ACP medicine, 3rd Edition


Urticaria, Angioedema, and Anaphylaxis

Vincent S. Beltrani M.D.1

1Visiting Professor of Medicine, University of Medicine and Dentistry of New Jersey

The author has no commercial relationships with manufacturers of products or providers of services discussed in this subsection.

February 2003


Urticaria (hives), angioedema, and anaphylaxis are the prototypical manifestations of mast cell activation. The common denominator in these conditions is the release of potent inflammatory mediators from activated mast cells1 [see 6:X Allergic Response]. Urticaria and angioedema are effected primarily by activation of cutaneous mast cells, which are preferentially located around capillaries, lymphatics, appendages, and nerves in the skin. Massive activation of mast cells in the intestinal tract, respiratory tract, and central nervous system produces the multisystemic, potentially catastrophic symptom complex of anaphylaxis.

Although the three conditions have common features and may occur in various combinations, they are more easily understood when discussed individually.


Urticaria is a cutaneous eruption that consists of erythematous, pruritic wheals. Although urticaria is typically transient, it can be persistent, with lesions occurring for weeks to months.


Urticaria is a common problem, with 15% to 23% of the general population experiencing at least one episode in their lifetime.2,3 The precise prevalence of urticaria may never be known. Many patients experience transient episodes of hives and do not report them to a health care provider because of their readily identifiable cause, inconsequential nature, and spontaneous resolution. If the papular urticaria that develops after an arthropod bite is included in the spectrum of urticarial lesions, urticaria must be considered a virtually universal human experience.


Injecting histamine into the skin will produce the so-called triple response of Lewis—a prototypical hive. This response comprises the following: (1) erythema, the clinical manifestation of vasodilatation; (2) a wheal, the result of vascular leakage; and (3) pruritus, caused by activation of dendritic itch receptors on nonmyelinated C fibers (neurons) in the epidermis [see Table 1]. A fourth feature of intradermally injected histamine is its spontaneous dissipation within 1 hour. Urticaria lasting longer than 1 hour is not caused solely by histamine. Multiple inflammatory mediators have been identified in the effluent of urticarial lesions, and some of these vasoactive mediators (e.g., prostaglandin D2 and platelet-activating factor) have produced urticaria—with and without pruritus—lasting longer than 1 hour when injected subcutaneously.

Table 1 Pathologic Changes in Urticaria and Their Associated Mediators


Pathologic Event



Vascular permeability

Histamine (H1)
Prostaglandin D2
Platelet activating factor
Leukotrienes C4, D4, E4



Histamine (H1)
Prostaglandin D2
Platelet activating factor
Leukotrienes C4, D4, E4


Sensory nerve stimulation

Histamine (H1)


Because histamine plays a leading role in the pathogenesis of urticaria, tracing the source and mechanism of histamine release is the key to understanding urticarial lesions. Most of the body's histamine is stored in tissue mast cells; much smaller amounts are present in basophils and CNS neurons. Mast cells at different anatomic locations, and even at a single site, can vary substantially in mediator content, sensitivity to agents that induce activation, quantity of mediator released, and response to pharmacologic agents.1 Agents having the ability to initiate the release of mediators from mast cells are called secretagogues. There is debate regarding whether the number of cutaneous mast cells in patients with persistent urticaria increases4 or remains unchanged.5 However, it has been generally agreed that these cells have a lower threshold for mediator release. Thus, a more appropriate label for chronic or idiopathic urticaria would be twitchy mast cell syndrome.

A practical categorization of urticaria is a three-part classification based on the etiology and mechanism of mast cell degranulation [seeTable 2]. The first category comprises cases with an identifiable cause; the second, idiopathic cases; and the third, mastocytosis. Mastocytosis encompasses a wide spectrum of clinical conditions, characterized by a localized or diffuse increase in mast cells in the skin or internal organs. Most cases of mastocytosis are transient, which suggests that this disorder represents a hyperplastic response to abnormal stimuli rather than a true neoplastic process.

Table 2 Classification of Urticarial Lesions

Identifiable cause
   Nonimmunologic (e.g., cyclooxygenase pathway, opiates)
   Physical urticaria
      Aquagenic urticaria
      Cholinergic urticaria
      Cold urticaria
      Contact urticaria (e.g., jellyfish, nettles)
      Delayed pressure
      Solar urticaria
      Vibratory urticaria
Nonidentifiable cause (idiopathic)
   Persistent—occurring almost daily
   Episodic—recurrent, with days of no hives between episodes
   Associated with an underlying disease
      Anaphylaxis (IgE-induced)
      Anaphylactoid (non-IgE-induced)
      Bullous pemphigoid
      Erythema multiforme
      Leukocytoclastic vasculitis
      Serum sickness (via immune complexes)
      Systemic lupus erythematosus
      Viral syndrome (via immune complexes)
      Urticaria pigmentosa
      Diffuse cutaneous mastocytosis
      Telangiectasia macularis eruptiva perstans (TMEP)
   Systemic mastocytosis


The diagnosis of urticaria is made almost exclusively from an appropriate, complete history. The history should include questions about substances or circumstances that may trigger the urticaria; the clinical features of the urticaria, including its duration, the presence and degree of pruritus, and whether the urticaria is localized or generalized; underlying illnesses; any previous diagnostic procedures or therapy for the condition; and family history of urticaria. A personal or family history of atopy should also be noted. Although the occurrence of urticaria with identifiable triggers is increased in atopic patients, whether the incidence of atopic disease is higher in patients with idiopathic urticaria remains debatable.6,7

Many patients presenting with IgE-induced urticaria can identify the cause of their generalized, very pruritic, explosive hives. By merely avoiding that trigger, they remain symptom free. These patients are at greater risk of developing fatal anaphylactic reactions, with or without urticaria.

Common Triggers of Urticaria

Before concluding that urticaria is idiopathic, the clinician must complete a systematic review of possible mast cell secretagogues. These include immunologic and nonimmunologic activators, as well as some whose mechanism is unknown [see Table 3].

Table 3 Mast Cell Secretagogues

Immunologic activators (act on receptors)

IgE antigens (e.g., foods, drugs, latex)
IgG directed against IgE (autoimmunity)
   Anti-FcεRI (IgE receptor) antibodies
Lectins (e.g., strawberries, conconavalin A)
Neuropeptides (e.g., substance P, somatostatin)
Complement activators (C3a, C5a)
Radiocontrast media
Blood products
   IL-1, IL-3, IL-6
   Granulocyte-macrophage colony-stimulating factor
   Histamine-releasing factors (HRF)
   c-kit ligand

Nonimmunologic activators

Ionophores (opiates, adrenocorticotropic hormone [ACTH], compound 48/80)
Arachidonic acid metabolic pathway inhibition (nonsteroidal anti-inflammatory drugs)
Direct effect on cell
Opiates (e.g., morphine, codeine)
Radiocontrast media
   Jellyfish, lobster, eosinophil major basic protein (EMB), polymyxin B, defensins
Physical contact (pressure, light, water)

Mechanism unknown

Alcohol, amphetamine, bradykinin, ciprofloxacin, papaverine, rifampin, thiamine, thiopental, tolazoline, vancomycin


Drugs are probably the most easily recognized of the identifiable causes of urticaria because the symptoms usually appear within 36 hours of administration of the drug.8 The penicillins, aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs), and sulfa drugs are most commonly involved, but virtually any drug may elicit urticaria. When urticaria develops within 1 to 2 weeks after initiation of therapy with a drug that is known to cause urticaria, that drug must be suspected.

Drugs can cause urticaria via immunologic and nonimmunologic mechanisms. The best understood mechanism involves drug-specific IgE antibodies. These IgE-induced reactions typically arise within 2 weeks after a drug is started, are not dose-related, occur from seconds to minutes after administration of the drug, and may herald an anaphylactic episode [see Figure 1].8 Non-IgE reactions to drugs (e.g., aspirin or other NSAIDs, opioids, and vancomycin) can occur on first exposure or from hours to days after ingestion, are dose related, and may herald an anaphylactoid reaction.9


Figure 1. Penicillin Reaction

Generalized, symmetrical, very pruritic urticaria appeared within 10 minutes of an intramuscular injection of penicillin G in this boy. The reaction is polymorphic, with papular urticaria evolving to larger, evanescent urticarial plaques that appear annular because of central clearing. The patient in this photograph subsequently demonstrated a positive prick test to the penicillin allergen penicilloyl polylysine.

