Acute Urticaria

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Background

Urticaria (hives) is a vascular reaction of the skin marked by the transient appearance of smooth, slightly elevated papules or plaques (wheals) that are erythematous and that are often attended by severe pruritus. Individual lesions resolve without scarring in several hours. Most cases of urticaria are self-limited and of short duration; the eruption rarely lasts more than several days, it but may be recurrent over weeks. Chronic urticaria is defined as urticaria with recurrent episodes lasting longer than 6 weeks.

The development of urticaria is often an isolated event without systemic reaction. Rarely, it can be a prelude to the development of an anaphylactic reaction. (See Anatomy.)

If any features of anaphylaxis (eg, hypotension, respiratory distress, stridor, gastrointestinal distress, swallowing problems, joint swelling, joint pain) are present, immediate medical intervention should occur. (See Physical Examination.)

Acute urticaria may be, in a short time, associated with life-threatening angioedema and/or anaphylactic shock, although it usually presents as rapid-onset shock without urticaria or angioedema. (See Emergency Care and Complications.)

New-onset episodes of urticaria can be associated with identifiable causes, and the method of exposure (ie, direct contact, oral or intravenous [IV] routes) can be deduced by taking a careful history. (See Etiology.)

Acute urticaria is generally diagnosed based on a detailed patient history and physical examination. (See Clinical Presentation.)

Although clinically distinctive, urticaria may be confused with a variety of other dermatologic diseases that can be similar in appearance and are pruritic, including atopic dermatitis (eczema), maculopapular drug eruptions, contact dermatitis, insect bites, erythema multiforme, pityriasis rosea, and others. Usually, however, the experienced clinician is able to distinguish these conditions from urticaria because of the lesions' hallmark appearance (see the images below), a lack of epidermal change, the intense pruritus, the presence of an advancing edge and a receding edge, the complete blanching of the lesions with pressure, and are the transient nature of the lesions.[1] (See Clinical Presentation.)



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Urticaria associated with a drug reaction.



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Urticaria developed after bites from an imported fire ant.



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Local urticaria on a patient with latex allergy who was touched with a latex glove.

The major goal of treatment is to control the severity of acute urticarial lesions. Antihistamines are the primary agents used to treat urticaria. (See Treatment Strategies and Management.)

Pathophysiology

Urticaria results from the release of histamine, bradykinin, leukotriene C4, prostaglandin D2, and other vasoactive substances from mast cells and basophils in the dermis.[2] These substances cause extravasation of plasma into the dermis, leading to the urticarial lesion. The intense pruritus of urticaria is a result of histamine released into the dermis. One study showed that D-dimer levels correlate with the severity of acute urticaria and may serve as a marker of disease severity.[75]  

Individual lesions of acute urticaria can appear at different locations and fade without scarring, often in a matter of hours. The development of urticaria can be an isolated event without systemic reaction or it can be a prelude to the development of an anaphylactic reaction. Although urticaria results from transient extravasation of plasma into the dermis, angioedema is the subcutaneous extension of urticaria that results in deep swelling within subcutaneous/submucosal tissues and is associated with pain but not pruritus.

Immune-mediated urticaria

Histamine is the ligand for 2 membrane-bound receptors, the H1 and H2 receptors, which are present on many cell types. The activation of the H1 histamine receptors on endothelial and smooth muscle cells leads to increased capillary permeability. The activation of the H2 histamine receptors leads to arteriolar and venule vasodilation.[3, 4, 5] This process is caused by several types of immune hypersensitivity mechanisms as follows:

Non­-immune-mediated urticaria

Complement-mediated urticaria includes viral and bacterial infections, serum sickness, and transfusion reactions. Urticarial transfusion reactions occur when allergenic substances in the plasma of the donated blood product react with pre-existing IgE antibodies in the recipient. Certain drugs (opioids, vecuronium, succinylcholine, vancomycin, and others) as well as radiocontrast agents cause urticaria due to mast cell degranulation through a non-IgE-mediated mechanism. Urticaria from nonsteroidal anti-inflammatory drugs (NSAIDs) may be IgE-mediated or due to mast cell degranulation, and there may be significant cross-reactivity among the NSAIDs in causing urticaria and anaphylaxis.[6]

Physical urticaria, in which some physical stimulus causes urticaria, includes immediate pressure urticaria, delayed pressure urticaria,[7] cold urticaria, and cholinergic urticaria.[8]

For some cases of urticaria, especially chronic urticaria, no cause can be found, despite exhaustive efforts. This is known as idiopathic urticaria,[2] although most of these are chronic autoimmune urticaria as defined by a positive autologous serum skin test (ASST).[9]

Etiology

In 50% of patients with acute urticaria, a specific etiology can be identified. Brief episodes of urticaria can be associated with identifiable causes, and the method of exposure (ie, direct contact, oral or intravenous routes) is usually known. Acute urticaria is often associated with a recent infection.

Food allergies

Food allergy should be considered in acute urticaria and urticaria in children. Such foods as tree nuts, peanuts, eggs, shellfish, and tomatoes should be considered (the involvement of food additives or preservatives is controversial).[10] ) Please visit our main article to learn more about food allergies.

Drug allergies

Theoretically, almost any drug can cause an allergic reaction (see the images below); thus, allergic reactions to a wide variety of drugs can occur. Antibiotics, such as penicillin, have been implicated most frequently.[11] Urticarial reactions to penicillin can occur as long as 14 days after a course of treatment has stopped. In this situation, serum sickness may be present.



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Urticaria associated with a drug reaction.



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Urticaria from drug reaction.

Physical contact

Contact urticaria is an allergic reaction to a substance that comes into contact with the skin (eg, an occupational exposure) (see the image below).

Insect bites

Papular urticaria is a variation of urticaria caused by insect bites (see the image below); the lesions may last longer than 24 hours.



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Urticaria developed after bites from an imported fire ant.

Hypersensitivity

Urticaria may be caused by other immediate hypersensitivity allergic reactions to an ingested, inhaled, or percutaneously inoculated substance (eg, latex, stinging insects, occupational exposures). See the following image.



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Local urticaria on a patient with latex allergy who was touched with a latex glove.

