risk activities and cold avoidance — As soon as the diagnosis has been made, the clinician should begin to educate the patient about the activities and procedures that may trigger systemic reactions or serious localized reactions:

Swimming - Swimming is the activity that most commonly induces systemic symptoms [6,11]. Patients who chose to continue to participate in aquatic activities should expose a limited area of the body first (eg, submerge a hand) and then wait to see if symptoms appear before exposing the rest of the body. If a threshold temperature is known for that patient, then they can more easily avoid lower temperatures. A water temperature above 25°C (77°F) is safe for most patients [11]. Wetsuits may be helpful, although this has not been formally studied.

Cold foods and beverages - Consumption of cold foods or beverages can induce oropharyngeal angioedema or anaphylaxis.

Surgery - Surgery is another setting in which patients with cold urticaria can develop systemic reactions [54,55]. The surgery and anesthesia teams should be informed about the patient's condition and should make efforts to keep the patient sufficiently warm throughout the procedure. Treatment for any symptoms that may develop should be immediately available. Premedication with antihistamines could be considered in patients with past systemic reactions to cold exposure.

Intravenous fluids and injections - Administration of cold intravenous solutions or injections can induce symptoms in some patients. Symptoms can develop with vaccines, biologics, and other injections given intramuscularly or subcutaneously, depending on the temperature and volume. Intravenous fluids pose the greatest risk and should be prewarmed.

General cold avoidance is recommended, since it is the most logical way to prevent symptoms. 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 [48]. (See 'Threshold testing' above.)

Pretreatment with an antihistamine prior to predictable cold exposure is recommended, because clinical experience suggests that antihistamine pretreatment can prevent 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 trained in its use or in the case of children, be accompanied by an adult who is trained in its use. (See 'Epinephrine for systemic symptoms' below.)

Treatment of acute signs and symptoms

Epinephrine for systemic symptoms — Epinephrine is an effective treatment for anaphylaxis caused by other triggers, and it appears to be effective in this setting as well, based on clinical experience and case reports [56,57]. 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: Emergency treatment" and "Anaphylaxis: Confirming the diagnosis and determining the cause(s)" and "Patient education: Using an epinephrine autoinjector (Beyond the Basics)".)

Treatment of milder symptoms — We also recommend that patients carry a few doses of H1 antihistamine for use in treating systemic symptoms that do not require therapy with epinephrine (eg, extensive urticaria and/or angioedema not involving the airway). Patients with significant angioedema may benefit from a short course of oral glucocorticoids.

Preventative therapies — Aside from avoidance of cold exposure, H1 antihistamines are the primary prophylactic therapy for cold urticaria. Other therapies have been reported to be helpful in small series.

The goal of treatment is to restore a quality of life that is acceptable to that patient. For example, patients who are content to avoid swimming and other high-risk activities may require minimal pharmacotherapy, while those who are committed to these activities or have occupations that routinely expose them to cold may require more extensive therapy. Patients with cold urticaria who are incompletely treated not only experience avoidable impairment in their quality of life but may also be at greater risk of developing life-threatening reactions upon cold exposure if they have a history of systemic reactions. However, the extent to which antihistamines prevent cold-induced systemic reactions is difficult to predict. The effects of antihistaminic treatment on histamine-induced wheals do not predict the clinical benefit of treatment in patients [58]. Therefore, patients must also be prepared to treat these reactions with epinephrine.

H1 antihistamines — H1 antihistamines have been shown in small randomized trials to reduce the frequency and severity of urticaria/angioedema episodes, as with other forms of chronic urticaria [59-64]. (See "Chronic spontaneous urticaria: Standard management and patient education", section on 'H1 antihistamines'.)

Choice of agent — Nonsedating second-generation H1 antihistamines are preferred for chronic treatment, although some of these medications may be sedating at higher doses. Several H1 antihistamines have demonstrated efficacy in patients with cold urticaria (eg, loratadine, cetirizine, desloratadine, ebastine, rupatadine, and bilastine; the last three are not available in the United States), whereas others have not been studied (eg, levocetirizine and fexofenadine) [59-62,64,65].

Cyproheptadine was commonly used in the past for treatment of cold urticaria. However, this drug is not known to be superior to other antihistamines for the treatment of cold urticaria, and it has the well-known adverse effects of the older first-generation antihistamines (eg, sedation, anticholinergic effects) [66].