Although urticarial reactions to aspirin and other NSAIDs are rarely induced through IgE, they occur most frequently in atopic persons.10Angioedema, with or without urticaria, is the most common symptom of NSAID hypersensitivity. Respiratory symptoms are not more likely to occur in patients who develop an urticarial reaction from an NSAID. Some cyclooxygenase-2 (COX-2) inhibitors, especially rofecoxib, are relatively safe in patients who experience urticaria or angioedema from standard NSAIDs.11 Patients whose history suggests a non-IgE drug reaction should not undergo routine skin testing and radioallergosorbent testing (RAST) [see 6:XI Diagnostic and Therapeutic Principles in Allergy].

Drug-specific IgE antibodies can be detected by skin testing, but penicillin is the only antibiotic for which reliable skin-test reagents have been developed. Standardized antigens for penicillin include penicilloyl-poly-l-lysine (penicilloyl polylysine), which is considered the major determinant and is commercially available, and several investigational minor determinants. With these reagents, numerous studies have documented the presence of penicillin-specific IgE antibodies in patients who have experienced penicillin-induced urticaria. In contrast, IgE antibodies to other antibiotics have not been demonstrated routinely in patients who have experienced an antibiotic-induced urticaria. Although it is possible that these reactions are not IgE mediated, it is more likely that the IgE antibodies have not been detected because the patients had antibodies directed against a drug metabolite not used in the testing.12 Consequently, the diagnostic test for confirming drugs (other than the penicillins) as an identifiable cause of an individual's urticaria is to carefully rechallenge the patient, under direct medical supervision, several weeks after the original episode has resolved. In practice, this is rarely done unless the drug in question is absolutely required to treat a disease.


Foods and additives are the second most easily recognized IgE-induced trigger. Symptoms usually appear within 1 hour after ingestion, and in 80% of these cases, GI symptoms (e.g., cramps, diarrhea, and nausea and vomiting) also occur. Respiratory or, less frequently, cardiovascular symptoms may also accompany or precede cutaneous reactions.13

Foods are a common cause of urticaria.14,15 Although studies of different populations of patients with urticaria provide estimates of the prevalence of food-induced urticaria, prevalence in the general population is unknown. Determining prevalence is complicated by the fact that even in patients with histories of adverse reactions to foods, only about 60% or fewer have reproducible reaction to foods.16

Urticarial reactions to foods may result from exposure by ingestion, injection, contact, or inhalation. Eggs, peanuts, milk, nuts, soy, wheat, fish, and shellfish are the foods most often implicated in allergic reactions, but IgE-mediated reactions to numerous other foods and to contaminating substances in foods, such as molds or antibiotics, have been reported.17 Certain foods, such as egg white, strawberries, and shellfish, have been shown to contain substances that liberate histamine directly through a nonimmunologic mechanism.18 Urticaria can also result from the ingestion of foods that contain large amounts of histamine, either naturally or as a result of spoilage (e.g., scombroidosis) [see 8:I Management of Poisoning and Drug Overdose].

Some children who experience urticaria after exposure to certain foods such as milk, eggs, soy, or wheat early in life may later tolerate these foods without difficulty. Loss of sensitivity to foods such as peanuts,19 nuts, or fish may occur less frequently.20

The diagnostic tools available to determine whether foods play a role in the production of urticaria in a patient include the history, physical examination, skin testing or RAST, diet and symptom diaries, elimination diets, and food challenges. Although slightly less sensitive than skin-prick test, RASTs for specific IgE antibodies are more widely available; they require only a serum sample and are performed by commercial laboratories, and therefore, they are practical in most primary care practices. As with skin tests, a negative result is very reliable in ruling out an IgE-mediated reaction to a particular food, but a positive result has low specificity.21 Many patients have positive skin tests and RASTs to several members of a botanical or animal species, indicating immunologic cross-reactivity, but very few patients have symptomatic intrabotanical or intraspecies cross-reactivity. The practice of avoiding all foods within a botanical family when one member is suspected of provoking allergic symptoms generally appears to be unwarranted.21

Occupational and hobby exposures

Contact urticarial reactions are seen in certain occupational situations, such as health care workers (latex induced) and food handlers (shellfish). Atopic individuals are at a higher risk of developing these immediate-type contact reactions, which may present as pruritus, urticaria, or anaphylaxis.

Latex or natural-rubber latex hypersensitivity is a fairly common identifiable IgE-induced cause of urticaria [see 2:V Contact Dermatitis and Related Disorders]. These patients may experience localized urticaria at the contact area, generalized urticaria with angioedema, or urticaria with systemic involvement (including anaphylaxis). The diagnosis is made from a history of exposure and confirmed by a skin-prick test or RAST.

Systemic illness

Urticaria occurs in a variety of autoimmune and infectious diseases. Urticaria is rarely the sole symptom of an underlying disease, however. If the history and physical examination do not suggest an underlying problem, routine laboratory testing is not indicated.

Generalized, urticarial lesions that persist for longer than 24 hours or that burn or sting more than they itch may be a manifestation of rheumatoid arthritis, systemic lupus erythematosus, or other rheumatic disease. Lesions associated with rheumatic illness usually do not blanch on diascopy and may leave ecchymosis and eventually hyperpigmentation. Patients who present in this manner should be assessed for rheumatic disease [see 15:I Introduction to Rheumatic Diseases].

Approximately 5% to 10% of patients with chronic urticaria have been reported to have antithyroid antibodies but are clinically and biochemically euthyroid.22,23 For that reason, autoimmune thyroid serologic studies have been recommended for patients with chronic urticaria.24 There is only anecdotal evidence that treating these patients with exogenous thyroid hormone leads to significant improvement of their urticaria, however.25,26

Changes in mast cell reactivity apparently can be part of the immune response to infection. Urticaria reportedly can be a feature of streptococcal pharyngitis, otitis media, infectious mononucleosis, and hepatitis (a slightly higher incidence of hepatitis C antibodies has been reported in patients with urticaria, but whether there is a causal relationship is questionable). Pathogens reportedly associated with urticaria include coxsackievirus, Mycoplasma, fungi, and Candida. A causative relationship of urticaria with Helicobacter pylori has not been confirmed.27,28 Extensive searches for occult focal infections (e.g., sinusitis) as the cause of urticaria are consistently unsuccessful.29

A number of parasitic infestations produce transient urticaria.30 The urticaria in these patients usually appears from the second to the sixth week of infestation. Random examinations of stool for ova and parasites rarely, if ever, prove positive in patients with urticaria who do not have typical symptoms of parasitic infestation.

Psychological factors

Emotional stress can influence mast cell and IgE activity, resulting in the release of vasoactive mediators and exacerbations of chronic urticaria.31 However, there is no good evidence that psychological factors by themselves can cause urticaria, so urticaria without an identifiable cause should not be dismissed as a psychosomatic illness.


Lymphomas and carcinomas may promote urticaria (paraneoplastic syndrome), but urticaria in patients with neoplasms is usually coincidental. In most cases, the malignancy is known; current evidence does not warrant routinely subjecting patients with unexplained urticaria to an exhaustive evaluation for an occult neoplasm.

Chronic urticaria may occur as part of Schnitzler syndrome, which also includes a monoclonal IgM gammopathy, intermittent fever, joint or bone pain, lymphadenopathy, leukocytosis, and an elevated erythrocyte sedimentation rate (ESR). In 15% of cases, Schnitzler syndrome evolves to lymphoplasmocytic malignancy.32

Genetic factors

Several of the physical urticarias can be familial. Examples include urticaria induced by cold, heat, light, water, and vibration (see below), as well as urticaria associated with erythropoietic protoporphyria. The Muckle-Wells syndrome is a form of familial urticaria associated with deafness and amyloidosis.33

Localized Urticaria

Papular urticaria, some of the physical urticarias, and contact urticaria are the entities to consider when urticaria is restricted to a limited area of the body. Dermatographism, cold urticaria, delayed pressure urticaria, solar urticaria, and aquagenic urticaria are localized wheals produced by specific physical stimuli (i.e., stroking of the skin, cold, sustained pressure, ultraviolet light, and water, respectively).

