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Allergy refers to conditions in which immune responses to environmental antigens cause tissue inflammation and organ dysfunction. The clinical features of each allergic disease reflect the diversity of immunologically mediated inflammatory responses in the affected organs or tissues. With IgE antibody-mediated allergy, a predictable sequence of events occurs: exposure to an allergen (an antigen capable of inducing an allergic response), sensitization (generation of an immune response), reexposure to the sensitizing antigen, and the target organ response.

Atopy refers to a genetically determined IgE antibody response to common environmental allergens. Atopy affects 10% to 30% of the population of the United States; allergic rhinitis and allergic asthma are the most common clinical manifestations. Atopic dermatitis is less common, and allergic gastroenteropathy is rare. Conditions such as rhinitis, asthma, eczematous dermatitis, anaphylaxis, and urticaria and angioedema may be caused by both IgE-mediated and non-IgE-mediated mechanisms. Non-IgE-mediated allergic diseases lack the genetically determined propensity and target-organ hyperresponsiveness that characterize atopy, and an atopic person is no more predisposed to these disorders than a nonatopic person.

The sensitization of atopic persons to ubiquitous allergens and the subsequent cascade of immunologic responses and clinical sequelae that occur on repeat exposure are not completely understood. However, it is clear that the physiologic process is complex, involving interactions and signaling between a variety of cell types, mediators of inflammation, and neural mechanisms. Given these intricate processes, it is likely that heterogeneity in a potentially large number of genes may form the basis of interindividual variability in IgE response to nonpathogenic allergens and expression of IgE-mediated disease.

Humoral and Cellular Mechanisms of Allergic Inflammation Associated with Immediate Hypersensitivity

The exposure of an appropriately sensitized person to his or her specific allergen results in an immediate-type hypersensitivity reaction that manifests itself within seconds to minutes. Immediate-type hypersensitivity is mediated by IgE antibodies that bind to specific receptors on mast cells and basophils. Interaction of allergen with IgE bound to the surface of mast cells and basophils activates a biochemical process that results in the elaboration of numerous mediators that recruit other inflammatory cells, such as eosinophils, and directly causes damage to tissues in the affected target organ.

A careful medical history is the most important portion of the clinical evaluation of suspected IgE-mediated allergic disease. The presence or absence of skin eruptions, headache, nasal pruritus, sneezing, rhinorrhea, postnasal drip, nasal congestion, nasal polyposis, eye irritation, hearing loss, dyspnea, cough, wheezing, and aspirin sensitivity should be determined. If a patient has several of these symptoms, allergy is probably present. If sneezing, rhinorrhea, and nasal congestion occur without nasal pruritus or ocular irritation, however, the symptoms are probably not allergic in origin. Unilateral nasal or ocular symptoms are seldom manifestations of allergy. Allergic symptoms usually occur intermittently; even when they are continuous, however, they are characterized by periods of waxing-and-waning intensity.

Because the propensity to generate IgE antibody on exposure to allergens is genetically determined, most allergic patients have a family history of atopy. A medication history that reveals a reduction of symptoms with antihistamines, cromolyn sodium, corticosteroids, or allergen injections suggests an allergic diathesis. Alternatively, the history may suggest that the patient's symptoms are caused by a drug. a-Sympathomimetic nasal sprays, rauwolfia, oral contraceptives, beta blockers, and tricyclic antidepressants may cause nasal obstruction. Various formulations of beta blockers, including topical ocular preparations, may cause dyspnea, cough, or wheezing. Angiotensin-converting enzyme (ACE) inhibitors can result in angioedema or cough.

The allergy history should allow correlations to be drawn between symptoms and the known site and time of exposure to various allergens . It is crucial to establish the severity and functional consequence of symptoms, the exact timing of symptoms during the year, and the fluctuation of symptoms in relation to geographic or specific environmental areas (e.g., barns, fields, damp basements, and factories). A detailed survey of the patient's home environment and school or work environment is often useful.

Protein-rich pollen grains (the male gametes of plants) are among the most important seasonal allergens. For the most part, to be allergenic, pollen must be antigenic, must be produced in large quantities by a common plant, and must primarily depend on the wind for dispersal. In the United States, most trees and grasses, as well as certain weeds, produce large quantities of highly allergenic, wind-borne pollen. The seasonal occurrence of these pollens varies with geographic location and accounts for the seasonality of allergic symptoms. The transfer of pollen between flowering plants is accomplished by insects, not by the wind; therefore, such pollens are not major allergens. Goldenrod, which is popularly considered a cause of hay fever, has little clinical significance because its pollen rapidly falls to the ground. In contrast, ragweed, which pollinates at the same time of year as goldenrod, has abundant, small, lightweight pollen that is dispersed by the wind, and it is therefore a major allergen.

Certain fungi, most notably Alternaria, Aspergillus, Cladosporium, and Penicillium species, are the most common allergenic fungi. They can colonize many habitats and produce spores prolifically. Although these allergens can result in perennial symptoms, certain climates (warm, humid weather followed by windy weather) result in large numbers of airborne spores and, in susceptible people, fluctuating seasonal exacerbation of symptoms. Certain habitats, such as damp basements, food-storage areas, and compost heaps, provide optimal conditions for spore production.

The excreta of house dust mites (Dermatophagoides species) are the major source of allergens in house dust. Because a major food source for dust mites is human dander, these vermin are quite plentiful in bedding. Dust mite-sensitive patients have perennial symptoms that are exacerbated when dust mites proliferate as a result of increased indoor warmth and humidity and when dust becomes aerosolized during housecleaning and bed making.

Another source of perennial indoor allergens is the serum proteins that are found in the urine or pelts of household pets, which are easily transferred to furniture, bedding, and rugs. Although cats and dogs are the pets that are most frequently involved, many other animals, including hamsters, gerbils, rabbits, and mice, are often the culprits. Similarly, certain occupational groups, such as veterinarians, farmers, ranchers, and laboratory workers, may be exposed to a variety of allergenic animals. In the allergic patient, sensitivity to animals must always be suspected. Because of emotional attachments, patients often underestimate the importance of this type of exposure. A patient with inhalant allergy whose symptoms begin to flare after a period of good pharmacologic control may live in a household where a pet has recently been introduced.

In the physical examination, particular attention should be paid to the skin, eyes, nose, throat, and chesu. The skin lesions of atopic dermatitis are variable and consist of erythematous patches, papules, vesicles, scaling, crusting, lichenification, or a combination of these lesions. The distribution of the lesions varies with the age of the patient. In adolescents and adults, atopic dermatitis tends to consist of pruritic, erythematous, papular, scaly patches on the forehead, periorbital areas, neck, antecubital and popliteal fossae, and hands. Allergic rhinoconjunctivitis is characterized by bilateral erythema and edema of the conjunctiva, a watery ocular discharge, and, occasionally, periorbital edema with a bluish discoloration around the eyes. Examination of the nasal cavity in the acute stages of allergic rhinitis demonstrates a pale, boggy mucosa. A clear, thin nasal secretion is often present; swollen turbinates may completely occlude the nostrils, resulting in mouth breathing, and nasal polyps may be noted. The nasal obstruction of allergic rhinitis may be accompanied by fluid accumulation in the middle ear. Chest examination in an asthmatic patient may be normal or may demonstrate use of the accessory muscles of respiration, diffuse inspiratory and expiratory wheezing, prolongation of the expiratory phase of respiration, and cyanosis.

Both in vivo and in vitro assays may be useful in the evaluation of a patient with atopic disease. Immediate hypersensitivity skin testing is a convenient, safe, and expeditious means of identifying allergen-specific IgE. For reliable results, the patient must not be taking antihistamines (astemizole and other long-acting agents can alter skin-test results for 6 to 8 weeks after discontinuance of therapy); the patient must not have a wheal-and-flare response when the skin is stroked (called dermatographism, which literally means writing on skin); the patient must not be suspected of being so exquisitely sensitive to a given allergen that there is a high risk of skin-test-induced anaphylaxis; and the skin to which the allergens will be applied must be free of disease.

The prick and intradermal skin tests are the tests that are most commonly used . In prick testing, a single drop of allergen in solution (concentrated allergen extract, typically in a strength of 20,000 to 100,000 allergy units/ml, 1:10 weight in volume [w/v], or 20,000 protein nitrogen units [PNU]/ml) is applied to the skin, and the skin is gently pricked with a needle; 20 minutes later, the size of the resulting histamine-induced wheal is assigned a grade of 1 to 4+ and compared with that of other wheals at positive (histamine) and negative (saline) control sites. The flare (erythema) component of the cutaneous response to allergen is an evanescent axon reflex that is not a major element of grading in most scoring systems. If a patient is suspected of having an atopic diathesis but does not have a positive response on prick skin testing, intradermal skin testing with a 1:10 or 1:100 dilution of the concentrated allergen extract should be performed. The control sites and scoring system used in intradermal testing are identical to those of prick skin testing.