Dose — 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 [60,61,63,64,67]. We start with the standard daily dose of a nonsedating second-generation antihistamine and increase it up to four times that dose if the patient continues to experience symptoms. Recent systematic reviews confirm that greater doses of nonsedating antihistamines are more effective than standard doses in controlling symptoms and that increasing the dose is not significantly associated with higher adverse event rates [68].

Studies evaluating the effects of various doses of antihistamines in patients with cold urticaria include the following:

The need for higher than standard doses was demonstrated in a randomized, three-way crossover trial of 30 patients with cold urticaria who were treated with 5 or 20 mg of desloratadine or placebo daily (each for 7 days separated by 14-day washout periods) [60]. Response to therapy was assessed by CST using TempTest 4.0. Both antihistamine doses decreased wheal size 15 and 90 minutes after cold provocation testing, improved the critical temperature threshold, and increased the critical stimulation time compared with placebo. The 20 mg dose was significantly more effective than the 5 mg dose for each of the endpoints.

Even with higher antihistamine doses, responses are variable and difficult to predict. This was shown in a subsequent randomized study of 30 patients, in which one-half received 5 mg desloratadine daily for six weeks, while the other one-half had the dose of desloratadine increased every two weeks to a maximum of 20 mg daily if symptoms were not controlled [63]. The severity of disease (ie, the higher the eliciting temperature, the more severe the disease) was assessed at baseline and monitored throughout by CST using the TempTest 4.0 device. No patient became symptom-free on 5 mg desloratadine, while two became symptom-free on 10 mg and a further three on 20 mg desloratadine daily. About 20 percent of patients did not experience any significant improvement, and there was no correlation between initial severity and response to therapy.

In a randomized, double-blind trial of 20 patients with cold urticaria, subjects were treated with different doses of bilastine or placebo in a 12-week crossover study. They received placebo, 20, 40, or 80 mg of bilastine daily, each for 7 days with 14-day washout periods. Bilastine 20 mg (the standard dose) was highly effective in reducing critical temperature thresholds. Sequentially increasing the dose to 80 mg significantly increased its effectiveness. At this higher dose, 19 of 20 (95 percent) patients responded to treatment, and 12 of 20 (60 percent) became symptom-free. Only one patient was refractory to treatment. Microdialysis levels of histamine, interleukin-6 (IL-6), and interleukin-8 (IL-8) assessed one to three hours after cold challenge were significantly decreased following up-dosing with 80 mg bilastine. Bilastine treatment was well-tolerated without evidence of increased sedation with dose escalation [64]. Bilastine is not available in the United States.

Rupatadine, a nonsedating H1-antihistamine with additional antagonist effects on platelet-activating factor (PAF), was shown in randomized trials and observational trials to reduce symptoms of cold urticaria at doses of 20 mg or 40 mg daily [61,69-71]. Rupatadine is not available in the United States.

Treatment of refractory symptoms — In patients with continued symptoms interfering with work or valued activities despite high-dose H1 antihistamines, treatment options include anti-immunoglobulin E (IgE) therapy (omalizumab) or cyclosporine.

Omalizumab has been reported to control symptoms in multiple case reports [4,72-76] and a placebo-controlled trial [5]. However, omalizumab is only approved in the United States and in Europe for the treatment of asthma and chronic spontaneous urticaria. Reimbursement for this costly therapy by third-party payers for use in cold urticaria must be arranged on a patient-by-patient basis. We initiate therapy at 300 mg every four weeks. Patients who respond to omalizumab typically do so within a couple of weeks, at which point antihistamines can be tapered down and discontinued. For patients who do not respond to 300 mg every four weeks, we increase the dose up to 600 mg. When a patient has responded fully, we typically extend the dosing interval (to five weeks or six weeks, for example) to see if the patient begins to react to cold again. If patients appear to be in remission, omalizumab can be discontinued after 12 months. Some patients only need omalizumab in the coldest months of the year. (See "Chronic spontaneous urticaria: Treatment of refractory symptoms", section on 'Omalizumab'.)

Cyclosporine (3 mg/kg daily) with subsequent dose reduction after the first month of treatment was successful in controlling symptoms in a patient refractory to high-dose antihistamines and glucocorticoids [77]. The use of cyclosporine in chronic urticaria, including dosing and monitoring, is reviewed separately. (See "Chronic spontaneous urticaria: Treatment of refractory symptoms", section on 'Cyclosporine'.)

Other pharmacotherapy — Several other therapies have been administered to patients with cold urticaria, as noted in case reports:

Antibiotic therapy was reported to be effective for some patients with cold urticaria in three observational studies [8,78,79]. In one of these series, 46 percent (13 of 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 [8]. The explanation for the apparent benefit of antibiotics is unclear, since patients responded regardless of whether an underlying infection could be detected, and the anti-inflammatory properties of some antibiotics would explain a temporary benefit but not remission of disease.