Nonallergic release of mediators

A number of drugs, such as aspirin, NSAIDs, opiates, succinylcholine, and certain antibiotics (eg, polymyxin, ciprofloxacin, rifampin, vancomycin, some beta-lactams) can cause urticaria by a nonallergic mechanism rather than by IgE-mediated hypersensitivity.

Certain foods or beverages, such as spoiled fish (scombroidosis), aged cheeses, or red wine, can contain histidine, which is closely related to histamine. These foods are often listed as causes of urticaria in the literature, but experimental evidence is scarce.

Certain venoms may cause urticaria.

Radiocontrast media sensitivity is not related to iodine, fish, or shellfish allergy.

Medical causes

Urticaria has been reported with infectious diseases. Viral infections associated with acute urticaria include acute viral syndromes, hepatitis (A, B, and C), Epstein-Barr virus, and herpes simplex virus. Streptococcal infection (see the photograph below) has been reported as the cause of 17% of acute urticaria cases in children.[12] Urticaria has also been reported with chronic parasitic infections.[13]



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Urticaria associated with acute group A beta-hemolytic streptococci infection.

Although sinusitis, cutaneous fungal infections, Helicobacter pylori infection, or other occult infections have been reported in the literature to cause urticaria, the data are not strongly supported.[14, 15, 16, 17, 18]

Hormonal causes via endocrine tumors or ovarian pathology are rare. Oral contraceptive use or changes in the menstrual cycle have been reported as a possible cause of urticaria: patients commonly report worsening of hives with the menstrual cycle. This may be hormonally mediated, and the cyclical use of analgesics should also be considered as a possible etiology.

Urticaria with pruritus can be the presenting symptom of lymphoma, and a careful history and review of systems is important.

Other medical causes of recurrent urticaria include the following:

Physical causes (physical urticaria)

See the list below:

Epidemiology

Urticaria (chronic, acute, or both) affects 15-25% of the population at some time in their lives.[22] The incidence of acute urticaria is higher in people with atopy,[22] and the condition occurs most commonly in children and young adults.[23]

Some patients can have both urticaria and angioedema, occurring simultaneously or separately. Approximately 50% of patients have both urticaria and angioedema, whereas 40% have urticaria alone, and 10% have angioedema alone.[24] Hereditary angioedema (C1 inhibitor deficiency) accounts for only 0.4% of cases of angioedema but is associated with a high mortality rate.

Acute urticaria resolves within 6 weeks. Urticaria longer than 6 weeks’ duration is considered chronic and must be ruled out as a symptom associated with a systemic medical illness.

Prognosis

The prognosis in acute urticaria is excellent, with most cases resolving within days. Acute urticaria usually can be controlled using only symptomatic treatment with antihistamines. If a known triggering factor is present, avoidance is the most effective therapy. Acute urticaria causes discomfort, but it does not cause mortality, unless it is associated with angioedema involving the upper airways.[25, 26, 27] If a patient continues to be exposed to a known trigger, the condition may become chronic.

Morbidity depends on the severity and duration of the condition. One study found that urticaria patients can have as much psychologic, social, and occupational distress as patients who are awaiting triple coronary artery bypass surgery.[28]

Patient Education

Avoidance of known triggering factors is important, and patients with urticaria should be discouraged from scratching or irritating the skin when active lesions are present. Pressure urticaria may worsen the intensity of the rash; therefore, avoiding tight-fitting clothes may be helpful.

History

Pruritus (itching) and rash are the primary manifestations of urticaria, and permanent hyperpigmentation or hypopigmentation is rare.

Lesions commonly last 20 minutes to 3 hours, disappear, and then reappear in other skin areas. An entire episode of urticaria often lasts 24-48 hours; individual lesions usually fade within 24 hours or so, but new lesions may be developing continuously. Rarely, acute urticaria can last 3-6 weeks.[29] Scars do not develop.

With delayed pressure urticaria, lesions may last as long as 48 hours. The lesions of urticarial vasculitis, which are palpable and purpuric, may last for several days or more and may lead to residual hyperpigmented changes.[30]

Typical lesions described by patients are edematous pink or red wheals of variable size and shape that are pruritic.[31] The lesions are often described as welts or hives, including pressure-induced hives, which can occur with elastic or tight clothing, as shown in the images below.[32] Patients may report a painful or burning sensation; such lesions are often associated with angioedema.[33] Pruritus of nonlesional skin may also occur.



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Photograph of dermographism.



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Pressure urticaria (dermatographia) developed after strokes.



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Acute urticaria associated with dermatographism.

Determining whether the lesions have an allergic (IgE) or nonallergic (non-IgE) basis is helpful in the management of the patient. A complete thorough medical and travel history is important to provide clues to urticaria resulting from a new infectious or medical problem. Questions asked to determine possible allergic and nonallergic causes include the following:

Physical Examination

If any features of anaphylaxis (eg, hypotension, respiratory distress, stridor, gastrointestinal distress, swallowing problems, joint swelling, joint pain) are present, immediate medical intervention should occur.

Assess for any features of angioedema (deep tissue or submucosal edema).[34] Angioedema appears as swellings of the tissues, with indistinct borders around the eyelids and lips. Swellings may also appear on the face, trunk, genitalia, and extremities. The face, hands, and feet are involved in 85% of patients. As many as 50% of children who have urticaria exhibit angioedema with swelling of the hands and feet. Hereditary angioedema (C1 inhibitor deficiency) accounts for only 0.4% of cases of angioedema but is associated with a high mortality rate.

Lesions of urticaria can be polymorphic and vary from several millimeters to large, continuous edematous plaques that have smooth surfaces with polycyclic curved borders. The lesions do not have scales but show an intense erythema in the newest areas, with a trailing clearing region in older areas. The central clearing can cause a target configuration in expanding plaques. The advancing border shows a discrete edge followed by a faint, trailing, diffuse border.

Look for any atypical skin lesions. Lesions that are purpuric, nonblanchable, and palpable are characteristic of urticarial vasculitis. These lesions may leave residual pigmented changes. Tiny pinpoint hives are characteristic of cholinergic urticaria.[35]

Edema can be observed by slightly stretching the skin to demonstrate whitish centers. Occasionally, large annular urticarial lesions as large as 30 cm in diameter with polycystic borders are observed.