Papular urticaria

Papular urticaria consists of 4 to 8 mm wheals or firm papules, often in grouped clusters and especially on areas of exposed skin. Papular urticaria that is very pruritic, persists longer than typical hives, and is located on exposed parts of the body is often caused by insect bites (fleas, bedbugs, scabies, and other mites). The pattern of the eruption corresponds to the biting habits of the offending insect (e.g., mosquito bites often comprise three quasilinear lesions—referred to as breakfast, lunch, and supper), and the seasonal occurrence corresponds to the peak prevalence of that insect. IgE and IgG antibodies against mosquito antigens have been detected in human sera,34but there have been no reported cases of anaphylaxis or death associated with hypersensitivity to mosquitoes. Arthropod bites are the only known cause of bulla on papular urticaria. Papular urticaria persists for 2 to 10 days and may leave postinflammatory hyperpigmentation. Occasionally, healed lesions may recrudesce when fresh crops appear.35


Firm stroking of the skin may elicit a wheal and erythema in 5% of a healthy population, but only in a minority of these persons does it also cause any pruritus (so-called symptomatic dermatographism) [see Figure 2]. The etiology of dermatographism is uncertain, but passive transfer tests are sometimes positive. Dermatographism (Darier sign) is a common finding in patients with idiopathic urticaria and may be associated with other conditions. For example, dermatographism can be elicited in more than 90% of patients with mastocytosis.36Confirmation of mastocytosis always requires biopsy, however. The elicitation of symptomatic dermatographism in patients with urticaria supports the use of both H1 and H2 receptor antagonists, which may more effectively reduce wheal size and duration of urticaria.37


Figure 2. Dermatographism

Dermatographism elicited by gentle stroking of the skin of the back.

Delayed pressure urticaria

Urticaria that results from localized, continuous (4 to 6 hours) pressure is seen most often in patients with persistent urticaria without an identifiable cause.38 It may be associated with systemic complaints such as myalgias, arthralgias, and fever. It responds best to aspirin or NSAIDs and poorly to antihistamines.

Cold urticaria

The lesions of cold urticaria develop 5 to 30 minutes after exposure to cold and can be caused by wind, bathing, contact, or eating cold foods or drinking cold liquids.39 Although the urticaria may appear during the period of exposure, more often it develops upon rewarming of the skin. The urticaria usually lasts approximately 30 minutes and resolves spontaneously.

Cold urticaria is often idiopathic and acquired. Patients with these lesions usually have a positive response to an ice-cube-challenge test.40Rare forms of acquired cold urticaria include delayed, localized, and reflex cold urticaria. In delayed cold urticaria, lesions develop several hours after exposure; localized cold urticaria lesions occur only at sites of injections or bites; and reflex cold urticaria lesions present as widespread whealing in response to a fall in core body temperature.

Much rarer than acquired forms of cold urticaria is familial cold urticaria. In this autosomal dominant disorder, lesions appear 30 minutes after exposure to generalized cooling, rather than to local application of cold, and may persist for up to 48 hours.

Solar urticaria

Solar urticaria is a rare idiopathic disorder in which erythema heralds a pruritic wheal that appears within 5 minutes after exposure to a specific wavelength of light and dissipates within 15 minutes to 3 hours after onset [see Figure 3].41,42 Solar urticaria is usually provoked by light in the visible spectrum, although the specific wavelength that leads to mast cell degranulation may vary from patient to patient. The severity of the reaction depends on the duration of the exposure, the intensity of the irradiation, and the light spectrum.43 These reactions are believed to result from the development of an antigenic photoproduct, which then triggers an IgE-mediated response. Patients should usually be referred to an allergist or dermatologist for provocative testing.


Figure 3. Solar Urticaria

Solar urticaria.

Aquagenic urticaria

Urticaria that appears 2 to 30 minutes after water immersion, regardless of its temperature or source (seawater or tap water) has been reported in a few patients.44 These pruritic, follicular, cholinergic-like wheals can be reproduced by applying wet compresses to the patient's back for at least 30 minutes. It is believed that aquagenic urticaria occurs when sensitized mast cells are activated by a water-soluble antigen that diffuses through the epidermis, causing the release of acetylcholine and histamine.

Vibratory urticaria

Urticaria that follows massage and vigorous toweling has been described in a single family.45

Contact urticaria

Immediate contact reactions can appear on normal or eczematous skin within minutes to an hour after exposure. The reaction then will disappear within a few hours. Itching, tingling, or burning accompanied by erythema are the mildest form of contact reactions. They are often caused by cosmetics, fruits, and vegetables. Generalized urticaria after a local contact is a rare phenomenon, but it can occur with some allergens.46

Contact reactions may have either immunologic or nonimmunologic mechanisms. Immunologic mechanisms require prior sensitization to the causative agent. The respiratory and gastrointestinal tracts are typically the routes of sensitization, but sensitization to natural latex and some foods may occur through the skin. The substances causing immunologic immediate contact reactions are usually proteins. Foods most commonly involved are fish, shellfish, and wheat flour. Most cases of protein contact dermatitis develop after the person has handled food products for a protracted period. Symptoms usually appear within 30 minutes after direct cutaneous contact with the offending agent.47Specific IgE antibodies against the causative allergen can be found by skin testing or RAST.

Most immediate contact reactions are nonimmunologic and occur without previous sensitization. These reactions remain localized. The pathophysiology of nonimmunologic immediate contact reactions has not been established, but it may involve direct influence on dermal vessel walls or a non-IgE release of inflammatory mediators. A list of chemicals that cause occupational allergic contact dermatitis can be found on the Internet at

Generalized Urticaria

The clinical features and natural history of generalized urticaria are as varied and unpredictable as the etiology. Generalized lesions tend to be numerous and symmetrical. Characteristically, they are intensely pruritic, especially at onset. Except for cholinergic papular urticaria, little information about the etiology can be obtained from the morphology. Individual lesions fade completely within 24 hours. Occasionally a halo of pallor surrounds the wheal [see Figure 4].


Figure 4. Generalized Urticaria

Lesions of generalized urticaria tend to be symmetrical and sometimes have a halo of pallor surrounding the wheal.

Cholinergic urticaria

The lesions of cholinergic urticaria are highly distinctive, consisting of 2 to 3 mm scattered papular wheals surrounded by large, erythematous flares. These lesions are extremely pruritic, and they may affect the entire body but often spare the palms, soles, and axilla.48 Precipitating stimuli include exercise, warm temperature, ingestion of hot or spicy foods, and possibly emotional stress. The condition often remits within several years but can last for more than 30 years. The diagnosis can be made by provocation with exercise or a hot bath. Cholinergic urticaria can be aborted by the prompt application of cold water or ice to the skin, and a refractory period of up to 24 hours can be induced by a hot bath.

Physical Examination

Recognition of urticaria does not usually present a problem. Unfortunately, except for the contact and physical urticarias, the examination does not facilitate identification of the cause. Episodes of angioedema occur in half the patients presenting with persistent urticaria. The individual swellings of angioedema always last longer than an individual hive and are almost always nonpruritic.

Laboratory Evaluation

The use of laboratory tests in patients with urticaria should be directed toward confirmation of diagnoses suggested by the history and physical examination. Routine laboratory testing should not be performed, because it has consistently proved disappointing for the identification of an etiology. A skin biopsy is indicated if the diagnosis of urticaria is in question. A biopsy should be performed on any urticaria that lasts more than 24 hours, is only mildly pruritic or nonpruritic, is associated with vesicles or bullae, or does not respond to appropriate therapy. The subtleties of the histologic variances demand interpretation by a dermatopathologist.


Eliminating or avoiding the triggers of mast cell activation is the basis of treatment for urticaria. However, this strategy may be impractical in patients with persistent idiopathic urticaria, which usually has multiple triggers. Any underlying disease should be treated. Idiopathic urticaria is managed symptomatically. Fortunately, the hyperreactive state in patients with idiopathic urticaria eventually resolves spontaneously.

H1 Receptor Antagonists

When used appropriately, antihistamines can offer significant relief to most patients with urticaria. The more the skin lesions resemble the triple response of Lewis, the better they respond to antihistamine treatment. Urticarial vasculitis and delayed pressure urticaria are resistant to antihistamines. Antihistamines compete with histamine for H1 receptor sites on effector cells and thereby prevent, but do not reverse, responses mediated by histamine alone. There are eight recognized chemical groups of H1 receptor antihistamines; all effectively compete for H1 receptor sites [see Table 4]. Among these groups are tricyclic antidepressants, which also have potent antihistaminic activity.

Table 4 H1 Antihistamines Available for Treatment of Urticaria

Chemical Group


Antihistaminic Activity


Anticholinergic Activity


Ethanolamine derivatives











Ethylenediamine derivatives

Tripelennamine (PBZ)










Piperidine derivatives






Fexofenadine (Allegra)*





Loratadine (Claritin)*





Piperazine derivatives






Cetirizine (Zyrtec)










Propylamine derivatives
















Phenothiazine derivatives











Tricyclic antidepressants











*Considered second-generation antihistamines, which are nonsedating (Zyrtec less so) and have other anti-inflammatory properties besides being antihistaminic.