In the author's clinic, patients are treated initially (ie, even before prescribing daily antihistamines) with a three-week course of doxycycline (100 mg twice daily), followed by three weeks of observation, since the response to treatment usually occurs in the weeks after the antibiotics are finished. We initially chose doxycycline, because it is safe and inexpensive. Randomized-controlled trials are needed to assess the efficacy of this treatment, and until better data are available, we are reluctant to promote the wider use of this approach [79].

H2 antihistamines (such as famotidine 20 mg twice daily) added to H1 antihistamines are helpful in some patients [80]. However, other patients experience no apparent benefit, and more conclusive studies are lacking.

The addition of the leukotriene antagonists montelukast or zafirlukast appeared to be beneficial in some patients [81,82], although not in others [83].

Etanercept and benralizumab have been reported to be of benefit in a single case report each [84,85].

Treatment with topical capsaicin, derived from chili peppers, prevented cold urticaria symptoms for four to seven days in a small case series [86]. Capsaicin treatment results in the depletion of neuropeptides from sensory nerve fibers that may contribute to the induction of cold urticaria skin reactions. However, it causes local irritation at the site of application.

Response to systemic glucocorticoids is variable [77,87]. Most patients do not report improvement, and this may be related to the absence of a late-phase cellular infiltrate. Those who do respond usually report only temporary improvement [88]. Thus, glucocorticoids are not recommended for routine treatment of cold urticaria.

Adjustment and discontinuation of therapy — For patients who have been entirely 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 six months to determine if remission has been achieved. Patients who participate in aquatic activities in the summer usually require year-round treatment, whereas others may need protection only during the winter months. The author routinely performs threshold tests with TempTest 4.0 to assess the efficacy of antihistamine therapy.

Cold desensitization — Desensitization to cold (cold "tolerance" induction or hardening) by repeatedly exposing the patient to baths/showers in cold water is another option for treatment, although it carries the risk of inducing systemic symptoms and must be performed under a clinician's supervision. In addition, it is not practical for most patients, because daily cold showers/baths are required to maintain the desensitized state. Still, several case series suggest that cold desensitization can be used as therapy [89-91]. 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 and protects the patient from future cold-induced symptoms.

Cold-tolerance induction needs to be initiated with great caution and under a clinician'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. For this reason, most patients do not continue this therapy for more than a few weeks to months.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Urticaria and angioedema (excluding hereditary angioedema)".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

Basics topic (see "Patient education: Inducible hives (The Basics)")

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 '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.)

In a patient with an appropriate clinical history, the diagnosis of cold urticaria is confirmed by the presence of a positive cold stimulation test (CST) (picture 2). In patients with a positive CST, temperature threshold testing is suggested. Laboratory testing is not needed in routine cases. (See 'Evaluation' above and 'Diagnosis' above.)

Most cases of cold urticaria are idiopathic, although a minority is related to an underlying disorder, such as an infection or a hematologic disorder. Cold-induced systemic inflammation (eg, fever, arthralgias) or purpuric lesions in response to cold suggest other disorders. (See 'Associated disorders' above and 'Differential diagnosis' above.)

Avoidance of cold exposure is the best prophylaxis, although complete avoidance is difficult for most patients. Patients should be educated about high-risk activities and situations, such as swimming, surgery, and ingestion of cold foods and beverages. (See 'Education about high-risk activities and cold avoidance' above.)

We prescribe epinephrine autoinjectors for those patients with a history of anaphylaxis, systemic symptoms, frequent or unavoidable cold exposure, and/or a high temperature threshold. We advise such patients to carry epinephrine at all times and periodically review how and when to administer it. (See 'Epinephrine for systemic symptoms' above.)

We recommend nonsedating second-generation H1 antihistamines for patients with cold urticaria who are unable to sufficiently avoid cold exposure and have frequent symptoms (Grade 1B). We typically begin with the standard dose and increase up to four times this dose, as needed, to control symptoms. Most patients respond, although some have residual symptoms. (See 'H1 antihistamines' above.)

For patients with symptoms refractory to higher doses of H1 antihistamines, we suggest omalizumab (Grade 2C). Successful treatment with several other therapies has been described in case reports and may be used if omalizumab is not available. (See 'Treatment of refractory symptoms' above.)

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Topic 8102 Version 25.0

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