The interpretation of the result of a properly performed skin test requires knowledge of the history and physical findings. A positive skin test demonstrates only that IgE antibody directed against a given allergen is present. Diagnosis of a specific allergen as causing an allergic diathesis requires integration of clinical and testing data. In the case of inhaled antigens, a positive skin test and a history that suggests clinical sensitivity strongly incriminate the allergen. Conversely, a negative skin test and lack of a history of clinical sensitivity exclude the allergen as clinically relevant. If there is no history suggestive of clinical sensitivity to an allergen but the skin test to that allergen is positive, the patient should be reevaluated during natural exposure to the allergen. If no symptoms occur, the patient's positive skin-test result should be viewed as an indication that allergen-induced disease may subsequently develop.

Serum IgE is usually measured by noncompetitive solid-phase radioimmunoassays and expressed in international units per milliliter (1 IU = 2.4 ng). IgE concentrations vary with age, sex, family history of allergic disease, and the presence of allergy. The mean IgE level is higher in atopic than in nonatopic persons, but these values have a wide overlap.

Clinically more important than quantitation of the total serum IgE level is the in vitro measurement of allergen-specific IgE. Such testing is useful in patients who cannot undergo immediate hypersensitivity skin testing, because they have been taking long-acting antihistamines or have extensive dermatitis, dermatographism, or a risk of anaphylaxis. The assays are modifications of noncompetitive solid-phase radioimmunoassays; the radioallergosorbent test (RAST) or a variant of RAST is the test that is most commonly used. In this assay, an allergen-bearing solid matrix is incubated with the patient's serum to permit binding of specific IgE. After washing, the solid-phase allergen-antibody complex is incubated with radiolabeled anti-human IgE antibody and washed again. The measured quantity of radioactivity bound to the solid matrix is proportional to the quantity of allergen-specific IgE in the serum; by comparing the value with known standards, the exact amount of allergen-specific IgE can be determined.

The results of RAST correlate well with those of a variety of in vivo provocation tests for allergy, including skin testing and nasal or bronchial challenge, and with in vitro tests for allergen-induced histamine release. However, RAST is less sensitive than immediate hypersensitivity skin testing. As with the results of in vivo skin testing, the results of RAST must be interpreted in the context of the patient's history and physical examination.

There are three principles of treatment of IgE-mediated allergic disease: allergen avoidance, pharmacotherapy, and immunotherapy (allergen injection). Because the development of IgE-mediated allergic disease requires interaction between allergen and antibody, the first tenet of allergy management is allergen avoidance . A person who manifests IgE sensitivity to a given food or drug should not ingest it. Animals that cause allergic symptoms should be removed from the patient's indoor environment. Dust mite-sensitive persons can reduce their exposure by using synthetic bedding and zippered plastic cases for the pillows, mattress, and box spring; by maintaining an indoor humidity of 50% or less and an ambient temperature of less than 68� F; and by removing upholstered furniture and curtains from the bedroom. To limit exposure to mold spores, the patient should avoid entering barns, mowing grass, and raking leaves. Damp areas in the home, especially the basement, should be equipped with dehumidification systems. To prevent the growth of mold, dehumidifier filters should be changed or cleaned regularly. For other inhaled allergens, such as grass, tree, and weed pollens, complete avoidance is practically impossible; however, air conditioners and air-filtration systems can reduce aeroallergen load.

The second tenet of allergy management is systemic and local pharmacotherapy to control allergic symptoms. Such therapy consists of the administration of epinephrine, bronchodilators, antihistamines, decongestants, corticosteroids, cromolyn sodium, nedocromil, or a combination of these agents. Pharmacologic interventions for specific manifestations of allergic disease are discussed in subsequent sections.

Allergen immunotherapy, in which increasing doses of allergen are injected subcutaneously over time, is the third tenet of management and is designed to prevent the allergic symptoms that occur in the sensitized person on exposure to allergen. Although this technique was first introduced by Noon in 1911 as a treatment for pollen-induced rhinitis, only in the past 35 years have rigorous double-blind trials validated the efficacy of conventional high-dose immunotherapy in the treatment of rhinitis and asthma caused by specific inhaled allergens. Conventional high-dose immunotherapy entails following various immunization schedules to reach a maintenance dose (0.1 to 0.5 ml of a 1:10 or 1:100 dilution of the most concentrated allergen extract) that is repeated every 3 to 5 weeks for several years.

Patients who should receive immunotherapy are those who have significant disease that is caused by inhaled allergens (pollen, mold spores, dust mites, or well-defined animal dander) and is not adequately controlled by environmental modification and pharmacotherapy. In addition, immunotherapy is indicated for patients with stinging-insect anaphylaxis (see below), but insect venom, not whole body extract, should be used. Patients with poorly controlled aeroallergen-induced asthma should not receive allergen immunotherapy, because the risk of allergen injection-induced side effects is greater in these patients. In addition, although certain foods, chemicals, drugs, and unusual environmental substances can result in IgE-mediated allergy, sensitivity to these agents should not be treated with immunotherapy.

There are several other techniques of allergen immunotherapy, including skin titration testing and treatment (the Rinkel method), subcutaneous provocation and neutralization, and sublingual provocation. However, these techniques have not been validated by rigorous controlled trials.

Allergic rhinitis is an IgE-mediated inflammatory disease involving the nasal mucous membranes. Symptoms usually begin in childhood or early adulthood but can occur at any age. Allergic rhinitis often occurs seasonally, when pollen comes into direct contact with the respiratory mucosa, but it can also occur perennially. Specific interactions between antigen and IgE occur on the surface of submucosal mast cells, leading to the release of mediators and the production of symptoms.

Mild symptoms of allergic rhinitis include nasal pruritus, rhinorrhea, and sneezing; more severe symptoms are violent paroxysms of sneezing and total obstruction of airflow caused by copious amounts of mucus. Other symptoms are lacrimation and soreness of the eyes, irritability, fatigue, lethargy, and anorexia. These symptoms may be aggravated by nonspecific irritants such as cigarette smoke, aerosols, strong odors, perfumes, and insecticides. Complicating inflammatory or infectious sinusitis results in maxillofrontal headache, postnasal discharge, and persistent nasal stuffiness. Occasionally, mild obstructive disease of the lower airways may be demonstrable without overt clinical symptoms of bronchial asthma.

The nasal physical findings include pale-blue mucous membranes; edematous turbinates coated with thin, clear secretions; dark circles under the eyes; and mouth breathing caused by nasal obstruction. Some patients may have erythematous nasal mucosa. Nasal polyps are uncommon in uncomplicated rhinitis. Lacrimation, scleral and conjunctival injection, periorbital edema and fluid, or retraction of the tympanic membrane may also be observed. Enlarged tonsils, adenoids, cervical lymph node swelling, and fever are not typically associated with allergic disease and should therefore prompt a search for complicating infection or other disease.

The diagnosis of allergic rhinitis depends on careful history taking, which includes a search for a family history of atopy, and identification of IgE directed against the responsible allergen. Seasonal patterns of symptoms should be noted and compared with locally coincident pollination. Determination of specific IgE against various allergens is usually documented by skin testing or RAST. The direct prick or intradermal skin test, using appropriate allergens, is the quickest and least expensive test currently available. However, in some patients (e.g., those with extensive eczema or marked dermatographism or those who take medications that may interfere with skin reactivity), the in vitro RAST may be more useful.

Normal or increased numbers of eosinophils may be found in the peripheral blood and nasal secretions of patients with either allergic or nonallergic rhinitis and therefore provide little diagnostic information. Examination of nasal secretions for eosinophils is often more useful than examination of peripheral blood. Positive nasal smears (> 20% eosinophils) are obtained in about 50% of patients with proven allergic rhinitis but are seldom found in normal persons or in those with rhinitis of other causes. Large numbers of neutrophils in the nasal smear suggest infection. The total serum IgE level is elevated in only 30% to 40% of patients with allergic rhinitis. Radiographs of the paranasal sinuses are usually normal in patients with allergic rhinitis unless infectious sinusitis is present.

Conditions and causes to consider in the differential diagnosis of seasonal allergic rhinitis are upper respiratory viral infection; excessive use of a-sympathomimetic nose drops and sprays; use of specific drugs, such as oral contraceptives, reserpine derivatives, beta blockers (e.g., propranolol), ACE inhibitors (e.g., captopril), hydralazine, aspirin, and other nonsteroidal anti-inflammatory drugs (NSAIDs); and hormonally related rhinitis, which occurs premenstrually or during pregnancy. The manifestations of upper respiratory tract infection usually last no longer than a week and may include fever, pain, and the presence of neutrophils in secretions.

Conditions that must be ruled out in cases of perennial allergic rhinitis include structural nasal abnormalities, such as septal deviation, and endocrine abnormalities, such as hypothyroidism, nasal mastocytosis, or perennial nonallergic rhinitis of unknown cause (vasomotor rhinitis). Structural abnormalities of the nose usually can be differentiated by physical examination; mastocytosis is detected by examination of a biopsy specimen of the nasal mucosa. The symptoms of perennial rhinitis of unknown cause often occur when there are changes in temperature or humidity or after exposure to irritants or air pollution.

Three strategies are used to treat allergic rhinitis: avoidance of offending allergens, use of antihistamines and other drugs, and allergen immunotherapy.