The choice of antihistamine is based on its effectiveness, frequency of administration, and side-effect profile. The dose of the agent selected should be increased to tolerance; if adequate relief is not achieved at the maximal tolerated dose, a drug from another group can be added. Patients do not all respond in the same way to agents from each group. Most of the so-called first-generation (sedative) antihistamines are virtually equivalent in effectiveness, with the major differences being the degree of sedation or anticholinergic effects. Activation of H1receptors in the brain is responsible for alertness; inhibiting these sites with antihistamines results in sedation. Second-generation (nonsedating) antihistamines tend not to cause drowsiness, because they cross the blood-brain barrier poorly.49 Many patients find the itching and urticaria to be most troublesome in the evening and at night, so a useful strategy is to combine sedating antihistamines given at bedtime with nonsedating antihistamines during the day. This combination is effective, promotes compliance, and is economical. Tachyphylaxis has not been noted with H1 receptor antagonists.

Because other mediators besides histamine are involved in urticaria, antihistamines are not a panacea. Also, none of the antihistamines have the ability to displace histamine from the H1 receptor site, so the best clinical results are attained when the antihistamines occupy those receptors before the arrival of histamine; hence, round-the-clock dosing is necessary for patients with persistent symptoms.

An effective cocktail for persistent urticaria is fexofenadine (180 mg) or loratidine (10 mg) in the early morning and cetirizine (10 to 20 mg) in the early evening. If this is insufficient, the tricyclic antidepressant doxepin, 10 to 50 mg, can be added at bedtime. (A single dose of doxepin suppresses the histamine-induced wheal and flare for 4 to 6 days.50) This cocktail controls symptoms in more than three quarters of patients with persistent urticaria. Prednisone, 0.5 to 1.0 mg/kg/day, should be used only for patients with refractory idiopathic urticaria or with urticarial vasculitis. The goal of treatment should not be to attain a hive-free status but, rather, to minimize compromise of the patient's quality of life from both the disease and its treatment.

In urticaria with an identifiable cause, antihistamines are discontinued once the substance is gone from the body. In persistent urticaria, antihistamines can be sequentially discontinued when patients have been completely free of hives for at least 96 hours. At that point, the morning dose of nonsedating antihistamines can be discontinued. If the patient is still symptom free after another 96 hours, the doxepin dosage can begin to be reduced and, lastly, the cetirizine can be discontinued.

H2 Receptor Antagonists

Human skin has H2 receptors as well as H1 receptors. H2 receptors are present on the cutaneous arterioles, and their activation can result in vasodilatation (noted as flushing). For that reason, combining H2 antagonists with H1 antagonists can be helpful in patients who have prominent flushing, dermatographism, or angioedema.51 The available evidence does not justify the routine addition of H2 antagonists to H1antagonists in patients with persistent urticaria or urticarial vasculitis.

Beta Agonists

Beta agonists increase intracellular levels of cyclic adenosine monophosphate (cAMP), thereby reducing mediator release by mast cells and promoting vasoconstriction of cutaneous vasculature. Any explosive, generalized urticaria demands the subcutaneous administration of 0.2 ml of aqueous epinephrine 1:1000 (which has combined alpha-agonist and beta-agonist properties), in addition to H1 antagonists and H2antagonists (e.g., doxepin, 10 mg). This is the treatment of choice for anaphylaxis (see below).

Oral beta agonists have been tried for chronic urticaria and angioedema in conjunction with H1 antagonists and H2 antagonists. Terbutaline (2.5 to 5.0 mg q.i.d.) deserves a trial in patients not responding to standard treatment. Some studies have demonstrated efficacy, and others have found none.52,53


Because corticosteroids do not inhibit cutaneous mast cell degranulation, they have no effect on acute urticaria. However, these agents are often used in patients with persistent urticaria whose symptoms are disabling and unresponsive to maximum standard therapy.54 In these cases, steroids are given in a pulse dose to break the cycle of a resistant episode. The recommended starting dosage of prednisone for persistent urticaria is 0.5 to 1.0 mg/kg/day. This dosage should not be reduced until the patient shows definite clinical improvement.

A protocol for steroid therapy for patients with persistent urticaria has been recommended by the Parameters of Care Committee of the American Academy of Allergy, Asthma and Immunology.55 Daily steroids are recommended only during the first 1 or 2 weeks for patients with persistent urticaria who have had no relief for a protracted period. The goal is then to utilize an alternate-day regimen with a gradually decreasing dosage over a period of months. Patients should be started on a daily dose of prednisone, 0.5 to 1.0 mg/kg (while continuing the maximum antihistamine regimen). If the symptoms become tolerable, the prednisone dose is decreased by 5 mg every 1 to 3 days until 25 mg a day is reached. The patient's progress is then reassessed every 1 to 2 weeks. Once the patient's condition stabilizes, the dose is decreased by 2.5 to 5 mg every 2 to 3 weeks. When the lowest dose is reached, alternate-day therapy may be tried. Usually, the alternate-day dose is 1.5 times the daily dose. Should some rebound occur on the off day, the alternate-day treatment can be given in divided doses (at 8 A.M. and at 5 P.M.). Once a maintenance dose is reached, the dose of prednisone should be reduced by 1 mg every 1 to 2 weeks.

Other Agents

There are recent reports of success using the anabolic steroid stanozolol for chronic urticaria,56 aquagenic urticaria,57 familial cold urticaria,58 and cholinergic urticaria. Nifedipine, 20 mg three times daily, has been reported effective for chronic urticaria.59 This treatment deserves further evaluation. Patients with chronic urticaria are advised to avoid aspirin and all NSAIDs, yet there are anecdotal reports of patients with urticaria who benefit from these drugs. Indomethacin has been used successfully in the management of urticarial vasculitis.60

Cyclosporine has proved effective in some cases of chronic idiopathic urticaria refractory to antihistamines, as well as in urticarial vasculitis and solar urticaria.61 Doses used are 2.5 to 6 mg/kg daily. Higher doses can cause elevation in the blood urea nitrogen (BUN) and serum creatinine levels, but these have returned to normal on discontinuance of the drug.

Leukotriene antagonists have been combined with antihistamines for the management of allergic rhinitis and have been noted to be more effective than the antihistamine alone. Therefore, many allergists have tried this combination for urticaria, with some anecdotal success. There is nothing in the literature to support its use, however, and in my experience, the use of a leukotriene antagonist with an antihistamine offers no advantage for persistent urticaria without angioedema.


Except for IgE-induced urticaria, which may progress to fatal anaphylaxis, the prognosis for the other urticarias is benign, although prolonged episodes of these disorders can be extremely bothersome. To date, there is no evidence that the natural history of any of the urticarial syndromes, whether induced by an identifiable cause or idiopathic, is influenced by treatment. Almost all cases of persistent urticaria eventually resolve, however; even the majority of cases of IgE-induced urticarias (especially those without anaphylaxis) are rarely permanent. Chronic urticaria tends to last longer in elderly persons than in younger ones. Studies of chronic (persistent) idiopathic urticaria have found that with or without treatment, 50% of cases will resolve within 6 to 12 months of onset; 20%, within 12 to 36 months; and another 20%, within 36 to 60 months. Less than 2% of cases persist for 25 years or longer. Over 50% of patients will have at least one recurrence.62 Interestingly, although anaphylactic or anaphylactoid reactions have been noted in patients with identifiable causes of urticaria, there have been no reports of these reactions ever occurring in patients with persistent urticaria without an identifiable cause. More than 50% of patients with idiopathic urticaria can be made comfortable with appropriate antihistamine therapy. Immunosuppression with corticosteroid dependence occurs in fewer than 5% of patients.


Angioedema is an episodic, asymmetrical, nonpitting swelling of loose tissue (usually skin) [see Figure 5]. It is usually nonerythematous and nonpruritic, and it may be painless. Angioedema rarely lasts less than 2 hours, and it frequently persists for 24 hours or longer. It may occur together with urticaria. Angioedema involving the face can be disfiguring during its course. Laryngeal swelling from angioedema may compromise the airway, leading to stridor and even asphyxiation. Gastrointestinal involvement can cause crampy abdominal pain, followed by watery diarrhea. Most cases of angioedema are a reaction to a food or a drug, but some episodes have no identifiable trigger. There are both hereditary and acquired forms of angioedema.


Figure 5. Angioedema of the Tongue

Angioedema of the tongue is evident in this photograph of a 54-year-old man. This episode, the patient's fifth, was unresponsive to epinephrine, antihistamines, and prednisone; his sixth episode required intubation for 92 hours, after which the angioedema resolved spontaneously.