Examine for dermographism, as it is often observed in conjunction with urticaria. Itching, erythema, and a raised wheal occur in areas that are scratched or stroked with a blunt object, such as a tongue blade.[36] The examiner can use the end of a tongue blade or similar blunt object to scratch the patient's skin and observe the area over the next 5-15 minutes for the development of whealing with erythema, as shown in the following image.



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Photograph of dermographism.

The remainder of the physical examination should be used to investigate any suspicions that were raised by the history.

Staging

According to a study, the cutaneous biopsy of urticaria lesions may be divided into the following categories, as the response to treatment could be different:

Approach Considerations

Acute urticaria is generally diagnosed based on a detailed patient history and physical examination (see Clinical Presentation),[39, 40, 41] and laboratory studies generally are not indicated. In pediatric cases, screening for streptococcal antigen may be indicated.[12] The patient's history and physical examination should direct any diagnostic studies.[42, 39, 43]

Imaging studies generally are not indicated unless a specific finding on clinical examination or history suggests an underlying etiology that may warrant further diagnostic studies.[44]

The 2013 EAACI/GA2LEN/EDF/WAO diagnosis guideline recommends using the urticaria activity score (UAS) proposed in the previous version of the guideline to measure disease severity and monitor treatment results in daily practice. The UAS assigns a score from 0 (no disease activity) to 3 (intense activity) for each of the 2 key urticaria symptoms, wheals and pruritus. The sum of the scores represents disease severity on a scale from 0 (minimum) to 6 (maximum).[76, 45]

Skin Tests

Selected allergy tests can be performed if food allergy or stinging insect hypersensitivity is suspected. This process may be helpful for some cases of acute urticaria, but these studies are rarely helpful in the evaluation of chronic urticaria.[14] However, they may be needed to rule out an atopic component and label the urticaria as idiopathic.

Skin tests or radioallergosorbent assay test (RAST) (specific IgE) can be performed to detect hypersensitivity to a limited number of antibiotics. Testing for pollen or other inhalants is generally not helpful, unless a severe allergy may be causing the urticaria, such as a severe allergy to pollens, cats, or latex (these may manifest as contact urticaria).

Routine allergy testing with a large battery of screening tests is not recommended. A few research centers perform an autologous serum skin test, but it is currently not a well-established procedure.

Physical Challenge Tests

Physical urticaria can be confirmed with physical challenge tests. These involve the application of the suspected stimuli (heat, pressure, light, vibration, scratching [dermographism], cold [ice cube]) to the skin. Exercise testing can also be performed to diagnose cholinergic urticaria. Ice cube test findings are typically negative in patients with familial cold autoinflammatory syndrome. With the exception of testing for dermographism, these tests are usually performed only by specialty centers.

Skin Biopsy

A diagnostic skin biopsy is not helpful but should be considered if lesions do not resolve in patients suspected of having urticarial vasculitis (eg, in patients who present with features such as fever, painful lesions, arthralgia, elevated erythroid segmentation rate, lesions that last 24 hours or longer, or lesions that resolve with residual petechiae or purpura).[30, 46]

Histologic Findings

The histologic findings of acute urticaria are not dramatic. No epidermal change is present. Acute urticaria demonstrates intravascular margination of neutrophils. Later lesions demonstrate diapedesis of neutrophils through the vessel wall in the absence of karyorrhexis. Late lesions demonstrate intravascular, perivascular, and interstitial neutrophils with little to no karyorrhexis. A moderate number of eosinophils may be present.[47]

Approach Considerations

Identify the etiology of the acute urticaria if possible. If an inciting agent can be identified, instruct the patient to avoid it. The major goal is to control the severity of acute urticaria lesions until the process resolves over 4-6 weeks.

Inpatient therapy may be required rarely if the urticaria is severe and does not respond to antihistamine therapy, or if the patient's condition progresses to laryngeal angioedema and/or anaphylactic shock.

The EAACI/GA2LEN/EDF/WAO panel consensus released an updated guideline in 2013 on the management of urticaria including a treatment algorithm for symptomatic management of chronic spontaneous urticaria.[76, 48, 49]

Pharmacologic Therapies

As advised in the 2013 EAACI/GA2LEN/EDF/WAO management guideline, due to the fluctuating nature of acute urticaria and the chance that spontaneous remission can occur at any time, continued or alternative drug treatment should be reevaluated every 3-6 months.[76, 48, 49]

In children, if a case is confirmed to involve streptococcal infection, penicillin G should be given either orally or by injection, depending on the patient’s age and circumstances.[12]

H1 antagonists (first-generation antihistamines)

Antihistamines are the primary agents used to treat urticaria.[11] The older, first-generation H1 antagonists (eg, diphenhydramine, hydroxyzine) are effective in reducing the lesions and pruritus but can produce a number of adverse effects, such as drowsiness, anticholinergic effects, and cognitive effects, which may continue until the next day.[50] Thus, these agents can be useful if administered at bedtime.

According to the EAACI/GA2LEN/EDF/WAO management guideline, first-generation sedating antihistamines should no longer be used as the first choice therapy except where second-generation antihistamines are not available or where their benefits outweigh their risks. The guideline advises against using older, sedating first-generation antihistamines in patients with urticaria who have no special indications.[76, 48, 49]

Any patient who is taking a medication that has potential sedative effects should be cautioned about driving and operating heavy machinery. Commonly used first-generation agents include diphenhydramine, hydroxyzine, chlorpheniramine, and cyproheptadine.

Most patients with urticaria can be treated with oral (PO) H1 antihistamines. Modern second-generation antihistamines are the first choice. Increasing the dose up to fourfold is permitted in patients who do not respond sufficiently to the standard dosing. For refractory cases, use a combination of H1 and H2 antihistamines.

The experimental evidence comparing the various possible regimens and rates of adverse effects in the long term is still minimal.

H1 antagonists (second-generation antihistamines)

The newer second-generation antihistamines are nonsedating in most patients, with very few adverse effects reported (cetirizine can cause drowsiness in up to 10% of patients).[51, 48, 49] Therefore, many specialists prefer the use of these agents for chronic urticaria, with first-generation agents reserved for acute or refractory cases. Commonly used second-generation antihistamines are cetirizine, levocetirizine, desloratadine, loratadine, and fexofenadine. Four times the approved doses can be used if needed in cases where standard dose is insufficient to control the symptom.