Although allergens usually cannot be completely avoided, measures to reduce exposure generally provide some relief . Exposure to dust can be reduced by the use of dustproof covers on pillows, mattresses, and box springs. Avoiding outdoor activities during the height of the pollen season can reduce exposure to these allergens. Patients sensitive to mold spores should avoid contact with hay and should not rake leaves or mow grass. Air conditioners and electrostatic filters are often helpful. Many nonspecific irritants that aggravate symptoms (e.g., smoke, pollution, or dust) should also be avoided.

Although the histamine-type 1 (H₁) receptor antagonists (antihistamines) possess numerous antiallergic effects, including inhibition of mediator release from mast cells and basophils and inhibition of inflammatory cell chemotaxis, their principal mechanism of action is their binding to H₁receptors without consequent receptor activation, thereby preventing histamine binding and activity. The clinical rationale for the use of the H₁receptor antagonists in patients with allergic rhinitis is based on several observations. First, nasal challenge of such patients with histamine reproduces rhinitic symptoms; second, nasal challenge with relevant antigen results in a local increase in histamine concentrations; third, pretreatment with an H₁antihistamine prevents nasal symptoms after challenge with histamine or relevant antigen; and fourth, intranasal histamine concentrations increase spontaneously during active disease.

The H₁receptor antagonists are categorized in terms of their structure, pharmacokinetics, and pharmacodynamics . The first-generation H₁antihistamines are composed of one or two heterocyclic or aromatic rings connected by nitrogen, carbon, or oxygen to an ethylamine group . The number of alkyl substitutions and heterocyclic or aromatic rings determines the lipophilic nature of the antihistamine. The ethylenediamines, phenothiazines, piperazines, and piperidines all contain nitrogen as their linkage atom, whereas the ethanolamines contain oxygen and the alkylamines contain carbon as their linkage atom.

The new nonsedating H₁antihistamines and second-generation H₁antihistamines have structural and pharmacokinetic profiles that are responsible for their longer duration of action and more favorable therapeutic index. In general, they have milder side effects. In the United States, the five currently available oral preparations are fexofenadine, astemizole, loratadine, cetirizine, and acrivastine. In addition, there are two topical nasal preparations, azelastine and levocabastine .

In allergic rhinitis, the H₁antihistamines prevent or relieve nasal pruritus, serous rhinorrhea, and sneezing; however, these agents are less effective for nasal blockage. Doubling the recommended dose does not result in significant increase in overall relief of symptoms. Although commonly used as rescue medication to be taken only when symptoms are present, the H₁ antihistamines are most effective when started shortly before pollination begins and when used regularly during the pollen season.

Numerous studies have compared the antihistaminic efficacy of second-generation H₁antagonists with that of first-generation antagonists in the treatment of allergic rhinitis. Uniformly, second-generation H₁antihistamines have been more effective than placebo and just as effective as first-generation H₁antihistamines. Studies comparing second-generation agents with one another found no dramatic differences in their ability to control the symptoms of allergic rhinitis. Although tolerance to antihistamines is a common concern of patients using these agents on a long-term basis, neither pharmacokinetic data nor clinical data substantiate this concern. Because of their lipophilic structure, first-generation H₁antihistamines, even in recommended doses, often have adverse side effects on the CNS, including somnolence, diminished alertness, slowed reaction time, and impaired cognitive function. Gastrointestinal upset, appetite stimulation, blurred vision, dry mouth, urinary retention, and impotence may be noted, and their incidence varies with the specific medication.

The incidence of adverse CNS effects caused by the second-generation H₁antihistamines is similar to that of placebo and is notably less than that of the first-generation H₁ antihistamines. In rare instances, terfenadine and astemizole have caused fatal or near-fatal cardiovascular events. An overdose or concomitant administration of these drugs with macrolide antibiotics (e.g., erythromycin, troleandomycin, and clarithromycin, but not azithromycin), imidazole antifungal agents (e.g., ketoconazole and itraconazole), or other medications that inhibit the cytochrome P-450 CY3A4 hepatic mixed-function oxygenase system may prolong the QT interval or cause polymorphic ventricular tachycardia (torsade de pointes) and other cardiac arrhythmias. This toxicity relates to the abilities of terfenadine (but not its liver metabolite) and astemizole and its active metabolite, desmethylastemizole, to block the outward (delayed) rectifier potassium current of ventricular myocytes. Patients with hepatic dysfunction, cardiac disorders associated with a prolonged QT interval, or metabolic disorders such as hypokalemia or hypomagnesemia may be especially prone to these adverse cardiac effects. Fexofenadine, the active liver metabolite of terfenadine, has not been associated with cardiac toxicity and has replaced terfenadine on the market. Loratadine and cetirizine do not have these cardiac toxicities, probably because they can be metabolized by two hepatic mixed-function oxygenase systems.

Antihistamine therapy alone is often insufficient, especially for nasal congestion. In such cases, the oral administration of sympathomimetic drugs, including phenylpropanolamine and pseudoephedrine hydrochloride, is recommended. Care must be taken when sympathomimetics are given to patients with cardiovascular disease, because these agents can elevate blood pressure and cardiac rate. The long-acting sympathomimetic pseudoephedrine sulfate, which is taken orally in a dosage of 120 mg twice daily, may be useful. Preparations containing combinations of antihistamines and decongestants are also available.

In cases in which avoidance of allergens and the use of antihistamines and decongestants do not reduce symptoms, intranasal application of 4% cromolyn sodium solution, which prevents the release of mast cell mediators, or of topical corticosteroids (beclomethasone dipropionate, flunisolide acetate, budesonide, fluticasone propionate, mometasone furoate, or triamcinolone acetonide) is recommended. The dosage of cromolyn sodium is usually one spray in each nostril three or four times daily. Corticosteroids are usually given in a dosage of one to two inhalations in each nostril one to three times daily; once-daily dosing is often possible after symptoms have been controlled. Clinical improvement is usually apparent within several days, but maximum clinical benefit may not be achieved for as long as 2 weeks. These topically administered corticosteroid preparations do not cause the side effects associated with systemic administration of corticosteroids. Local nasal irritation is the principal side effect of intranasal steroids, and about 10% of patients sneeze or experience some burning or irritation after corticosteroid administration. Systemic corticosteroids are seldom indicated; in very severe cases, however, their use for short periods (up to 1 week) can dramatically reduce symptoms.

Patients with allergic rhinitis who are not attaining satisfactory clinical improvement with environmental control and symptomatic drug treatment can be treated with allergen immunotherapy (see above). In most cases, 6 months to 1 year after immunotherapy is begun, a decrease in symptoms and in the need for medication becomes apparent; maximum efficacy is reached in 2 to 3 years. In controlled, double-blind studies, immunotherapy has been shown to be effective for allergic rhinitis caused by ragweed, grass, and tree pollens. Efficacy has been correlated with the total dose administered, but relapses can occur, even after maintenance therapy of 3 to 5 years' duration is discontinued. The results are specific for the particular allergens that are employed in the therapy.

Patients receiving immunotherapy undergo a number of immunologic changes that entail alterations in both humoral and cellular immune responses. Characteristic alterations in serum immunoglobulins are found, with an initial increase in allergen-specific IgE followed by a blunting of seasonal increases in pollen-antigen-specific IgE over several years. This is accompanied by an increase in allergen-specific IgG1 and IgG4, the so-called blocking antibodies, which by competing with IgE for allergen binding or causing steric hindrance of IgE receptor aggregation may inhibit IgE-dependent mast cell and basophil activation.

Immunotherapy reduces the early-phase IgE-mediated immune response of allergen-induced mast cell inflammatory mediator (histamine and prostaglandin D₂) release. Paralleling this reduction in inflammatory mediators is a reduction in the number of mast cells in the respiratory epithelium. In addition to this inhibition of the early-phase response to allergen, immunotherapy inhibits late-phase responses as evidenced by a decrease in the number of infiltrating eosinophils.

In keeping with the recent paradigm of cytokine elaboration profile definition of helper T cell subsets, one way in which immunotherapy may result in these humoral and cellular immune responses is by modifying the T cell response to subsequent natural allergen exposure. Studies of peripheral blood cells and in the target-organ mucosa of atopic patients treated with immunotherapy have demonstrated a shift in the balance of T cell subsets away from IL-4-producing and IL-5-producing T_H2 type in favor of interferon-gamma-producing T_H1 type. This immune derivation may be caused by either anergy of T_H2 cells or increases in T_H1 responses. Amplifying or complementing this immune deviation may be immunotherapy-induced suppressor CD8⁺ T cell activity, which may have a down-regulating effect on T_H2 cell bioactivity.

On the basis of this model of the immunology of IgE-mediated allergy and the effects of immunotherapy, investigations are currently exploring novel therapeutic approaches, including the use of T cell reactive peptides, which may down-regulate the T_H2 immune response without risking traditional allergen-administration-associated anaphylaxis. In addition, immunotherapy coupled with the administration of IL-12, a potent inducer of the T_H1 immune response, may potentiate immune deviation away from the T_H2-predominated, IgE allergic phenotype.