It is estimated that approximately 10% of the population will experience at least one episode of angioedema.63 Angioedema occurs episodically in 50% of patients with urticaria. Of patients who have angioedema as their primary disorder, approximately 20% will also experience episodes of urticaria.64


Angioedema can be induced by a variety of mechanisms, including IgE, inhibition of the cyclooxygenase pathway of arachidonic acid metabolism, activation of the kinin-forming system, and activation of complement. In some patients, none of these mechanisms can be identified; these cases are labeled idiopathic.


IgE-induced angioedema resembles IgE allergy and is typically provoked by foods or drugs. It tends to occur in atopic persons and can be confirmed by prick skin testing or RAST.

Cyclooxygenase Inhibition

There is increasing evidence that the inhibition of the enzyme cyclooxygenase causes the de novo release of leukotrienes, an inflammatory mediator derived from arachidonic acid, in response to injury. Of particular interest in the skin is leukotriene B4, which can induce neutrophil chemotaxis and increase vascular permeability.65 Aspirin and other NSAIDs directly inhibit the ability of cyclooxygenase to decrease the formation of prostaglandins and thromboxanes, but not leukotrienes, from arachidonic acid. Angioedema (with or without urticaria) may occur in 100% of patients with hypersensitivity to aspirin or other NSAIDs.11 Interestingly, not all patients who are hypersensitive to aspirin react to other NSAIDs,66 and in one study, only 3% of patients sensitive to both aspirin and other NSAIDs reacted to the COX-2 inhibitor rofecoxib.67

Activation of the Kinin-Forming System

Bradykinin increases vascular permeability. Angiotensin-converting enzyme (ACE) inhibitors inhibit the kininase enzymes required for degradation of bradykinin, and the resulting elevation in bradykinin levels may lead to angioedema.68 Angioedema has been reported in approximately 0.1% to 0.5% of patients who take ACE inhibitors.69 However, because these agents are so widely used, ACE inhibitor-induced angioedema is relatively common.

Angiotensin II receptor blockers (ARBs), such as losartan and valsartan, do not increase bradykinin levels. Nevertheless, rare instances of angioedema have been reported with the use of ARBs.70

Complement Activation

Increased susceptibility to angioedema can result from either an inherited defect in C1-esterase inhibitor (C1-INH) activity or an acquired deficiency of C1-INH. The inherited form of the disease, known as hereditary angioedema, is rare. There are two principal types of hereditary angioedema: type 1, which accounts for 80% to 85% of cases and is caused by decreased production of C1-INH, and type 2, in which normal or elevated amounts of functionally deficient C1-INH are produced.71 A third, very rare form of hereditary angioedema that may be X-linked has recently been described in women.72

Acquired angioedema results from increased metabolism or destruction of C1-INH. Two types of acquired angioedema have been described. Type 1, which is caused by excessive activation of complement and subsequent consumption of C1-INH, typically occurs in patients with rheumatologic disorders and B cell lymphoproliferative diseases. Patients with type 2 produce autoantibodies against C1-INH, leading to its inactivation.73,74


Angioedema is consistently described as a variant of urticaria in which the subcutaneous tissues, rather than the dermis, are mainly involved. However, unlike urticaria, which seems to be mediated primarily by histamine, angioedema seems to be mediated primarily by bradykinin and leukotrienes. Anecdotal evidence indicates that although urticaria can be elicited with a histamine prick or intradermal injection, the injection of histamine deeper in the dermis does not produce angioedema. On the other hand, there are patients whose angioedema will dissipate with the administration of antihistamines (especially the combination of H1 and H2 receptor antagonists).75 These observations suggest that several vasoactive mediators are capable of producing angioedema.

Unfortunately, angioedema is almost never biopsied, so there are no documented pathologic descriptions of the disorder. The histopathology is always included with urticaria, and its morphology seems to be assumed. Teleologically, the vasodilatation and vascular leakage occur deeper in the skin, and the specific cellular infiltrate, if any, remains uncertain.


Diagnosis of angioedema is usually straightforward. Cellulitis, edematous states, trauma (stings), and fasciitis occasionally are considerations in the differential diagnosis. Insights into causes and mechanisms of induction are derived primarily from the history.

The history in a patient with angioedema—especially one who has had repeated episodes—should include the following questions: (1) Is the angioedema always, sometimes, or never associated with urticaria? (2) Is the swelling pruritic? (3) Are there accompanying gastrointestinal symptoms (e.g., pain, nausea and vomiting, or diarrhea)? (4) Is the patient taking any medications? (5) Can the patient identify any apparent triggers for the angioedema?

Patients with IgE-induced angioedema are most likely to present with concomitant urticaria. This form of angioedema may be pruritic and may progress to an anaphylactic reaction. Typically, IgE-induced angioedema occurs within 30 minutes after contact with the IgE antigen. It is most likely to occur in atopic patients. Gastrointestinal symptoms may occur but are uncommon. IgE-induced angioedema often occurs as a drug reaction, with β-lactam antibiotics being the most common trigger.

Cyclooxygenase inhibitors (i.e., aspirin or other NSAIDs) are more apt to cause nonpruritic angioedema. NSAID-induced angioedema is occasionally accompanied by urticaria.

Angioedema induced by ACE inhibitors is nonpruritic and rarely occurs with urticaria. No sex predominance has been noted in patients without gastrointestinal tract involvement, but all patients with GI involvement have been women.76

Complement-activated angioedema is never pruritic and is not accompanied by urticaria. In 20% to 25% of patients with hereditary angioedema, there is no family history of the disease (these cases may represent new mutations).77 Therefore, a positive family history of hereditary angioedema is not a prerequisite for the consideration of this disorder in the differential diagnosis when typical symptoms are present. Symptoms of hereditary angioedema are usually mild or nonexistent during childhood, typically first manifesting during the second decade of life. Acquired angioedema usually develops during or after the fourth decade of life.

Hereditary and acquired angioedema have similar clinical presentations. Episodes can occur without provocation, but some episodes may be associated with trauma, medical procedures, emotional stress, menstruation, oral contraceptive use, infections, or the use of medications such as ACE inhibitors.71 Manifestations include marked edema of the skin and lining of hollow visceral organs. GI tract involvement results in varying degrees of intestinal obstruction, with severe abdominal pain, nausea, and vomiting. Despite the absence of fever and leukocytosis, these cases are often mistaken for an acute abdomen, which occasionally leads to unnecessary surgical exploration of the abdomen. Typically, the attacks last about 2 to 5 days before resolving spontaneously.

laboratory tests

IgE-induced drug reactions are readily identifiable with skin-prick tests or RAST. In complement-activated angioedema, a low level of the complement component C4 is a constant finding and therefore represents a sensitive screening test. A normal level, especially during an attack, rules out both hereditary and acquired angioedema. In patients with suspected complement-activated angioedema, confirmation of the diagnosis can be obtained by measuring antigenic levels of C1-INH, which are low in 85% of patients, or functional levels, which are low in 100% of patients. Hereditary forms of complement-activated angioedema can be distinguished from acquired forms by measurement of C1q complement—levels of which are normal in hereditary forms but decreased in acquired forms.


Discontinuance of the causative agent is an obvious initial step in angioedema. Emergency measures are necessary to secure the airway if there is airway obstruction by a swollen tongue, uvula, or epiglottis. Monitoring the airway in these patients until the angioedema resolves is imperative. Subcutaneous epinephrine should be given and is helpful in most types of angioedema, except those associated with low levels of C1-INH. Aerosolized epinephrine sprayed on the swollen mucous membrane may at times be helpful.

Antihistamines (both H1 and H2 receptor antagonists) are indicated for IgE-induced angioedema (see above). Idiopathic angioedema has been split into those presentations that respond to antihistamine therapy and those that do not.78 Doxepin (see above) should be given to all patients with idiopathic angioedema, but results are often disappointing if this agent is administered without epinephrine. Leukotriene inhibitors counteract the vasodilation produced by leukotrienes and can reduce the edema.

Intramuscular or intravenous glucocorticoids (prednisone, 0.5 to 1 mg/kg/day, or methylprednisolone, 0.4 to 0.8 mg/kg/day) can be used as adjunctive treatment. However, the anti-inflammatory action of these agents does not affect the underlying cause of the inflammation, and they require hours to take effect. Injectable C1-INH concentrate has been developed and is effective in treating patients with hereditary angioedema,79 but it is difficult to obtain.

To prevent future episodes of angioedema, patients should avoid identified triggers. ACE inhibitors are contraindicated in patients with idiopathic or C1-INH deficiency, and ARBs should be used only with extreme caution. Patients with idiopathic angioedema should undergo an annual general medical evaluation to identify any underlying occult disease.