H2 antagonists

These drugs are usually used to decrease gastric acid secretion. H2 antagonists are not effective when used as single agents for urticaria; however, the combination of an H1 antagonist with an H2 antagonist has been shown to be more effective than an H1 antagonist alone.[52, 53] Any of the H2 blockers can be used. Two of the most commonly used agents are ranitidine and cimetidine.

Corticosteroids

In some instances of acute or chronic urticaria, antihistamines may fail, even at high doses, or adverse effects may be problematic. In addition, mediators other than histamine may be involved. In such situations, corticosteroids can be highly effective. Corticosteroids may also be used in urticarial vasculitis, which usually does not respond to antihistamines.

The EAACI/GA2LEN/EDF/WAO management guideline recommends the use of corticosteroids only in severely affected patients.[48, 49]

A short course of an oral corticosteroid (administered daily for 5-7 d, with or without a taper) or a single dose of a long-acting injectable steroid is not usually associated with long-term sequelae and can be helpful when used for an acute episode of urticaria nonresponsive to antihistamines.[24] Examples of corticosteroid preparations include prednisolone, methylprednisolone, and prednisone

Because of adverse effects of chronic or recurrent use of systemic corticosteroids, the long-term use of these agents should be avoided, when possible. If urticaria is severe and cannot be safely controlled with other medications, low-dose therapy and/or alternate-day therapy can be considered.

Corticosteroids stabilize mast cell membranes and inhibit further histamine release, as well as reduce the inflammatory effect of histamine and other mediators. The efficacy of corticosteroids in acute urticaria remains controversial. In one study, acute urticaria improved more quickly in the group treated with prednisone than in the group treated with placebo.[54]

In adults, 40-60 mg daily of prednisone for 5 days is a reasonable therapeutic regimen. In children, the treatment is 1 mg/kg/d for 5 days. Tapering of the corticosteroid dose is not necessary in most cases of acute urticaria.[1]

S ympathomimetic agents

Sympathomimetic agents cause vasoconstriction and reduction in vascular dilation, which contributes to urticaria formation.

The efficacy of epinephrine in acute urticaria is controversial.[48, 49] If angioedema is present with urticaria, epinephrine should be administered via the IM route. Remember that converting enzyme inhibitor (ACEI)–induced angioedema usually does not respond to epinephrine or most other common therapies, as it is not an IgE-mediated process.[55]

Immunomodulatory and anti-inflammatory therapy

Cyclosporine has been shown to be effective in 2 double-blind placebo-controlled studies.[56, 57] IV gammaglobulin and plasmapheresis have been described as useful in a limited number of case studies.[58, 59] These therapies can be a consideration in severe urticaria, particularly of the autoimmune type that is unresponsive to medications, but such treatment is usually only initiated by specialists with considerable expertise in urticaria.

Colchicine and dapsone have also been reported to be useful for refractory urticaria and urticarial vasculitis,[60, 61] perhaps because of their ability to modulate polymorphonuclear lymphocyte (PMN) function. PMNs and a mixed infiltrate can be present in some urticarial lesions, particularly urticaria that is severe or refractory to antihistamine treatment.

Some reports describe the effectiveness of the antileukotriene agents in urticaria,[62, 63] but extensive clinical trials have not been performed, so their usefulness is still questionable. Clinical trials might in the future support the theory that the antileukotriene agents can provide a synergistic response when used in conjunction with antihistamines.

Omalizumab (monoclonal antibody to IgE) is a recombinant biologic molecule effective for chronic urticaria based on two large positive phase III studies and is currently FDA approved for treatment of chronic urticaria. Patients can be treated with 150 or 300 mg subcutaneously every four weeks.[77] The role in acute urticaria has not been determined and further studies are needed. 

Because the use of the aforementioned agents is not widespread, details of dosage and administration are not provided, but references are listed in the bibliography. The use of corticosteroids is more common and is discussed in Medication.

Tricyclic antidepressants

Tricyclic antidepressants (TCAs) are a complex group of drugs that have central and peripheral anticholinergic effects, as well as sedative effects. TCAs block the active reuptake of norepinephrine and serotonin; and some (eg, doxepin) have antihistamine effects, blocking both the H1 and H2 receptors, and have been used in the treatment of allergic reactions, especially urticaria.

Nonpharmacologic Therapies

Food and symptom diaries

Suspected food allergies can be confirmed or disproved with the use of food diaries. A food or symptom diary for a fixed duration (eg, 2-4 wk) may be helpful. Note all activities in which the patient was involved for 6-8 hours before the onset of urticaria. Cases have been reported in which a food or activity (such as jogging) by itself results in no symptoms but when combined (eg, eating a shrimp cocktail and then jogging) may result in urticaria with or without progression to anaphylaxis. Excessive or prolonged use of a food or symptom diary is unlikely to be of benefit.

Avoidance

If a trigger can be identified, avoidance is the most effective form of management. This would include any food, medication, physical agent, or other factor that triggers the urticaria.

Aspirin,[65, 66] NSAIDs,[67] opiates, and alcohol have been reported to be nonspecific triggers of urticaria and might lower the threshold for urticaria in selected patients. Therefore, some specialists advise all patients with urticaria to avoid these agents. However, little experimental evidence is available to support this recommendation.

Removing offending ectoparasites can prevent papular urticaria, and insect repellent may lessen the chance of bites or stings from offending insects. Desensitization strategies are not recommended, except for stinging insect venoms.

Although the need for cold cardiopulmonary bypass surgery in patients with cold-induced urticaria is uncommon, one study reported success using an anti-inflammatory regimen before surgery and during recovery to prevent a systemic reaction of urticaria.[68]

Emergency Care and Complications

Acute urticaria is a common disorder that often prompts patients to seek treatment in the emergency department (ED). In fact, acute urticaria is the most common cutaneous disease treated in the ED.[69] Determining whether urticaria is part of an anaphylactic reaction is important. If an anaphylactic reaction occurs, the patient needs prompt treatment and careful monitoring

The management of urticaria in the ED is straightforward and typically is not altered by underlying etiology. The mainstay is avoidance of further exposure to the antigen and antihistamines.