Allergic conjunctivitis is the ocular analogue of allergic rhinitis, occurring in 30% to 40% of patients with seasonal allergic rhinitis; it is also caused by an IgE-mediated mast cell and basophil response. As a result of allergen-IgE interaction on the surface of mast cells in the conjunctivas, histamine and other mediators are liberated. Patients with acute allergic conjunctivitis have an increased amount of IgE in their tears and increased numbers of eosinophils in ocular scrapings. A consequence of the IgE-allergen interaction is local conjunctival vasodilatation and edema.

Pruritus is always a prominent feature in patients with allergic conjunctivitis. Both eyes are usually involved, but only one eye may be affected when the cause is manual contamination by allergens such as food or animal dander. The conjunctivas generally appear injected and edematous. In severe cases, the eyes may be swollen shut. Allergic conjunctivitis seldom occurs without allergic rhinitis; in some patients, however, ocular symptoms may be more prominent than nasal symptoms.

The diagnosis of allergic conjunctivitis is based on the history and physical examination. Symptoms usually occur seasonally and are accompanied by a personal or family history of atopy. Skin testing may confirm suspected seasonal allergens. Hansel stain of conjunctival secretions usually reveals numerous eosinophils. The differential diagnosis includes viral and bacterial conjunctivitis, contact dermatitis from the instillation of drugs or from airborne irritants, keratoconjunctivitis sicca, and vernal conjunctivitis.

Treatment consists of allergen avoidance, medication, and, if necessary, immunotherapy. Avoidance of ubiquitous aeroallergens is difficult; however, effective therapy for symptoms can usually be achieved with topical medications such as vasoconstrictors, antihistamines, 4% cromolyn sodium (ophthalmic solution), and corticosteroids. Many preparations used to treat allergic conjunctivitis contain a combination of an antihistamine and a vasoconstrictor. The usual dosage is two drops in each eye every 3 to 4 hours as needed. If this combination is not effective, ophthalmic cromolyn sodium should be tried next, before corticosteroids. Corticosteroid therapy usually should be limited to a period of 1 week. If longer therapy is necessary, intraocular pressure should be measured before therapy is started and every 3 to 4 weeks thereafter. Medrysone, an effective corticosteroid, is poorly absorbed and is less likely to cause changes in intraocular pressure than the more readily absorbed corticosteroids. The dosage is one drop of 4% solution in each eye four times daily. Loteprednol etabonate in both 0.5% and 0.2% concentrations has been shown to be effective in the treatment of seasonal allergic conjunctivitis. Importantly, 6 weeks of treatment with 0.2% suspension (one drop to each eye four times daily) had a safety profile comparable to that of placebo.

Before a patient is given topical corticosteroids, herpes simplex conjunctivitis should be ruled out because corticosteroids will exacerbate and spread the infection. Hyperemia and an infiltrative conjunctivitis that is associated with a typical vesicular eruption along the dermatomal distribution of the ophthalmic branch of the trigeminal nerve are characteristic of herpes zoster. If a diagnosis of allergic conjunctivitis cannot be made with certainty, an ophthalmologic consultation should be obtained before institution of specific therapy.

There are no controlled, double-blind studies of allergen immunotherapy in patients with allergic conjunctivitis, but it is thought that immunotherapy for associated allergic respiratory disease often relieves ocular symptoms.

Asthma is characterized by narrowing of the airways in response to various stimuli. Unlike the more fixed or permanent airflow obstruction typical of chronic bronchitis, emphysema, cystic fibrosis, bronchiectasis, and bronchiolitis, the airflow obstruction associated with asthma is reversible . Asthma is a chronic disease, yet the degree of airflow obstruction can vary widely over time and change within minutes or over a period of days to weeks.

Increased responsiveness of the airways to various stimuli is seen even in asymptomatic asthma with normal function. Bronchoconstriction can be triggered by a variety of stimuli that have little or no impact on the airways of nonasthmatic persons. The stimulus need not be a specific allergen or chemical in the workplace; a nonspecific (i.e., nonantigenic) stimulus such as strenuous exercise may trigger the response.

Increased responsiveness of the airways and reversible airflow obstruction are not unique to asthma. Many patients with chronic obstructive lung disease (e.g., chronic bronchitis or cystic fibrosis) exhibit nonspecific bronchial hyperreactivity and significant changes in lung function over time. In particular, some current or past cigarette smokers with chronic bronchitis and airflow obstruction manifest episodic wheezing and shortness of breath that closely mimic asthma. There is no consensus on how such patients should be classified, but we prefer to consider their ailment not as asthma but as asthmatic bronchitis, a subcategory of chronic bronchitis that has features in common with asthma . This distinction is important in epidemiologic studies of the prevalence and mortality of asthma.

Wheezing in association with childhood respiratory tract infections and long-standing asthma in adults with irreversible obstruction are ambiguous situations that reflect inevitable deficiencies in the definition of a disease for which there is no pathognomonic feature or definitive diagnostic test. Fortunately, in clinical practice, asthma is generally far easier to recognize than it is to define.

The severity of airflow obstruction in patients with asthma varies enormously, ranging from virtually nonexistent to very severe with associated respiratory failure.

During an attack of asthma, spirometric indices are those typical of an obstructive ventilatory defect . The forced vital capacity may remain within the normal range during mild obstruction but may be reduced during a severe attack to 50% of normal or lower because of airway closure with gas trapping. Decreases in the forced expiratory volume in 1 second (FEV₁) and in the peak expiratory flow (PEF) provide objective measurements for assessing the severity of airflow obstruction and for monitoring the course of an exacerbation of asthma. Although there is considerable variability, on average, a patient requiring emergency treatment has an FEV₁ or PEF that is 30% to 35% of normal.

Residual volume increases as airflow obstruction worsens and may exceed values of four times normal. In moderate to severe attacks of asthma, functional residual capacity (FRC) may increase by as much as 1 to 2 L above normal. In part, contraction of inspiratory muscles during the expiratory phase of the respiratory cycle, when inspiratory muscles are normally at rest, may serve to maintain this hyperinflated FRC. Except in cases involving severe airflow obstruction, total lung capacity (TLC) remains within the normal range.

Residual abnormalities in lung function may persist even after complete symptomatic resolution of acute episodes of asthma. Typically, decreases in maximal flow rates and increases in residual volume may persist for days to weeks after an acute attack and may represent persistent low-grade airway inflammation.

The diffusing capacity of the lungs for carbon monoxide may be elevated in some patients, possibly because of greater recruitment of capillaries from higher pulmonary arterial pressure. Because of ventilation-perfusion mismatching, an elevation in the alveolar-arterial oxygen difference (A-aDo₂) is common, but severe hypoxemia is rare. The severity of hypoxemia cannot be accurately determined from the degree of airflow obstruction-an observation that has led to the idea that hypoxemia may be more related to peripheral than to central airways obstruction.

The tachypnea and alveolar hyperventilation that are observed during an asthmatic exacerbation result not from chemoreceptor stimulation but from neural reflexes within the lungs. Hypocapnia and respiratory alkalosis are the most common findings on arterial blood gas analysis. Metabolic (lactic) acidosis may also be seen if there is severe hypoxemia in combination with the increased work of breathing. When airflow obstruction becomes very severe (FEV₁ > 25% of normal), dead space ventilation increases, whereas total ventilation can increase no further, causing a rise in carbon dioxide tension (Pco₂) back to normal levels. Ultimately, despite increasing CO₂ production, total minute ventilation begins to fall; as a result, alveolar ventilation decreases still further and hypercapnia ensues. Respiratory muscle fatigue has been postulated as a potential cause of hypercapnic respiratory failure in patients with asthma.

The classic symptoms of asthma are wheezing, cough, and shortness of breath. The cough can be nonproductive or raise copious amounts of sputum that, in the absence of infection, is typically mucoid and often tenacious. Eosinophils and their debris may cause a yellow discoloration of sputum, even when infection is absent. Occasionally, cough is the only manifestation of asthma.

Dyspnea tends to vary greatly over time, depending on the severity of airflow obstruction. At times, airflow obstruction prevents any significant physical exertion; at other times, strenuous exercise is possible but may trigger wheezing and shortness of breath . During a severe attack, a desperate hunger for air is the overwhelming symptom. Chest tightness commonly occurs with dyspnea and may be confused with angina pectoris. Most patients associate their chest tightness with the sensation of being unable to take in a full and satisfying breath.

During periods of relatively normal lung function, patients are likely to have no physical findings. Wheezing is the most common finding during acute airway obstruction, and the chest may be hyperresonant on percussion. As airflow obstruction becomes severe, a number of physical signs may become manifest and offer clues to the severity of the attack. Tachypnea and tachycardia are common. A fall in systolic blood pressure of more than 10 to 12 mm Hg during inspiration (paradoxical pulse) is found in approximately half of patients whose FEV₁ is 1 L or less during acute exacerbations. Accessory muscle usage and paradoxical pulse with decreasing intensity of breath sounds signify severe obstruction.