Anaphylaxis is an explosive, massive activation of mast cells, with release of their inflammatory mediators in the skin, respiratory tract, and circulatory system resulting in urticaria, wheezing, and hypotension.

The term anaphylaxis has been restricted to IgE-mediated mast cell and basophil activation. Anaphylactoid reactions, although similar in presentation, result from non-IgE-dependent mechanisms and are less likely to have a fatal outcome.80 For practical purposes, however, it does not matter whether the patient is having true anaphylaxis or an anaphylactoid reaction, because the clinical manifestations and the treatment of these two types of reactions are identical.


The authors of all epidemiologic reports regarding anaphylaxis believe the incidence to be underestimated because of failure to report or recognize every episode. A Dutch study estimated that only 4% to 8% of anaphylactic reactions were reported.81 From the combined results of reported series, several significant conclusions can be drawn: First, the occurrence of atopy in anaphylaxis patients can be as high as 53%.82 Second, the incidence of females predisposed to anaphylactic episodes can be as high as 61%.83 Third, when the cause of anaphylaxis is found, food and drugs head the list, with peanuts and shellfish being the most common offending foods and NSAIDs and antibiotics being the most common drug offenders.84 Fourth, cutaneous symptoms are by far the most common manifestation.85 Fifth, the risk of anaphylaxis in hospitalized patients is reported to be 196 per million population, with the risk being highest in women and in persons younger than 30 years.86


A number of substances are known to cause anaphylactic and anaphylactoid reactions [see Table 5]. IgE-mediated anaphylaxis is caused by agents that act as haptens (e.g., β-lactam antibiotics) or by complete antigens (e.g., venoms, foods, allergen extracts). Anaphylatoxins (C3a and C5a) often mediate reactions to human plasma and blood products. The nonimmunologic mast cell activators include radiocontrast media, opiates, and some muscle relaxants. Other anaphylactoid-inducing agents include those agents that modulate arachidonic acid metabolism (i.e., aspirin and other NSAIDs). In a number of cases, the mechanism that leads to anaphylactic or anaphylactoid reactions is unknown (i.e., idiopathic, exercise, and cold urticaria or cholinergic urticaria with anaphylaxis; mastocytosis; and some drug-induced reactions).87 Patients with idiopathic persistent urticaria or episodic urticaria do not experience anaphylaxis.

Table 5 Estimated Incidence or Prevalence of Acute Anaphylactic Reactions91



General cause

1 per 2,700 hospitalized patients

Insect sting

0.4%–0.8% of United States population

Radiocontrast medium

1 per 1,000–14,000 procedures

Penicillin (fatal outcome)

1.0–7.5 per million treatments

General anesthesia

1 per 300 inductions


1 per 1,000–5,000 sessions

Immunotheraphy (severe reactions)

0.1 per million injections


Any of the mast cell secretagogues [see Table 3] have the potential to induce an anaphylactic or anaphylactoid reaction. Activation of the mast cell through the FcεRI receptor by an antigen releases the greatest amount of histamine. The physiologic responses to the release of inflammatory mediators include smooth-muscle spasm in the bronchi and GI tract, vasodilatation, increased vascular permeability, and stimulation of nociceptor nerve endings.


The classic symptoms of anaphylaxis include flushing, urticaria, angioedema, pruritus, bronchospasm, and abdominal cramping with nausea, vomiting, and diarrhea. Hypotension and shock can result from intravascular volume loss, vasodilatation, and myocardial dysfunction. Symptoms usually begin within 5 to 30 minutes after the causative agent is introduced into the body and within 2 hours after it is ingested. The shorter the latent period, the more ominous the prognosis. In rare cases, symptoms can be delayed in onset for several hours. These are called late reactions. The biphasic reaction, which includes both immediate and late reactions, tends not to be recognized and therefore is more likely to result in a fatal outcome. Least common is the protracted reaction, in which the immediate reaction persists for hours.

Clinical Manifestations

At the onset of anaphylaxis, patients often initially experience a sense of impending doom, accompanied by generalized pruritus and flushing. Almost all patients with anaphylaxis present with cutaneous manifestations that include pruritus, flushing, urticaria, or angioedema.

Anaphylaxis is graded by its clinical presentation [see Table 6]. Cases with signs and symptoms limited to the skin are designated as group I. Group II comprises cutaneous manifestations plus nausea, dyspnea, tachycardia, or hypotension; group III includes all the manifestations of groups I and II plus bronchospasm and true shock. Group IV consists of respiratory arrest, cardiac arrest, or both, with or without other manifestations.

Table 6 Grading System for Anaphylaxis


Clinical Manifestations


Pruritus, flushing, urticaria, or angioedema


Pruritus, flushing, urticaria, or angioedema

Nausea, dyspnea, tachycardia, or hypotension


Pruritus, flushing, urticaria, or angioedema

Nausea, dyspnea, tachycardia, or hypotension

Bronchospasm and shock


Respiratory arrest

Cardiac arrest

Other manifestations may be present

Physical Examination

Cutaneous involvement

Flushing, urticaria, and angioedema have been reported in 88% to 100% of patients experiencing anaphylaxis. Pruritus, especially of the scalp, soft palate, palms, soles, and anogenital areas, usually heralds an impending anaphylactic or anaphylactoid reaction or may be the only cutaneous signs of the episode. Conjunctival pruritus, injection, and edema are not unusual.

Respiratory involvement

Nasal congestion (occurring in up to 56% of patients), rhinorrhea (16%), laryngeal edema, dyspnea (47%), bronchospasm (24% to 47%), cough, and hoarseness may all be part of the anaphylaxis syndrome.

Cardiovascular involvement

Tachycardia and hypotension are common cardiovascular manifestations of anaphylaxis. Uncommon findings include bradycardia (6%), angina (6%), syncope, palpitations, and cardiac arrest (2% to 14%).

Gastrointestinal involvement

GI symptoms, including nausea, vomiting, diarrhea, abdominal cramps, and bloating occur in 30% of patients with anaphylaxis.

Neurologic involvement

Dizziness or syncope (33%), headache (up to 15%), and seizures (1.5%) may be among the presenting symptoms of anaphylaxis.

Laboratory Evaluation

Anaphylaxis is a clinical diagnosis. Laboratory studies are rarely helpful. Postmortem testing may help clarify the diagnosis in cases of so-called sudden death or in patients who are dead on arrival at the emergency department.

If a patient is seen shortly after an episode, plasma histamine, urinary histamine, or serum tryptase may be helpful in confirming the diagnosis. Plasma histamine levels rise within 10 minutes, but they fall again within 1 hour. Serum β-tryptase levels peak by 1 hour and may remain elevated for as long as 5 hours. However, a negative histamine and tryptase study does not completely rule out the diagnosis of anaphylaxis. Skin testing and RAST for the causative agent (e.g., food, Hymenoptera venom, latex, or drug), if indicated, should be performed 4 to 6 weeks after the episode for greatest sensitivity.


The essential steps in the treatment of anaphylaxis are (1) prevention, (2) recognition, (3) prompt therapy, and (4) early transport to an emergency care facility.


Prevention depends on recognition of persons at risk. Use of oral rather than parenteral medications should always be considered in patients at high risk for anaphylaxis. This includes patients with atopy or those with a possible history of allergic reactions to drugs. If drugs are administered parenterally, such patients should remain in a medically supervised area for at least 30 minutes afterward. Patients with known food or drug allergies must read labels to avoid the foods or drugs to which they are allergic. Severely food-allergic patients must be especially careful when dining out and may wish to avoid eating in restaurants altogether. Patients with a history of anaphylactic reaction to Hymenoptera venom should be given information on avoiding future stings and should be referred to an allergist for consideration of venom immunotherapy [see 6:V Allergic Reactions to Hymenoptera]. Patients with a history of anaphylaxis should always carry an epinephrine autoinjector (Epi-Pen).


Immediate diagnosis of a developing reaction is imperative. Because of the risk of respiratory and cardiovascular collapse, the patient's airway, breathing, and circulation (the so-called emergency ABCs) must be rapidly assessed.

Prompt Initiation of Therapy

Anaphylaxis can rarely be overtreated. Treatment must be expeditious and appropriate. A protocol and supplies for prompt treatment should be in place at every medical office or facility. A protocol for diagnosis and management of anaphylaxis has been developed by the Joint Task Force on Practice Parameters.88 The supplies should include oxygen, aqueous epinephrine, injectable antihistamines, intravenous or intramuscular glucocorticoids, oropharyngeal airways, and I.V. fluids. If the clinical assessment even suggests an anaphylactic reaction, it is best to call 911 and initiate therapy.