Most cases of acute urticaria respond to pharmacotherapy (see Medication). Antihistamines are the first line of therapy for urticaria.[48, 49] Modern second-generation antihistamines are also effective as first-line treatment. Diphenhydramine (25 mg IV or 50 mg IM or PO) or hydroxyzine (50 mg IM or PO) can be administered also and have benefit in helping patients sleep at nights.[48, 49]

If any features of anaphylaxis (eg, hypotension, respiratory distress, stridor, gastrointestinal distress, swallowing problems, joint swelling, joint pain) are present, immediate medical intervention should occur.

Acute urticaria may progress to life-threatening angioedema and/or anaphylactic shock in a very short time, although it usually presents as rapid-onset shock with no urticaria or angioedema.[70]

If associated angioedema is present, especially if laryngeal angioedema (eg, hoarseness, stridor) is suspected, prehospital administration of 0.3-0.5 mg of intramuscular [IM] epinephrine may be warranted. If associated bronchospasm is present, prehospital nebulized albuterol may be warranted.

Other measures may be appropriate, such as continuous electrocardiography (ECG); blood pressure and pulse oximetry monitoring; administering IV crystalloids if the patient is hypotensive; and administering oxygen. If the patient has angioedema that is treated successfully in the ED, the patient should be sent home with an EpiPen prescription. The patient should be instructed to keep the EpiPen with him or her at all times and to use it if swelling of the lips, tongue, or face develops or if his or her voice becomes acutely hoarse.

Diet

Dietary modification is only necessary if food allergy or food additive hypersensitivity has been established. If such hypersensitivity is identified, the patient should avoid the offending food or food additive.

Activity

If the patient has physical urticaria, activity should be carefully monitored, depending on the trigger (eg, cold or hot temperatures, exposure to sun or water, pressure or vibration).

Individuals with cold urticaria must be particularly cautious and not immerse themselves suddenly in cold water. Patients should avoid swimming in lakes, streams, or oceans.

Consultations

A primary care provider can manage most cases of acute urticaria. If a trigger is easily identified and avoidance leads to resolution, then referral is not necessary. If an allergic trigger is suspected but not easily identified, then referral to an allergy specialist is warranted.[71] Similarly, if avoidance of a trigger does not lead to resolution or if the patient does not respond well to antihistamines, then referral to an allergist or dermatologist is warranted.[71]

Long-term Monitoring

Identify the etiology of the acute urticaria if possible. If an inciting agent can be identified, instruct the patient to avoid it. The major goal is to control the severity of acute urticaria lesions until the process resolves over 4-6 weeks.

Medication Summary

Use of antihistamines is the mainstay of therapy. In acute cases, a short course of steroids can be very effective. Long-term treatment with steroids should be avoided, if possible, but may be necessary in severe cases. A number of other classes of medicines have been found to be effective, mostly on an experimental basis. If urticaria does not respond to antihistamine treatment (with the possible addition of a short course of steroids), then referral to a specialist is indicated.[71, 39, 53, 72, 73]

Diphenhydramine (Benadryl, Diphen, Banophen, Genahist)

Clinical Context:  Diphenhydramine is a common first-generation agent that is available without a prescription in the United States and can be used to control pruritus. It acts by competitive inhibition of histamine at the H1 receptor, which mediates the wheal-and-flare reactions.

Cyproheptadine

Clinical Context:  Cyproheptadine is a first-generation agent and historically has been a drug of choice for prophylaxis of primary acquired cold-induced urticaria.

Chlorpheniramine (Chlor-Trimeton, Aller-Chlor, Ed-Chlortan)

Clinical Context:  Chlorpheniramine is a first-generation agent and is one of the safest antihistamines to use during pregnancy.

Hydroxyzine (Vistaril)

Clinical Context:  Hydroxyzine is used for control of pruritus. It is an effective first-generation agent but frequently produces sedation, particularly with higher doses. Historically, it has been considered a drug of choice for cholinergic urticaria. SC and IV are not recommended administration routes. Hydroxyzine also may suppress histamine activity in the subcortical region of the CNS.

Class Summary

Primary agents used for urticaria.[11] The older, first-generation H1 antagonists (eg, diphenhydramine, hydroxyzine) are effective in reducing the lesions and pruritus but can produce adverse effects, such as drowsiness and anticholinergic effects.[50]  These are no longer first-line treatments, but can be helpful when sedation is needed.

The first-generation agents can be useful if administered at bedtime because the sedative effects can help with sleep; however, the patient must be warned that the sedation and cognitive effects may continue until the next day. Any patient who is taking a medication that has potential sedative effects should be cautioned about driving and operating heavy machinery. Commonly used first-generation agents include diphenhydramine, hydroxyzine, doxepin, chlorpheniramine, and cyproheptadine.

Loratadine (Claritin, Alavert)

Clinical Context:  Loratadine selectively inhibits peripheral histamine H1 receptors. It is tolerated very well, with a rate of sedation that is not significantly different from that of placebo. The once-daily dosing makes it convenient.

Fexofenadine (Allegra)

Clinical Context:  Fexofenadine is a second-generation agent that is effective in urticaria. It is tolerated very well, with a rate of sedation that is not significantly different from that of placebo. Fexofenadine competes with histamine for H1 receptors on the GI tract, blood vessels, and respiratory tract, reducing hypersensitivity reactions.

Desloratadine (Clarinex)

Clinical Context:  Desloratadine is a long-acting tricyclic histamine antagonist selective for H1 receptors. It is a major metabolite of loratadine, which, after ingestion, is metabolized extensively to active metabolite 3-hydroxydesloratadine.

Levocetirizine (Xyzal)

Clinical Context:  Levocetirizine is a histamine1-receptor antagonist and an active enantiomer of cetirizine. Peak plasma levels are reached within 1 hour, and the half-life is about 8 hours. It is available as a 5-mg breakable (scored) tab and is indicated for uncomplicated skin manifestations of chronic idiopathic urticaria

Cetirizine (Zyrtec)

Clinical Context:  Cetirizine is a second-generation agent that is frequently used in urticaria. It acts by competitive inhibition of histamine at the H1 receptor. Once-daily dosing makes it convenient, and sedation occurs in approximately 10% of patients. Dosing qhs may be useful if sedation is a problem. Although the standard dose is 5-10 mg qd, some specialists increase this to 10 mg bid for chronic urticaria that is not responding to the usual FDA-approved maximum dose.