The stimuli that trigger attacks vary among persons. Some stimuli are unique to certain subgroups-for example, allergens such as ragweed or animal dander, housedust containing antigens from dust mites and cockroaches, strong odors or fumes, and ingested substances such as certain foods, sulfiting agents, aspirin, and tartrazine . Emotional upset and stress may trigger symptoms in some patients, but the precise role of the central nervous system in regulating airway function is difficult to quantitate. Reflux of gastric acid into the lower esophagus may exacerbate asthmatic symptoms, presumably via vagally mediated parasympathetic nervous reflexes; persistent posterior drainage of nasal mucus may also be an aggravating factor. Indirect evidence indicates that nasal and sinus disease increase airway responsiveness and thereby exacerbate asthma. This inference is based on changes in responsiveness and clinical severity after nasal administration of steroids. Other stimuli are virtually universal precipitants of asthma. Such stimuli include strenuous exercise, particularly if it is performed in cold air; respiratory illnesses, usually viral in origin; inhaled irritants such as ozone, sulfur dioxide, and smoke; and beta-adrenergic blocking agents, angiotensin-converting enzyme inhibitors, and ethanol . Specific antigen responsiveness may be more severe after exposure to environmental pollutants. Some women with asthma have been noted to have a significant increase in exacerbations in the perimenstrual period.

Persons whose asthma is triggered by identifiable inhaled antigens (aeroallergens) usually have atopic disease. Exceptions include cases of asthma caused by certain sensitizing antigens encountered in the workplace that may not elicit an IgE antibody response . Certain laboratory test results support a diagnosis of atopic disease: peripheral blood eosinophilia; increased total serum IgE levels; increased specific IgE levels, determined by a radioallergosorbent test (RAST) directed at a particular antigen; and positive wheal-and-flare reactions to antigens pricked or injected into the skin.

A distinction is often made between persons with asthma who have known allergic precipitants of their bronchoconstriction (extrinsic asthma) and those who do not (intrinsic asthma). Patients who show evidence of an atopic contribution to their asthma may have a greater rate of decline of lung function than those who do not. However, this distinction has probably been overemphasized and may be misleading, since it implies a differentiation of etiology or pathogenesis that is not supported by current data. Categorization into extrinsic or intrinsic asthma groups is difficult: allergic precipitants may not be recognized, symptoms of other atopic diseases may be ambiguous, and laboratory test results may be intermediate or falsely positive. Fortunately, the management of asthmatic patients is not dependent on the distinction between extrinsic and intrinsic types.

No laboratory test alone can establish a diagnosis of asthma, but a test for bronchodilator responsiveness can provide supportive evidence when asthma is suspected on clinical grounds. In patients with baseline airflow obstruction, a large (> 15%) increase in airflow after inhalation of a bronchodilator suggests asthma. Unfortunately, as a diagnostic test, bronchodilator responsiveness lacks both sensitivity and specificity. False negative results are likely in asthmatic patients who have near-normal baseline lung function, in patients who are tested shortly after self-administration of a bronchodilator, and in patients with severe airflow obstruction resulting from airway inflammation and luminal obstruction by secretions. False positive bronchodilator responses may be observed in some patients with chronic bronchitis, emphysema, or other diseases associated with chronic airflow obstruction. A false positive response is especially likely when the baseline FEV₁ is very low, in which case even a small absolute increment in expiratory flow represents a relatively large percentage increase.

Because asthma is episodic, a diagnosis of asthma may be suspected, even if there is normal pulmonary function. Bronchoprovocation may be a useful diagnostic test in this setting. In bronchial challenge testing, a nonspecific stimulus is administered and pulmonary function is then measured. It is anticipated that asthmatic patients will experience airflow obstruction in response to the provocative stimulus. Stimuli used for bronchoprovocation include exercise, eucapnic hyperventilation, and aerosolized methacholine or histamine. Although bronchoprovocation tests are very sensitive, they are not specific for asthma . An alternative is demonstration of lability by use of a self-operated peak flowmeter; a diurnal variation in PEF of 15% or more is highly suggestive of asthma.

In an adult with new onset of asthmatic symptoms, a chest radiograph is warranted to exclude alternative diagnoses. The chest radiograph is usually normal; occasionally, subtle changes indicative of bronchial wall thickening are detected, and during an episode of severe airflow obstruction, radiographic signs of hyperinflation may be present. Chest radiographs of patients treated for exacerbations reveal unsuspected pulmonary infiltrates, atelectasis, pneumothorax, or pneumomediastinum only 2% of the time.

Viral tracheobronchitis, which can be caused by several pathogens (e.g., adenovirus, rhinovirus, influenza virus), can constitute an acute respiratory illness associated with wheezing . Churg-Strauss syndrome is a form of vasculitis characterized by asthmalike airflow obstruction and wheezing.

Many diseases associated with chronic airflow obstruction cause episodic wheezing. Some restrictive diseases have an airway component that is mistaken for asthma. For example, sarcoidosis may cause endobronchial granuloma formation with resultant airflow limitation, cough, wheezing, and dyspnea that are refractory to the usual bronchodilator medications. In addition, rheumatoid arthritis may be associated with bronchiolitis, producing findings that mimic asthma.

Congestive heart failure and pulmonary embolism cause dyspnea and wheezing. Wheezing in association with interstitial pulmonary edema is common enough to have been labeled cardiac asthma. Improvement after inhaled bronchodilator administration does not exclude cardiac asthma as the cause of wheezing. Wheezing is also a rare manifestation of pulmonary embolism. Although in the acute setting either disease might be mistaken for asthma, a detailed evaluation of the patient and the clinical course should clarify the diagnosis.

The conditions most likely to be confused with asthma over a more protracted period are those that cause partial upper airway obstruction . In this context, the term upper airway refers to the single lumen airway from the carina upward. Dyspnea and wheezing associated with upper airway obstruction may be continuous and fail to respond to bronchodilators-a pattern that suggests focal anatomic obstruction. However, in other cases, signs and symptoms may be intermittent and may be brought on by exercise (because of the increased airflow across the narrowed orifice) or by certain postures. In further mimicry of asthma, epinephrine or corticosteroids occasionally relieve symptoms by decreasing edema. Findings that suggest the correct diagnosis are the patient's perception that the problem is in the throat, wheezes that are heard loudest over the neck and transmitted with less intensity to the lung periphery, hoarseness, a cough that sounds unusual, and a normal A-aDo₂ gradient. A helpful diagnostic clue is a history of trauma, surgery, or prolonged intubation of the upper airway.

Upper airway obstruction produces characteristic flow-volume loops . Other tests that may prove helpful in the diagnosis of upper airway obstruction are tracheal tomograms, especially those obtained with the current generation of CT scanners, and laryngoscopy or fiberoptic bronchoscopy in selected cases.

Atopic dermatitis (AD) is a common chronic inflammatory dermatosis. The term atopy was coined in the early 1920s to describe the associated triad of asthma, allergic rhinitis, and dermatitis. The role of reaginic antibodies and allergies in the etiology of AD is controversial; in 80% of patients with AD, however, serum immunoglobulin IgE is elevated, sometimes markedly.

AD is a complex integration of environmental and genetic factors. The lifetime prevalence in children between 3 and 11 years of age is 20% and is on the rise, possibly because of increasing contact with causative agents in the environment.

AD can be quickly exacerbated by environmental trigger factors. Wool, lanolin, and harsh detergents are particularly irritating. Emotional stress can also lead to flares. The role of airborne and foodborne allergens is difficult to assess.

AD remains a clinical diagnosis. Major diagnostic criteria are (1) personal or family history of atopy (AD, allergic rhinitis, allergic conjunctivitis, allergic blepharitis, or asthma); (2) characteristic morphology and distribution of lesions; (3) pruritus; and (4) chronic or chronically recurring dermatosis. Several minor features can be added .

Pruritus is a consistent feature of AD. The lack of itching or of another major diagnostic criterion should prompt consideration of alternative diagnoses . Cutaneous signs can vary, depending on the age of the lesions.

Acute lesions of AD are eczematous-erythematous, scaling, and papulovesicular. Weeping and crusted lesions may develop . Scratching results acutely in linear excoriations, presenting as erosions or a hemorrhagic crust. In extremely severe cases, exfoliative dermatitis (erythroderma) may occur, with generalized redness, scaling, weeping, and crusting. There may be accompanying systemic toxicity, sepsis, lymphadenopathy, altered thermoregulation (either hyperthermia or hypothermia), and high-output cardiac failure. Erythroderma is a potentially life-threatening condition.

Chronic lesions tend not to be eczematous (thus, atopic eczema is not an ideal synonym for AD). Instead, lichenified plaques or nodules predominate. Lichenification denotes areas of thickened skin divided by deep linear furrows. Lichenified plaques result from repeated rubbing or scratching and thus often occur in areas of predilection, such as the popliteal and cubital fossae. As is typical of lesions in AD, lichenification is poorly demarcated. There may be accompanying acute signs. Lichenified lesions are very difficult to treat; once established, they may persist for months even with adequate therapy and avoidance of rubbing or scratching.