Whenever possible, decrease the absorption of the antigen. With insect bites and stings on an extremity, for example, apply a tourniquet above the injection site to block venous return and remove the insect stinger. Inject epinephrine (1:1000) locally.

Give supplemental oxygen, 6 to 8 L/min, and administer epinephrine (1:1000) subcutaneously or intramuscularly. The epinephrine dose is 0.2 to 0.5 mg in adults and 0.01 mg/kg in children. If the patient is in cardiopulmonary arrest, epinephrine (1:10,000) should be administered intravenously, in a dose of 0.1 to 1.0 mg for adults and 0.001 to 0.002 mg in children. Patients and their caregivers should recognize that more than one dose of epinephrine may be required.89

Intravenous H1 antihistamines (e.g., diphenhydramine, 50 mg) and H2 antihistamines (e.g., ranitidine, 50 mg, or cimetidine, 300 mg) should be given. If the patient can swallow, H2 antihistamines can be given orally. Bronchospasm may be treated with aerosolized beta-adrenergic agonists (albuterol). Severe bronchospasm may require endotracheal intubation or cricothyrotomy. Respiratory failure can occur with or without upper airway compromise. Persistent hypoperfusion and ischemia may lead to myocardial infarction, cerebral ischemia, or renal failure.

Once the acute reaction is under control, systemic corticosteroids (e.g., hydrocortisone sodium phosphate, 100 mg every 2 to 4 hours) may be administered. The patient can be transferred to the emergency department.


Most patients experience only a single episode of anaphylaxis,82 but some patients have three or more episodes.90 Death from anaphylaxis is uncommon. Complications are also unusual; most patients recover completely. However, respiratory failure from severe bronchospasm or laryngeal edema can cause hypoxia, which if prolonged could lead to brain injury. Hypotension and hypoxia may lead to cardiac ischemia or arrhythmias.