Class Summary

The newer second-generation antihistamines are nonsedating in most patients, with very few adverse effects reported. These agents are preferred for acute and chronic urticaria, with first-generation agents reserved for efractory cases. Commonly used H1 antagonists currently available in the United States are cetirizine, levocetirizine, desloratadine, loratadine, and fexofenadine.

Famotidine (Pepcid)

Clinical Context:  Famotidine is an H2 antagonist that, when combined with an H1 type, may be useful in treating allergic reactions that do not respond to H1 antagonists alone.

Cimetidine (Tagamet)

Clinical Context:  Cimetidine is an H2 antagonist that, when combined with an H1 antagonist, may be useful in treating itching and flushing in urticaria and contact dermatitis that do not respond to H1 antagonists alone. Use in addition to H1 antihistamines.

Ranitidine (Zantac)

Clinical Context:  Ranitidine is an H2 antagonist that, when combined with an H1 type, may be useful in treating urticaria when urticaria is not responsive to H1 antagonists alone.

Class Summary

These are reversible, competitive blockers of histamine at H2 receptors, particularly those in gastric parietal cells. The H2 antagonists are highly selective, do not affect H1 receptors, and are not anticholinergic agents. They block the vasodilation mediated by the H2 receptors in blood vessels, possibly leading to less edema formation in urticaria.

When used as single agents for urticaria, they are not effective. However, the combination of an H1 antagonist with an H2 antagonist is more effective than an H1 antagonist alone.[52, 53] Any of the H2 blockers can be used. Two of the most commonly used agents are ranitidine and cimetidine.

Prednisolone (Millipred, Orapred, Pediapred)

Clinical Context:  Prednisone is a commonly used oral agent that must be metabolized to the active metabolite prednisolone for effect. Conversion may be impaired in liver disease. It is useful in cases that have not responded to traditional antihistamine. For extensive, symptomatic urticaria, a burst of prednisone over 4 days can lead to marked improvement and control of symptoms. Prednisone decreases inflammation by suppressing migration of polymorphonuclear leukocytes and by reversing increased capillary permeability.

Methylprednisolone (Medrol, Depo-Medrol, Solu-Medrol)

Clinical Context:  Methylprednisolone is used for the treatment of severe urticaria reactions. It reverses increased capillary permeability.

Prednisone (Deltasone, Rayos)

Clinical Context:  Prednisolone is available in both tablet and liquid forms. It reduces capillary permeability.

Class Summary

In instances of acute or chronic urticaria in which antihistamines may fail, even at high doses, or adverse effects may be problematic, mediators other than histamine may be involved. In such situations, corticosteroids may be administered. The current recommendation is to avoid prednisone when possible. If not, then consider the possibility of another disease process (eg, malignancy, mastocytosis,[74] vasculitis). Corticosteroids may also be used in urticarial vasculitis, which usually does not respond to antihistamines.

In refractory cases, a short course of an oral corticosteroid (administered daily for 5-7 d, with or without a taper) or a single dose of a long-acting injectable steroid is not usually associated with long-term sequelae and can be helpful when used for an acute episode of urticaria nonresponsive to antihistamines.[24]

Because of adverse effects of chronic or recurrent use of systemic corticosteroids, the long-term use of these agents should be avoided, when possible. If urticaria is severe and cannot be safely controlled with other medications, low-dose therapy and/or alternate day therapy can be considered.

A large number of preparations are available. Representative examples are prednisolone, methylprednisolone, and prednisone.

Epinephrine (Adrenalin, Epi-Pen)

Clinical Context:  Epinephrine is DOC for the treatment of severe or generalized urticaria as part of an anaphylactic reaction. The alpha-agonist effects of this medication increase peripheral vascular resistance and reverse peripheral vasodilatation, vascular permeability, and systemic hypotension. Conversely, the beta-agonist effects of epinephrine produce bronchodilatation, cause positive inotropic and chronotropic cardiac activity, and result in an increased production of intracellular cAMP. Any patient who has had a potentially life-threatening allergic reaction should have injectable epinephrine available for use at all times (eg, portable Epi-Pen). Intramuscular administration of epinephrine is preferred over subcutaneous.

Class Summary

These agents cause vasoconstriction and reduction in vascular dilation, which contributes to urticaria formation.

Montelukast (Singulair)

Clinical Context:  Montelukast is a potent and selective antagonist of leukotriene D4 (LTD4) at the cysteinyl leukotriene receptor, CysLT1. It prevents or reverses some of the pathologic features associated with the inflammatory process mediated by leukotrienes C4, D4, and E4. It is available as a tablet, chewable tablet, or PO granules. Granules may be administered directly in the mouth or dissolved in 1 tsp of cold or room-temperature baby formula, breast milk, or food (stable with applesauce, carrots, rice, or ice cream).

Zafirlukast (Accolate)

Clinical Context:  Zafirlukast inhibits the effects by leukotriene receptors, whose activity has been associated with airway edema, smooth muscle contraction, and cellular activity associated with the symptoms.

Class Summary

In recent years, leukotriene receptor antagonists (eg, montelukast) have been added to antihistamines to control urticaria. These can be used as third-line agents as there is only weak evidence to support their use in acute urticaria.

Doxepin

Clinical Context:  Doxepin inhibits histamine and acetylcholine activity and has proven to be useful in the treatment of allergic dermatologic disorders. It has both H1 antagonist activity and H2 antagonist activity that is far more potent than traditional antihistamines. It also has antidepressant properties attributed to blocking MAO.

Class Summary

These agents are a complex group of drugs that have central and peripheral anticholinergic effects, as well as sedative effects, and block the active reuptake of norepinephrine and serotonin. Some TCAs (eg, doxepin) have antihistamine effects, blocking both the H1 and H2 receptors and have been used in the treatment of allergic reactions, especially urticaria.

Omalizumab (Xolair)

Clinical Context:  Omalizumab, a recombinant humanized monoclonal antibody against immunoglobulin E (IgE), has been successfully used in patients with physical urticaria, including symptomatic dermographism. Patients should undergo a full allergy evaluation prior to starting omalizumab, if needed, because it interferes with prick skin test and in vitro serum specific IgE assay results.