Clinical expression of AD also varies with the age of the patient. The infantile stage of AD occurs up to approximately 2 years of age. Of all cases of AD, approximately 90% arise before the fifth year and 60% in the first year of life; onset before 2 months of age is unusual, however. During infancy, ill-defined, erythematous scaling patches and confluent, edematous papules and vesicles are typical. These lesions may become crusted and exudative. Intense pruritus leads to scratching, which induces linear excoriations and, with time, lichenification. Before the infant begins to crawl, the scalp and face are most often involved , although lesions may be seen anywhere. After the child begins crawling, the extensor surfaces-particularly the knees-become involved. Involvement of fingers can be severe if the child sucks them frequently. Intense pruritus can lead to sleep disturbances of child and parents. Other features may arise . Perifollicular accentuation and papules are commonly seen at any point in the life of an atopic patient, particularly in persons of Asian or African ancestry.

During childhood, the clinical features evolve into those seen in adults. Lesions tend to become less eczematous and drier, with increasing flexural and neck involvement. Scaling, fissured, and crusted hands may become especially troublesome. Infraorbital folds (sometimes called Morgan's lines or Dennie's sign) and pityriasis alba can appear. Chronic or chronically relapsing pruritic, erythematous, papulovesicular eruptions that progress to scaling, lichenified dermatitis in a flexural distribution typify adult AD. Extensive areas of skin may be involved, including the face, chest, neck, flanks, and hands. Areas of dyspigmentation may result from repeated skin trauma. Approximately 10% to 15% of childhood AD persists after puberty.

There are many associated features of AD. Asthma and allergic rhinitis, the major and minor criteria, respectively, have already been mentioned. Another important association, cutaneous infection, is related to diminished cutaneous cell-mediated immunity and defective chemotaxis. S. aureus is usually found on AD skin, and its density correlates with lesion severity. Although such observations have implicated S. aureus as a cause of AD, it is also clear that reduction in AD lesions reduces bacterial colonization. Regardless, the high bacterial counts in lesional skin and the relative ease of their reduction suggest the desirability of extra efforts (e.g., use of topical steroids) to reduce the presence of S. aureus before elective procedures are performed through involved skin. Frank infection also occurs more commonly in AD, which results in pustules and oozing, crusted lesions.

Cutaneous fungal and viral infections also occur frequently and with increased severity in patients with AD. Eczema herpeticum, an extensive eruption of 2 to 3 mm vesicles, pustules, and punched-out erosions caused by herpes simplex virus, may coalesce into extensive areas of eroded skin. Frequently, the condition is most severe on the face (where it often arises from a herpetic lesion) and diminishes as it progresses to the trunk and extremities. Secondary bacterial infection is common. Lymphadenopathy, fever, and malaise may develop. Antiviral and antibiotic therapy can be lifesaving and should be started empirically upon presentation. Tzanck test, viral culture, and direct fluorescent antibody detection of viral antigens can confirm the diagnosis.

Molluscum contagiosum and common warts are also problematic in patients with AD, as are dermatophyte infections. Because of similar appearance, foot eczema must be distinguished from tinea pedis by potassium hydroxide preparation or fungal culture.

Numerous ocular complications of AD exist. These include anterior subcapsular cataracts, retinal detachment, keratoconus, blepharitis, conjunctivitis, and iritis.

The differential diagnosis of AD includes the eczematous conditions and ichthyoses described in this subsection and other immunologic, metabolic, neoplastic, and rheumatologic disorders . Because 80% to 85% of patients with occupational hand dermatitis have AD, the possibility of coexisting AD and contact dermatitis needs to be considered. Another important element of the differential diagnosis is cutaneous T cell lymphoma. Cutaneous T cell lymphoma can arise clinically as scaling, ery-thematous patches or exfoliative erythroderma. The classic distribution-near axillae, buttocks, and groin-is distinct from that of AD, and patches are frequently well demarcated. There is often sufficient clinical overlap between the two conditions, however, to necessitate further investigation, including histology, immunophenotyping, and gene rearrangement analysis of T cell receptors. Cutaneous T cell lymphoma can arise in patients with AD, and the lack of conclusive clinical or laboratory tests for either disease can make distinction difficult. Reassessment from time to time in such cases is recommended.

Reduction of trigger factors (e.g., harsh chemicals, detergents, and wool) and avoidance of occupations that require contact with trigger factors (e.g., hairdressing, nursing, and construction) can be helpful. Appropriate behaviors should be taught to patients and parents early during life, when habits are more easily formed.

The use of mild, nonalkali soaps and frequent use of emollients are important elements in the long-term management of AD. Because moisture evaporating off the skin can trigger flares, bathing is sometimes discouraged. A better approach is the prompt application of an emollient such as petrolatum (finishing within 3 minutes of the end of the bath), which can serve to seal the moisture from the bath. Lotions and creams containing high amounts of water are usually inadequate, however, and can actually worsen AD. Products containing hydroxy acids, phenol, or urea can reduce dryness and scaling, but these can sting inflamed skin and should therefore be used with caution. Bubble baths and scented salts and oils can be irritating. Scalp care should include a bland shampoo. Topical tar products, such as shampoos and bath solutions, and topical creams and lotions containing 5% to 10% liquor carbonis detergens can help. Baths, soaks, and compresses with Burow's solution can ameliorate crusted, infected, eczematous patches. Cotton clothing, washed to remove finishing (which often releases formaldehyde), is preferable to wool or synthetics.

Topical corticosteroids are another mainstay of therapy. Application immediately after bathing improves cutaneous penetration. Lowering the risk of side effects with less potent preparations must be balanced against gaining control of a flare quickly with more potent preparations. Long-term use of inadequately potent topical corticosteroids may pose a greater risk of adverse effects than brief use of more potent agents followed by a rapid taper to bland emollients. Because steroid-induced cutaneous atrophy is a greater risk on the face, in intertriginous areas (e.g., groin, axillae, and inframammary folds), and under diapers, less potent steroids (e.g., hydrocortisone and desonide) should be used in these areas, and they should be used with particular caution. For the remainder of the body, midpotency preparations such as 0.1% triamcinolone acetonide are helpful. More potent ointments, such as fluocinonide and desoximetasone, are useful for lichenified plaques. Flurandrenolide tape is useful for nodular prurigo (so-called picker's nodules) because it also physically protects the area from manipulation. For the scalp, solutions are preferred.

Systemic corticosteroids (e.g., prednisone, 20 to 80 mg/day orally) may be useful to treat severe, acute flares. Because of the risks of gastrointestinal, endocrine, skeletal, central nervous system, and cardiovascular complications, however, they should not be used more than twice yearly.

Antihistamines can sometimes be helpful in breaking the itch-scratch cycle in AD. Sedating antihistamines, such as hydroxyzine and diphenhydramine, are particularly useful-especially when itching prevents sleep. Nonsedating antihistamines are less useful. Doxepin, a tricyclic antidepressant known to have antihistaminic effects, can be beneficial when applied topically in a 5% cream.

Virtually every phototherapy regimen has been reported to ameliorate AD. Some patients cannot tolerate the heat generated by the equipment, however-particularly that used in UVB irradiation. In addition to UVB, the following can be beneficial: UVA, longwave UVA1, narrow-band UVB, UVA-UVB, and PUVA. Extracorporeal photochemotherapy (photopheresis) is also emerging as an effective therapy for recalcitrant disease. Although some patients may benefit from natural sunlight, the risk of sunburn and induction of malignancy by ultraviolet light must be considered.

Antimicrobials are obviously important for patients with infection. Less clear is whether antimicrobial agents can directly treat AD by reducing bacterial products thought to exacerbate the condition. Antistaphylococcal therapy has been advocated for use in patients with AD; however, a doudble-blind, placebo-controlled study of flucloxacillin did not show improvement in AD despite reduced bacterial counts. Ketoconazole, likewise, has been used; its success, however, may be due to anti-inflammatory, rather than antifungal, effects.

More advanced therapeutic options exist for severe, recalcitrant AD. The altered expression of cytokines in AD [see Etiology and Pathogenesis, above] has led investigators to explore the use of interferon gamma. Clinical trials have demonstrated that for some patients, daily subcutaneous administration of interferon gamma is effective in reducing both signs and symptoms of AD and that long-term treatment can maintain the benefit.

Oral cyclosporine (2.5 to 5 mg/kg/day orally), methotrexate (15 to 25 mg/wk orally), and azathioprine (100 to 200 mg/day orally) can be used in severe, recalcitrant disease provided that patients are monitored for adverse effects specific to those agents.

Traditional Chinese herbal medicine has been found to be effective in the treatment of AD, both in children and in adults. The mechanisms of action of these preparations are unclear. Patients should be cautioned that herbal remedies are not risk-free and may carry a potential for hepatotoxicity, cardiomyopathy, and other adverse effects; such remedies should be monitored as should any other treatment.

Although evening primrose oil has for many years been proposed to be effective in AD, a well-controlled study failed to show any benefit to patients taking either evening primrose oil or a combination of evening primrose oil and fish oil compared to those receiving placebo. The importance of well-controlled studies to assess efficacy of treatments must be stressed because AD patients on the placebo arms of most controlled studies tend to show benefit from the placebo.