  1. Galli SJ: New concepts about the mast cell. N Engl J Med 328:257, 1993
  2. Doutre M: Physiopathology of urticaria. Eur J Dermatol 9:601, 1999
  3. Longley J, Duffy TP, Kohn S: The mast cell and mast cell disease. J Am Acad Dermatol 32:545, 1995
  4. Haas N, Toppe E, Henz BM: Microscopic morphology of different types of urticaria. Arch Dermatol 134:41, 1998
  5. Bedard PM, Brunet C, Pelletier G, et al: Increased compound 48/80 induced local histamine release from nonlesional skin of patients with chronic urticaria. J Allergy Clin Immunol 78:1121, 1986
  6. Kaplan AP: Urticaria and angioedema. Allergy: Principles & Practice, 5th ed. Middleton E, Reed CE, Ellis EF, et al, Eds. Mosby, St Louis, 1998, p 1104
  7. Plumb J, Norlin C, Young PC: Exposures and outcomes of children with urticaria seen in a pediatric practice-based research network: a case-control study. Arch Pediatr Adolesc Med 155:1017, 2000
  8. Shipley D, Ormerod AD: Drug-induced urticaria: recognition and treatment. Am J Clin Dermatol 2:151, 2001
  9. Bircher AJ: Drug-induced urticaria and angioedema caused by non-IgE mediated pathomechanisms. Eur J Dermatol 9:657, 1999
  10. Sanchez-Borges M, Capriles-Hulett A: Atopy is a risk factor for non-steroidal anti-inflammatory drug sensitivity. Ann Allergy Asthma Immunol 84:101, 2000
  11. Sanchez Borges M, Capriles-Hulett A, Caballero-Fonseca F, et al: Tolerability to new COX-2 inhibitors in NSAID-sensitive patients with cutaneous reactions. Ann Allergy Asthma Immunol 87:201, 2001
  12. Gruchalla RS, Beltrani VS: Drug-induced cutaneous reactions. Allergic Skin Disease. Leung DYM, Greaves MW, Eds. Marcel Dekker, New York, 2000, p 318
  13. Sampson HA: Food allergy. Part 2: diagnosis and management. J Allergy Clin Immunol 103:981, 1999
  14. Sehgal VN, Rege VL: An interrogative study of 158 urticaria patients. Ann Allergy 31:279, 1973
  15. Eggesbo M, Halvorsen R, Tambs K, et al: Prevalence of parentally perceived adverse reaction to food in young children. Pediatr Allergy Immunol 10:122, 1999
  16. Bock SA, Sampson HA, Atkins FM, et al: Double-blind, placebo-controlled food challenge as an office procedure: a manual. J Allergy Clin Immunol 82:986, 1988
  17. Rockwell WJ: Reactions to molds in foods. Food allergy: a practical approach to diagnosis and management. Chiaramonte LT, Schneider AT, Lifshitz F, Eds. Marcel Dekker, New York, 1988, p 153
  18. Anderson JA: Milestones marking the knowledge of adverse reactions to food in the decade of the 1980s. Ann Allergy 72:143, 1994
  19. Spergel JM, Beausoleil JL, Pawlowski NA: Resolution of childhood peanut allergy. Ann Allergy Asthma Immunol 85:435, 2000
  20. Bock SA: Natural history of severe reactions to foods in young children. J Pediatr 107:676, 1985
  21. Sicherer SH, Sampson HA: Food hypersensitivity and atopic dermatitis: pathophysiology, epidemiology, diagnosis, and management. J Allergy Clin Immunol 104:S114, 1999
  22. Leznoff A, Sussman GL: Syndrome of idiopathic chronic urticaria and angioedema with thyroid auto-immunity: a study of 90 patients. J Allergy Clin Immunol 84:66, 1989
  23. Turktas I, Gokcora N, Demirsoy S, et al: The association of chronic urticaria and angioedema with autoimmune thyroididitis. Int J Dermatol 36:187, 1997
  24. Zauli D, Delonardi G, Foderaro S, et al: Thyroid autoimmunity in chronic urticaria. Allergy Asthma Proc 22:93, 2001
  25. Rumbyrt JS, Katz JL, Schocket AL: Resolution of chronic urticaria in patients with thyroid autoimmunity. J Allergy Clin Immunol 96:901, 1995
  26. Heymann WR: Chronic urticaria and angioedema associated with thyroid autoimmunity: review and therapeutic implications. J Am Acad Dermatol 40:229, 1999
  27. Liutu M, Kalimo K, Uksila J, et al: Etiologic aspects of chronic urticaria. Int J Dermatol 37:515, 1998
  28. Schnyder B, Helbling A, Pichler WJ: Chronic idiopathic urticaria: natural course and association with Helicobacter pyloriinfection. Int Arch Allergy Immunol 119:60, 1999
  29. Nelson H: Routine sinus roentgenograms and chronic urticaria. JAMA 251:1680, 1984
  30. deGentile L, Grandiere-Perez L, Chabasse D: Urticaria and parasites. Allergy Immunol (Paris) 31:288, 1999
  31. Picardi A, Abeni D: Stressful life events and skin diseases: disentangling evidence from myth. Psychother Psychosom 70:118, 2001
  32. Lipsker D, Veran Y, Grunenberger F, et al: The Schnitzler syndrome: four new cases and review of the literature. Medicine (Baltimore) 80:37, 2001
  33. Muckle TJ: The ‘Muckle-Wells’ syndrome. Br J Dermatol 100:87, 1979
  34. Demain JG, Taylor TM: Reactions to stinging and biting arthropods. Cutaneous Allergy. Charlesworth EN, Ed. Blackwell Science Publications, Cambridge, England, 1996, p 299
  35. Stibich AS, Schwartz RA: Papular urticaria. Cutis 68:89, 2001
  36. Tharp MD, Longley BJ Jr: Mastocytosis. Dermatol Clin 19:679, 2001
  37. Kobza-Black A: Management of urticaria. Clin Exp Dermatol 27:328, 2002
  38. Sibbald RB: Physical urticaria. Dermatol Clinics North Am 4:57, 1984
  39. Wanderer AA: Cold urticaria syndromes: historical background, diagnostic classification, clinical and laboratory characteristics, pathogenesis, and management. J Allergy Clin Immunol 85:965, 1990
  40. Neittaanmaki H: Cold urticaria: clinical findings in 220 patients. J Am Acad Dermatol 13:636, 1985
  41. Monfrecola G, Masturzo E, Riccardo AM, et al: Solar urticaria: a report of 57 cases. Am J Contact Dermat 11:89, 2000
  42. Uetsu N, Miyauchi-Hashimoto H, Okamoto H, et al: The clinical and photobiological characteristics of solar urticaria in 40 patients. Br J Dermatol 142:32, 2000
  43. Ryckaert S, Roelandts R: Solar urticaria. Arch Dermatol 134:71, 1998
  44. Luong KV, Nguyen LT: Aquagenic urticaria: report of a case and review of the literature. Ann Allergy Asthma Immunol 80:483, 1998
  45. Paterson R, Mellies CJ, Blankenship ML, et al: Vibratory angioedema: a hereditary type of physical hypersensitivity. J Allergy Clin Immunol 50:174, 1972
  46. Lahti A: Immediate contact reactions. Curr Probl Dermatol 22:17, 1995
  47. Hjorth N, Ree-Peterson J: Occupational protein contact dermatitis in foodhandlers. Contact Derm 2:28, 1976
  48. Hirschmann JV, Lawlor F, et al: Cholinergic urticaria. Arch Dermatol 123:462, 1987
  49. Lee EE, Maibach HI: Treatment of urticaria: an evidence-based evaluation of antihistamines. Am J Clin Dermatol 2:27, 2001
  50. Goldsobel AB, Rohr AS, Siefel SC, et al: Efficacy of doxepin in the treatment of chronic idiopathic urticaria. J Allergy Clin Immunol 78:867, 1986
  51. Mansfield LE, Smith JA, Nelson HS: Greater inhibition of dermographia with combination of H1 and H2 antagonists. Ann Allergy 50:264, 1983
  52. Kennes B, De Maubeuge J, Delespesse G: Treatment of chronic urticaria with a beta2-adrenergic stimulant. Clin Allergy 7:35, 1977
  53. Spangler DL, Vanderpool GE, Carroll MS, et al: Terbutaline in the treatment of chronic urticaria. Ann Allergy 45:246, 1980
  54. Kaplan AP: Clinical practice: chronic urticaria and angioedema. N Engl J Med 346:175, 2002
  55. The diagnosis and management of urticaria: a practice parameter. Part I: acute urticaria/angioedema; part II: chronic urticaria/angioedema. Joint Task Force on Practice Parameters. Ann Allergy Asthma Immunol 85:521, 2000
  56. Parsad D, Pandhi R, Juneja A: Stanozolol in chronic urticaria: a double-blind, placebo controlled trial. J Dermatol 28:299, 2001
  57. Fearfield LA, Gazzard B, Bunker CB: Aquagenic urticaria in HIV virus infection treated with stanozolol. Br J Dermatol 137:620, 1997
  58. Omerud AD, Smart L, Reid TM, Milford-Ward A: Familial cold urticaria: investigation of a family and response to stanozolol. Arch Dermatol 129:34, 1993
  59. Bressler RB, Sowell K, Huston DP: Therapy of chronic idiopathic urticaria with nifedipine: demonstration of beneficial effect in a double blinded, placebo controlled cross-over trial. J Allergy Clin Immunol 83:756, 1989
  60. Millins JL, Randle HW, Solley GO, et al: The therapeutic response of urticarial vasculitis to indomethacin. J Am Acad Dermatol 3:349, 1980
  61. Grattan CE, O'Donnell BF, Francis DM, et al: Randomized double-blind study of cyclosporin in chronic ‘idiopathic’ urticaria. Br J Dermatol 143:365, 2000
  62. Beltrani VS: An overview of chronic urticaria. Clin Rev Allergy Immunol 23:147, 2002
  63. Hedner T, Samuelsson O, Lunde H, et al: Angioedema in relation to treatment with angiotensin converting enzyme inhibitors. Br Med J 304:941, 1992
  64. Champion RH: Urticaria and angio-edema: a review of 554 patients. Br J Dermatol 81:588, 1969
  65. Henig NR, Henderson WR Jr: Anti-leukotriene agents in the treatment of asthma. Current Review of Allergic Diseases. Kaliner MA, Ed. Current Medicine, Philadelphia, 2000, p 71
  66. Quiralte J, Bianco C, Castillo R, et al: Intolerance to nonsteroidal anti-inflammatory drugs: results of controlled drug challenges in 98 patients. J Allergy Clin Immunol 98:678, 1996
  67. Kelkar PS, Butterfield JH, Teaford HG: Urticaria and angioedema from cyclooxygenase-2 inhibitors. J Rheumatol 28:2553, 2001
  68. Agostini A, Cicardi M, Cugno M, et al: Angioedema due to angiotensin-converting enzyme inhibitors. Immunopharmacology 15:21, 1999
  69. Hedner T, Samuelsson O, Lunde H, et al: Angioedema in relation to treatment with angiotensin converting enzyme inhibitors. BMJ 304:941, 1992
  70. Rodgers JE, Patterson JH: Angiotensin II receptor blockers: clinical relevance and therapeutic role. Am J Health Syst Pharm 58:671, 2001
  71. Nzeako UC, Frigas E, Tremaine WJ: Hereditary angioedema: a broad review for clinicians. Arch Intern Med 161:2417, 2001
  72. Bork K, Barnstedt SE, Koch P, et al: Hereditary angioedema with normal C1-inhibitor activity in women. Lancet 356:213, 2000
  73. Laurent J, Guinnepain MT: Angioedema associated with C1 inhibitor deficiency. Clin Rev Allergy Immunol 17:513, 1999
  74. Jackson J, Sims RB, Whelan A, et al: An IgG autoantibody which inactivates C1-inhibitor. Nature 323:722, 1986
  75. Black AK, Greaves MW: Antihistamines in urticaria and angioedema. Clin Allergy Immunol 17:249, 2002
  76. Chase MP, Fiarman GS, Scholz FJ, et al: Angioedema of the small bowel due to an angiotensin-converting enzyme inhibitor. J Clin Gastroenterol 31:254, 2000
  77. Agostini A, Ciccardi M: Hereditary and acquired C-1 inhibitor deficiency: biological and clinical characteristics in 235 patients. Medicine (Baltimore) 71:206, 1992
  78. Cicardi M, Bergamaschini L, Zingale LC, et al: Idiopathic nonhistaminergic angioedema. Am J Med 106:650, 1999
  79. Bork K, Barnstedt SE: Treatment of 193 episodes of laryngeal edema with C1 inhibitor concentrate in patients with hereditary angioedema. Arch Intern Med 161:714, 2001
  80. Luskin AT, Luskin SS: Anaphylaxis and anaphylactoid reactions: diagnosis and management. Am J Ther 3:515, 1996
  81. Van der Klauw MM, Stricker BHCH, Herings RMC, et al: A population-based case-cohort study of drug-induced anaphylaxis. Br J Clin Pharmacol 35:400, 1993
  82. Yokum MW, Butterfield J, Klein J, et al: Epidemiology of anaphylaxis in Olmsted County, a population-based study. J Allergy Clin Immunol 104:452, 1999
  83. Yocum MW, Khan DA: Assessment of patients who have experienced anaphylaxis: a 3-year survey. Mayo Clin Proc 69:16, 1994
  84. Kemp SF, Lockey RF, Wolf BL, Lieberman P: Anaphylaxis: a review of 266 cases. Arch Intern Med 155:1749, 1995
  85. Perez C, Tejedor MA, Hoz A, et al: Anaphylaxis: a review of 182 patients (abstr). J Allergy Clin Immunol 95:368, 1995
  86. Kaufman DW: An epidemiologic study of severe anaphylactic and anaphylactoid reactions among hospital patients: methods and overall risks—abstract from report from the International Collaborative Study of Severe Anaphylaxis. Epidemiology 9:141, 1998
  87. Boxer M, Greenberger PA, Patterson R: Clinical summary and course of idiopathic anaphylaxis in 73 patients. Arch Intern Med 147:26, 1987
  88. The diagnosis and management of anaphylaxis. Joint Task Force on Practice Parameters, American Academy of Allergy, Asthma and Immunology, American College of Allergy, Asthma and Immunology, and the Joint Council of Allergy, Asthma and Immunology. J Allergy Clin Immunol 101:S465, 1998
  89. Korenblat P, Lundie MJ, Dankner RE, et al: A retrospective study of epinephrine administration for anaphylaxis: How many doses are needed? Allergy Asthma Proc 20:383, 1999
  90. Weiler JM: Anaphylaxis in the general population: a frequent and occasionally fatal disorder that is under-recognized. J Allergy Clin Immunol 104:271, 1999
  91. Sim TC: Anaphylaxis. How to manage and prevent this medical emergency. Postgrad Med 92:277, 1992

Editors: Dale, David C.; Federman, Daniel D.