Definition
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 multisys-temic, 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
Urticaria is a cutaneous eruption that consists of erythema-tous, pruritic wheals. Although urticaria is typically transient, it can be persistent, with lesions occurring for weeks to months.
Epidemiology
Urticaria is a common problem, with 15% to 23% of the general population experiencing at least one episode in their life-time.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.
Etiology
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 hista-mine 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.
Pathogenesis
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 secre-tagogues. There is debate regarding whether the number of cutaneous mast cells in patients with persistent urticaria increas-es4 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 de-granulation [see Table 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.
Diagnosis
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
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.
Table 1 Pathologic Changes in Urticaria and Their Associated Mediators
|
Symptom |
Pathologic Event |
Mediators |
|
Wheal |
Histamine (H1) |
|
|
Vascular permeability |
Prostaglandin D2 Platelet activating factor |
|
|
Bradykinin |
||
|
Leukotrienes C4, D4, E4 |
||
|
Flare |
Histamine (H1) |
|
|
Prostaglandin D2 |
||
|
Vasodilatation |
Platelet activating factor |
|
|
Bradykinin |
||
|
Leukotrienes C4, D4, E4 |
||
|
Pruritus |
Sensory nerve stimulation |
Histamine (H1) |
|
Table 2 Classification of Urticarial Lesions |
|
Identifiable cause |
|
Immunologic |
|
Nonimmunologic (e.g., cyclooxygenase pathway, opiates) |
|
Physical urticaria |
|
Aquagenic urticaria |
|
Cholinergic urticaria |
|
Cold urticaria |
|
Contact urticaria (e.g., jellyfish, nettles) |
|
Delayed pressure |
|
Dermatographism |
|
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) |
|
Mastocytosis |
|
Mastocytoma |
|
Urticaria pigmentosa |
|
Diffuse cutaneous mastocytosis |
|
Telangiectasia macularis eruptiva perstans (TMEP) |
|
Systemic mastocytosis |
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 secre-tagogues. These include immunologic and nonimmunologic activators, as well as some whose mechanism is unknown [see Table 3].
Drugs 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 nonim-munologic 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
Although urticarial reactions to aspirin and other NSAIDs are rarely induced through IgE, they occur most frequently in atopic persons.10 Angioedema, 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 cyclooxy-genase-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 ra-dioallergosorbent 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 su-pervision, 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.
Table 3 Mast Cell Secretagogues
|
Immunologic activators (act on receptors) |
IgE antigens (e.g., foods, drugs, latex) |
|
O O O ‘ ‘ O ‘ ‘ IgG directed against IgE (autoimmunity) |
|
|
Anti-FcsRI (IgE receptor) antibodies |
|
|
Lectins (e.g., strawberries, conconavalin A) |
|
|
Neuropeptides (e.g., substance P, somato-statin) |
|
|
Complement activators (C3a, C5a) |
|
|
Radiocontrast media |
|
|
Blood products |
|
|
Cytokines |
|
|
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 |
|
|
Peptides |
|
|
Jellyfish, lobster, eosinophil major basic protein (EMB), polymyxin B, defensins |
|
|
Irradiation |
|
|
Dextran |
|
|
Physical contact (pressure, light, water) |
|
|
Mechanism unknown |
Alcohol, amphetamine, bradykinin, ciprofloxacin, papaverine, rifampin, thi-amine, thiopental, tolazoline, vancomycin |
Figure 1 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.
Foods 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.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.
Urticarial reactions to foods may result from exposure by in-gestion, 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., scom-broidosis) [see 8:IManagement 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 ecchy-mosis 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 con-firmed.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.
Neoplasms 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.