Promising therapies in clinical trials include the topical macrolides ascomycin and tacrolimus (FK506) and the cAMP phosphodiesterase inhibitor CP80633. These new agents, which are based on the emerging pathogenic concepts of altered cytokine production and cyclic nucleotide regulation (see above), may prove to reduce pruritus and dermatitis effectively without producing unacceptable side effects.

Food allergy or hypersensitivity results from an IgE-mediated reaction to a food or food additive. Gastrointestinal mast cells coated with IgE specific for a food antigen degranulate and release mediators; these mediators induce local changes in vasopermeability, stimulate mucus production, increase muscle contraction, stimulate pain fibers, and recruit inflammatory cells.

Shellfish, nuts, peanuts, eggs, and dairy products are the foods that most commonly cause severe anaphylaxis; peanuts are the most frequent cause of fatal anaphylaxis. An allergy to peanuts is not outgrown. Persons who are allergic to peanuts should be made aware that this food is often a hidden additive in cookies, pastries, egg rolls, chili, cooking oil, and candy.

The clinical expression of food allergy is influenced by the age of the patient, the quality and quantity of food ingested, and the type and extent of associated medical problems. Edema and pruritus of the lips, oral mucosa, and pharynx occur when the food comes in contact with the oropharynx. Such reactions are transient and are not necessarily followed by other symptoms. Entry of the offending food into the stomach and intestine may result in nausea, cramping pain, abdominal distention, vomiting, flatulence, and diarrhea. Food allergy can also be expressed as urticaria, angioedema, asthma, and rhinoconjunctivitis. Systemic anaphylaxis can occur within minutes but occasionally may take hours to manifest.

Symptoms generally develop within minutes to 2 hours after ingesting the food allergen. A food suspected of being an allergen may fail to consistently cause allergic reactions because of variability in the amount consumed; the simultaneous ingestion of other foods, which may delay digestion; and the manner in which the food is prepared. For instance, although the ingestion of fresh fruits or vegetables may be associated with pruritus and angioedema of the lips, tongue, palate, and throat, the ingestion of cooked varieties of the same fruits or vegetables often produces no noxious symptoms. Similarly, if the skin of an offending fruit or vegetable is removed before it is eaten, allergic symptoms may not occur.

The diagnosis of IgE-mediated food allergy is established by the clinical history, results of selective immediate hypersensitivity skin testing or RAST, complete elimination of the suspected food allergen from the diet for 2 weeks to determine whether symptoms resolve, and double-blind, placebo-controlled food challenges.

IgE to specific food groups can be demonstrated by skin tests or RAST. False positive skin tests occur, but false negative tests are unlikely if the tests are performed correctly. Thus, the best use of skin testing appears to be to support a clinical impression that one or more foods are capable of causing IgE-mediated reactions in a given person.

Using an elimination diet is helpful if it is not clear whether ingestion of a specific food causes the symptoms. The likelihood of establishing a diagnosis by use of elimination diets is greater when fewer foods are responsible for the symptoms. Offending foods that are identified in this way should be eliminated from the diet permanently. If removal of one or several foods from the diet does not eliminate symptoms, initiation of a severely limited diet is warranted. Extensive elimination diets should include lamb and rice because these foods seldom cause allergic reactions. Failure of such a diet to eliminate symptoms indicates that the symptoms are not caused by food.

If the correlation between specific foods and symptoms remains unclear, oral challenge with a suspected food may be used for diagnosis; however, oral challenge should be avoided when the suspected food is associated with a history of anaphylaxis. Furthermore, no food challenge is without risk of side effects, and the patient must be made aware of this fact. Such procedures should be done only under the supervision of an allergist.

It is important to distinguish IgE-mediated food allergy from other food reactions.

Treatment is primarily preventive. Breast-feeding should be encouraged because it prevents early exposure of the immature gastrointestinal system of an infant to foreign milk and soy proteins. There is as yet no evidence that immunotherapy or oral desensitization is beneficial. A long-term elimination diet must be designed to provide optimal nutrition while completely eliminating the offending foods. Such diets should be designed in conjunction with a nutritionist. The development of gastrointestinal symptoms after inadvertent food ingestion is usually treated with antihistamines. Patients with a history of anaphylaxis after ingestion of certain foods should be provided with a syringe of epinephrine so they can self-administer the drug in an emergency; these patients should also have antihistamines available at all times. An identification tag that states the patient's food sensitivity is also recommended.

Insects of the order Hymenoptera (i.e., those with true stingers) are the insects that are most relevant to allergists. Hymenopterans whose stings cause allergic reactions include the honeybee; certain members of the Vespidae family, or social wasps, including the yellow jacket, the white-faced hornet, the yellow hornet, and the Polistes wasp; and fire ants of the genus Solenopsis.

The stinging apparatus, consisting of a sac containing venom attached to a barbed stinger, originates in the abdomen of the female insect. Because the honeybee's stinger has multiple barbs, it remains rooted in the victim of a sting, and the stinging apparatus detaches from the insect, causing self-evisceration and death. In contrast, the stingers of the vespids have few barbs, enabling these insects to inflict multiple sequential stings. The fire ant attaches itself to its victim by biting with its jaws; it then pivots around its head and stings at multiple circumferential sites, and within 24 hours, diagnostic sterile pustules develop at the sting sites.

The major allergenic constituents of hymenopteran venom are proteins with enzymatic activity. Honeybee venom contains phospholipase A₂, hyaluronidase, a high-molecular-weight substance with acid phosphatase activity, and melittin. The allergens in vespid venom are phospholipase, hyaluronidase, and a protein named antigen 5. Although phospholipase and hyaluronidase have enzymatic activity in both bee and vespid venoms, there is little or no immunologic cross-reactivity between the allergens of the vespids and those of the bees. In addition to containing enzymes, the venoms of hymenopterans contain vasoactive amines and peptides that facilitate venom absorption.

Localized reactions usually follow insect stings, but anaphylaxis may occur in persons who are sensitized. The frequency of sting reactions is similar in atopic and nonatopic persons. The prevalence of sensitivity to the venoms of hymenopterans in the general population, as gauged by a positive skin-test result or by the demonstration of venom-specific IgE antibody in a person's serum, is 20% to 25%. However, among this large group of sensitive people, only 3.3% have a history of systemic reactions. Only 20% of patients who have both a positive skin-test result and no history of systemic reaction wil l experience a systemic reaction when they are stung by one of these insects.

Unlike stinging insects, biting insects seldom cause clinically significant allergic reactions. Biting insects, such as mosquitoes, deposit salivary gland secretions that have no relation to venom allergens and that generally do not evoke an IgE antibody-mediated immune response. Exceptions are the bites of the deerfly, kissing bug, and bedbug, which can cause anaphylactic reactions. Other venomous bites and stings and their treatment are discussed elsewhere .

The usual nonimmunologic, or so-called normal, reaction after a hymenopteran sting is localized pain, erythema, and edema. This reaction responds well to analgesics and cold compresses and usually resolves in several hours.

More extensive local reactions are not uncommon. A large area of erythema and swelling may result from release of mast cell mediators via IgE-mediated or nonimmunologic mechanisms. These large local reactions are often confused with infectious cellulitis. In fact, infection seldom develops at the site of an insect sting. The presence of complicating infection would be suggested by ascending lymphangitis and regional lymphadenopathy. Large local reactions are best treated with analgesics, H₁-blocking antihistamines, and, if the swelling is extensive and debilitating, a short course of a systemic corticosteroid. Persons who have had a large local reaction to an insect sting typically have similar reactions to subsequent stings. With subsequent stings, the risk of anaphylaxis is less than 5% per episode. Because these persons are not candidates for venom immunotherapy (see below), they do not require immediate hypersensitivity skin testing or in vitro evaluation with RAST.

If a nonsensitized person sustains multiple (20 to 50) simultaneous stings and thereby receives a large dose of allergens and vasoactive substances, a toxic systemic reaction that is dominated by hypotension and that has the appearance of an anaphylactic reaction may occur. Because exposure to large amounts of insect venom frequently stimulates the production of venom-specific IgE antibodies, persons who sustain multiple stings may have positive results to venom on skin testing. In such circumstances, these persons are at risk for allergic reactions to a subsequent single sting.

Unusual delayed-onset reactions, including vasculitis, neuritis, encephalitis, nephritis, and serum sickness, can be temporally associated with insect stings. ^62, ⁶⁸ Because of the induction of venom-specific IgE antibodies, after subsequent insect stings patients in whom venom-induced serum sickness develops may be at risk for anaphylaxis.

The most dramatic reaction to an insect sting is anaphylaxis. Only one third of persons who have had a systemic allergic reaction to the sting of a hymenopteran have a history of atopic disease. The clinical symptoms of insect venom-induced anaphylaxis range from isolated dermal reactions, which are characterized by flushing, generalized urticaria, and angioedema, to more serious sequelae, such as circulatory collapse, upper airway angioedema with obstruction, bronchospasm, arrhythmias, and gastrointestinal distress with vomiting, diarrhea, cramping abdominal pain, or a combination of these symptoms. In older persons with atherosclerotic disease, ischemic injury to susceptible organs may cause misleading presentations, such as myocardial infarction or cerebrovascular accident. In most patients, anaphylactic symptoms occur within 20 minutes after being stung. In general, the sooner the symptoms occur, the more severe the reaction. Severe anaphylaxis can occur at any age, but most deaths occur in adults.