Class Summary

Agents in this class are recombinant DNA-derived humanized immunoglobulin G monoclonal antibodies that bind selectively to human immunoglobulin E on the surface of mast cells and basophils. The drug reduces mediator release, which promotes an allergic response.

What is acute urticaria (hives)?How does acute urticaria (hives) develop?What are the signs and symptoms of anaphylaxis in acute urticaria (hives), and what must be done if these features are present?What is the role of history in the evaluation of acute urticaria (hives)?How is acute urticaria (hives) diagnosed?How is acute urticaria (hives) differentiated from other dermatologic conditions?What is the goal of treatment for acute urticaria (hives)?What is the pathophysiology of acute urticaria (hives)?What is the duration of acute urticaria (hives)?What is the role of immune hypersensitivity in the pathophysiology of acute urticaria (hives)?What is complement-mediated urticaria?What are the types of physical urticaria?What is idiopathic urticaria?How frequently is an etiology for acute urticaria (hives) identified?What is the role of food allergy in the etiology of acute urticaria (hives)?Which drugs are most frequently the cause of acute urticaria (hives)?What is contact urticaria?What causes papular urticaria?What are the possible causes of acute urticaria (hives)?Which drugs cause acute urticaria (hives) by a nonallergic mechanism?What is the role of histidine in the etiology of acute urticaria (hives)?What are nonallergenic causes of acute urticaria?Which infectious diseases cause acute urticaria (hives)?What is the role of hormones in the etiology of acute urticaria (hives)?What does acute urticaria with pruritus indicate?What are medical causes of recurrent acute urticaria (hives)?What are physical causes of acute urticaria (hives)?What is the prevalence of acute urticaria (hives)?How often does acute urticaria (hives) occur simultaneously with angioedema?What is the duration of acute urticaria (hives)?What is the prognosis of acute urticaria (hives)?What should patients be told about acute urticaria (hives)?What are the signs and symptoms of acute urticaria (hives)?How long do urticaria (hives) lesions usually last?How are urticaria (hives) lesions characterized?What should be the focus of history for suspected acute urticaria (hives)?What are the signs and symptoms of anaphylaxis with acute urticaria (hives)?What are the physical findings of angioedema in patients with acute urticaria (hives)?Which physical findings are characteristic of urticaria?What the physical findings characteristic of urticarial vasculitis?What are the physical findings of edema in acute urticaria (hives)?How is dermographism identified in the evaluation of acute urticaria (hives)?How are the cutaneous biopsy findings of urticarial lesions (hives) categorized?How frequently is the cause of acute urticaria (hives) identified?Which dermatologic conditions should be included in the differential diagnosis for acute urticaria (hives)?What causes chronic urticaria?What are the differential diagnoses for Acute Urticaria?How is acute urticaria diagnosed?What is the urticaria activity score (UAS) and how is it used in the evaluation of (hives)?What is the role of allergy testing in the evaluation of acute urticaria?What is the role of physical challenge testing in the evaluation of acute urticaria (hives)?What is the role of skin biopsy in the evaluation of acute urticaria (hives)?Which histologic findings are characteristic of acute urticaria (hives)?What can prevent acute urticaria (hives) from worsening?When is inpatient therapy indicated for the treatment of acute urticaria (hives)?What is included in the EAACI/GA2LEN/EDF/WAO treatment guidelines for urticaria (hives)?When should pharmacologic therapies be reevaluated in patients with acute urticaria?How should penicillin G be administered in children with acute urticaria?What is the role of antihistamines in the treatment of acute urticaria (hives)?When are first-generation sedating antihistamines used in the treatment of acute urticaria (hives)?Which first-generation sedating antihistamines are used in the treatment of acute urticaria (hives), and how should patients taken them be advised?What is the role of second generation antihistamines in the treatment of acute urticaria (hives)?What is the role of H2 antagonists in the treatment of acute urticaria (hives)?What is the role of corticosteroids in the treatment of acute urticaria (hives)?How should oral corticosteroids be administered in the treatment of acute urticaria (hives)?What is the mechanism of action for corticosteroids in the treatment of acute urticaria (hives)?What is the therapeutic regimen for corticosteroids as treatment for acute urticaria (hives)?What is the role of sympathomimetic agents in the etiology of acute urticaria (hives)?What is the role of epinephrine in the treatment of acute urticaria (hives)?Which pharmacologic therapies can be a used to treat severe urticaria (hives)?What is the efficacy of antileukotriene agents in the treatment of acute urticaria (hives)?What is the role of omalizumab in the treatment of urticaria (hives)?What is the role of tricyclic antidepressants (TCAs) in the treatment of acute urticaria (hives)?What is the role of a food or symptom diary in the treatment of acute urticaria (hives)?How are urticaria triggers managed?What are nonspecific triggers of urticaria (hives)?How can papular urticaria be prevented?How can a systemic reaction of urticaria be prevented before surgery and during recovery?How frequently are patients with acute urticaria (hives) seen in the emergency department (ED)?Which agents are effective in the treatment of acute urticaria?When is immediate medical intervention required for acute urticaria (hives)?How might acute urticaria progress?How is angioedema managed in a patient with acute urticaria?When are dietary modification indicated in the treatment of acute urticaria (hives)?What activity modifications are needed in the treatment of physical urticaria?When is consultation with an allergist or dermatologist indicated for the treatment of acute urticaria (hives)?What is the benefit of identifying the etiology of the acute urticaria (hives)?Which medications are used in the treatment of acute urticaria (hives)?Which medications in the drug class Monoclonal Antibodies, Anti-asthmatics are used in the treatment of Acute Urticaria?Which medications in the drug class Tricyclic Antidepressants are used in the treatment of Acute Urticaria?Which medications in the drug class Leukotriene Receptor Antagonist are used in the treatment of Acute Urticaria?Which medications in the drug class Sympathomimetic Agents are used in the treatment of Acute Urticaria?Which medications in the drug class Corticosteroids are used in the treatment of Acute Urticaria?Which medications in the drug class H2 antagonists (antihistamines) are used in the treatment of Acute Urticaria?Which medications in the drug class H1 Antagonists (second-generation antihistamines) are used in the treatment of Acute Urticaria?Which medications in the drug class H1 Antagonists (first-generation antihistamines) are used in the treatment of Acute Urticaria?

Author

Henry K Wong, MD, PhD, Professor and Chairman, Department of Dermatology, University of Arkansas for Medical Sciences College of Medicine

Disclosure: Serve(d) as a director, officer, partner, employee, advisor, consultant or trustee for: Seattle Genetics, Actillion, Celgene, Kyowa-Kirin<br/>Serve(d) as a speaker or a member of a speakers bureau for: Amgen<br/>Received income in an amount equal to or greater than $250 from: Celgene<br/>Received honoraria from Amgen for speaking and teaching; Received grant/ Received grant/research funds from Celgene for none; Received grant/research funds from Abbott Labs for independent contractor; Received grant/research funds from Amgen for none; Received honoraria from Seattle Genetics for consulting. for: Actelion-Advisory board, grants;Seattle Genetics - Advisory board.

Coauthor(s)

Umer Najib, MD, Clinical Research Fellow, Department of Medicine, Division of Allergy and Inflammation, Beth Israel Deaconess Medical Center

Disclosure: Nothing to disclose.

Specialty Editors

Francisco Talavera, PharmD, PhD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

Chief Editor

Michael A Kaliner, MD, Clinical Professor of Medicine, George Washington University School of Medicine; Medical Director, Institute for Asthma and Allergy

Disclosure: Nothing to disclose.

Additional Contributors

Javed Sheikh, MD, Assistant Professor of Medicine, Harvard Medical School; Clinical Director, Division of Allergy and Inflammation, Clinical Director, Center for Eosinophilic Disorders, Beth Israel Deaconess Medical Center

Disclosure: Received grant/research funds from Genentech for other.

Acknowledgements

Jeffrey P Callen, MD Professor of Medicine (Dermatology), Chief, Division of Dermatology, University of Louisville School of Medicine

Jeffrey P Callen, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, American College of Physicians, and American College of Rheumatology

Disclosure: Amgen Honoraria Consulting; Abbott Honoraria Consulting; Electrical Optical Sciences Consulting fee Consulting; Celgene Honoraria Safety Monitoring Committee; GSK - Glaxo Smith Kline Consulting fee Consulting; TenXBioPharma Consulting fee Safety Monitoring Committee

Kevin P Connelly, DO Clinical Assistant Professor, Department of Pediatrics, Division of General Pediatrics and Emergency Care, Virginia Commonwealth University School of Medicine; Medical Director, Paws for Health Pet Visitation Program of the Richmond SPCA; Pediatric Emergency Physician, Emergency Consultants Inc, Chippenham Medical Center

Kevin P Connelly, DO is a member of the following medical societies: American Academy of Pediatrics, American College of Osteopathic Pediatricians, and American Osteopathic Association

Disclosure: Nothing to disclose.

Stephen C Dreskin, MD, PhD Professor of Medicine, Departments of Internal Medicine, Director of Allergy, Asthma, and Immunology Practice, University of Colorado Health Sciences Center

Stephen C Dreskin, MD, PhD is a member of the following medical societies: American Academy of Allergy Asthma and Immunology, American Association for the Advancement of Science, American Association of Immunologists, American College of Allergy, Asthma and Immunology, Clinical Immunology Society, and Joint Council of Allergy, Asthma and Immunology

Disclosure: Genentech Consulting fee Consulting; American Health Insurance Plans Consulting fee Consulting; Johns Hopkins School of Public Health Consulting fee Consulting; Array BioPharma Consulting fee Consulting

Dirk M Elston, MD Director, Department of Dermatology, Geisinger Medical Center

Dirk M Elston, MD is a member of the following medical societies: American Academy of Dermatology

Disclosure: Nothing to disclose.

Daniel J Hogan, MD Clinical Professor of Internal Medicine (Dermatology), Nova Southeastern University College of Osteopathic Medicine; Investigator, Hill Top Research, Florida Research Center

Daniel J Hogan, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, American Contact Dermatitis Society, and Canadian Dermatology Association

Disclosure: Nothing to disclose.

Shih-Wen Huang, MD Professor Emeritus, Pulmonology and Allergy, Department of Pediatrics University of Florida College of Medicine

Shih-Wen Huang, MD, is a member of the following medical societies: American Academy of Allergy Asthma and Immunology

Disclosure: Nothing to disclose.

Harumi Jyonouchi, MD Associate Professor, Division of Pulmonary Allergy/Immunology and Infectious Diseases, Department of Pediatrics, UMDNJ-New Jersey Medical School

Harumi Jyonouchi, MD is a member of the following medical societies: American Academy of Allergy Asthma and Immunology, American Academy of Pediatrics, American Association of Immunologists, American Medical Association, Clinical Immunology Society, New York Academy of Sciences, Society for Experimental Biology and Medicine, Society for Mucosal Immunology, and Society for Pediatric Research

Disclosure: Nothing to disclose.

Robert A Schwartz, MD, MPH Professor and Head, Dermatology, Professor of Pathology, Pediatrics, Medicine, and Preventive Medicine and Community Health, University of Medicine and Dentistry of New Jersey-New Jersey Medical School

Robert A Schwartz, MD, MPH is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, American College of Physicians, and Sigma Xi

Disclosure: Nothing to disclose.

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment

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Urticaria associated with a drug reaction.

Urticaria developed after bites from an imported fire ant.

Local urticaria on a patient with latex allergy who was touched with a latex glove.

Urticaria associated with a drug reaction.

Urticaria from drug reaction.

Urticaria developed after bites from an imported fire ant.

Local urticaria on a patient with latex allergy who was touched with a latex glove.

Urticaria associated with acute group A beta-hemolytic streptococci infection.

Photograph of dermographism.

Pressure urticaria (dermatographia) developed after strokes.

Acute urticaria associated with dermatographism.

Photograph of dermographism.

Urticaria associated with a drug reaction.

Urticaria developed after bites from an imported fire ant.

Local urticaria on a patient with latex allergy who was touched with a latex glove.

Urticaria from drug reaction.

Photograph of dermographism.

Pressure urticaria (dermatographia) developed after strokes.

Acute urticaria associated with dermatographism.

Urticaria associated with acute group A beta-hemolytic streptococci infection.

Acute urticaria in a toddler affecting the face. Likely cause is postviral syndrome.