Only 50% to 60% of people who have previously had stinging-insect-induced systemic reactions, positive results to venom on skin testing, and no venom immunotherapy have anaphylaxis after subsequent stings. Almost all patients who have had a large local reaction to an initial sting have similar reactions to subsequent stings. As a rule, the rate of severe systemic allergic reactions to subsequent stings is lower in children than in adults. In children who have only a systemic dermal reaction (flushing, urticaria, angioedema, or a combination of these symptoms), the risk of systemic reactions to subsequent stings is low. If reactions do occur, they tend to be mild and confined to the skin. On the other hand, patients of all ages who have severe or life-threatening anaphylactic symptoms after an initial sting are likely to have a similarly severe response after subsequent stings.

Stinging-insect allergy is diagnosed on the basis of documentation of a sting, the presence of an in situ barbed stinger, and a positive skin test to venom.

The diagnostic method of choice is skin testing with protein extracts of purified hymenopteran venom. The whole body extract of the insect contains little or no venom and does not distinguish allergic from nonallergic persons. Five venoms are available for clinical use: honeybee, yellow jacket, yellow hornet, white-faced hornet, and Polistes wasp. Because sting reactions may have occurred to only one insect type despite previous sensitization to others, skin testing should always be performed with a complete set of venoms and a diluent-negative control. Venom from the responsible insect will cause the most intense skin reaction. Almost all patients with a well-documented sting have clearly positive skin tests. If tests are properly performed, false positive results are exceedingly rare. Skin tests may be negative if months have passed since the sting occurred; this finding is thought to indicate a loss of sensitivity.

In vitro demonstration of venom-specific IgE antibody, as determined by RAST, is less sensitive and less specific than skin testing. About 15% to 20% of patients with positive venom tests have negative results on RAST. RAST should be performed, however, if the results of skin testing are equivocal or negative but the history strongly suggests an insect sting.

To minimize exposure to the stings of hymenopterans, persons who are at risk for stinging-insect-induced allergic reactions should wear gloves when gardening and shoes and long pants when walking through grass or fields. Because white and pastel colors, cosmetics, perfumes, and hair sprays all attract these insects, dark or drab-colored clothes are preferable, and the use of scented toiletries should be avoided. Food and odors also attract hymenopterans, particularly yellow jackets. All persons who are at risk for systemic sting reactions should carry, as well as understand the proper use of, a kit containing diphenhydramine tablets and a syringe of epinephrine solution.

Treatment of acute insect-sting reactions varies with the clinical manifestations. Large local reactions can be suppressed by the application of cold compresses and by oral antihistamines (e.g., diphenhydramine, 50 mg every 4 hours, either orally or intramuscularly). A brief course of oral corticosteroids (e.g., oral prednisone, 40 to 60 mg/day for 3 or 4 days) may be beneficial for massive reactions or for local reactions that involve the head, face, and neck. Antihistamines are adequate for generalized cutaneous reactions but are ineffective against progressive anaphylaxis. All patients with systemic reactions must be observed for about 4 hours, and treatment similar to that recommended for anaphylaxis should be instituted .

Because avoiding exposure to stinging insects is usually not practical, persons at risk for systemic sting reactions, such as those who have had sustained upper airway edema, respiratory distress, cardiovascular compromise, or serum sickness as a result of a hymenopteran sting, should undergo venom immunotherapy. Patients who have had only large local or generalized dermal reactions, negative results on skin testing and RAST after sting anaphylaxis, or positive results on skin testing after uneventful stings are not candidates for venom immunotherapy. Fewer than 3% of those immunized exhibit symptoms after a challenge sting; reactions that do occur are usually less severe than those in unprotected persons.

Immunotherapy with the appropriate venom is administered weekly until a maintenance level is reached (a 100 mg dose, which is equivalent to the venom contained in two stings). Venom immunotherapy should be continued for at least 5 years or until the skin test or RAST becomes negative. Whole body extract of the hymenopteran is not effective and should not be used.

Urticaria is characterized by pruritic red wheals of varying sizes that can occur with any medication. When deep dermal and subcutaneous tissues are also swollen, the reaction is known as angioedema.

Urticaria and angioedema usually result from a type I immediate hypersensitivity reaction. This mechanism is typified by immediate reactions to penicillin and other antibiotics. Binding of the drug or its metabolite to IgE bound to the surfaces of cutaneous mast cells leads to activation, degranulation, and release of such vasoactive mediators as histamine, leukotrienes, and prostaglandins.

Urticarial reactions may also result from nonimmunologic activation of inflammatory mediators. Drugs such as acetylsalicylic acid and nonsteroidal anti-inflammatory drugs (NSAIDs), radiocontrast media, and narcotic analgesics may directly cause release of histamine from mast cells, independently of IgE. Angiotensin-converting enzyme (ACE) inhibitors are frequent causes of angioedema. The mechanism of this reaction is unclear but may relate to accumulation of bradykinin or activation of the complement system.

Although medications tend to cause urticaria, angioedema, or both, other causal agents are food, physical factors (e.g., dermatographism and cholinergic urticaria), and idiopathic factors. Certain foods containing proteins that can cross-react with latex proteins, such as bananas, kiwifruit, avocados, and chestnuts, can cause oral itching and swelling, hives, or wheezing after ingestion. People at greatest risk of developing latex allergy include children with spina bifida and health care workers. Latex allergy can manifest as contact urticaria at sites of latex exposure, such as lip swelling in a person who has blown up a balloon or sucked on a pacifier. Contact with aerosolized powder from latex gloves to which the latex protein can adhere may cause mucosal symptoms, such as itchy, swollen eyes, runny nose, sneezing, or wheezing. Anaphylaxis may also occur.

Signs and symptoms of IgE-mediated allergic reactions are typically pruritus, urticaria, cutaneous flushing, angioedema, nausea, vomiting, diarrhea, abdominal pain, nasal congestion, rhinorrhea, laryngeal edema, and bronchospasm or hypotension or both. Fever is not associated with urticaria or angioedema reactions. In general, individual lesions of urticaria last for less than 24 hours, although new lesions can continually develop. With ACE-inhibitor therapy, the onset of the adverse reaction is usually within hours but can occur as late as 1 week to several months into therapy. With treatment, the resulting angioedema usually resolves within 48 hours.

Skin testing may be helpful in cases of IgE-mediated urticaria. For example, penicillin skin testing with the major and minor determinants identifies approximately 99% of patients who have had an IgE-mediated reaction to penicillin. A latex skin test is a sensitive indicator of IgE sensitization. For large-molecular-weight agents, such as insulin, protamine, and egg-containing vaccines, positive immediate skin-test reactions identify patients at risk for IgE-mediated reactions.

Withdrawal of the causative agent is recommended. When angioedema or anaphylaxis occurs, immediate therapy with epinephrine and systemic steroids may be needed. Symptomatic relief can generally be achieved with antihistamines (H₁ receptor blockers).

Allergic reactions to drugs constitute only 6% of adverse drug reactions; such reactions occur even when only small doses of the drug are administered. Drug allergy must be distinguished from drug intolerance, an undesirable pharmacologic effect that may occur at low concentrations, and from idiosyncratic reactions, which result from biochemical alterations in the metabolism of a drug. An idiosyncratic reaction is independent of the dose, does not require previous exposure, and is not a pharmacologic effect of the drug.

The b-lactam family of antibiotics, most notably penicillin and penicillin derivatives, accounts for most allergic reactions to drugs and 97% of the deaths caused each year by anaphylactic drug reactions . Between 1% and 5% of patients who receive penicillin have an allergic reaction. Other agents that can cause allergic reactions include sulfa-containing antibiotics, streptomycin, aspirin, local anesthetics, opiates, hormones, heparin, protamine, streptokinase, radiocontrast media, diagnostic reagents such as sulfobromophthalein and Congo red, dehydrocholic acid, dextran, vitamins, tetracycline, and organic iodine.

One of the most common clinical manifestations of drug allergy is the development of a mild systemic illness, similar to serum sickness, that is characterized by urticarial eruptions, arthralgias or arthritis, lymphadenopathy, and fever. These symptoms begin 6 to 12 days after the administration of a drug and may take several days to a week to subside after cessation of the drug. Drug-induced fever can occur alone or in combination with the symptoms described and usually develops during the second week of treatment.

Generalized anaphylaxis is a serious and sometimes fatal manifestation of drug allergy that must be dealt with promptly. Symptoms usually appear minutes after injection of the offending drug, although oral administration can occasionally produce this reaction. Initial symptoms are generalized pruritus associated with skin hyperemia, angioedema, laryngeal edema, and swelling of the eyelids. These manifestations may be followed by a decrease in the plasma volume, which results in hypotension, vascular collapse, and shock.

One or more of the following observations suggest an allergic drug reaction: the reaction does not correspond to the known pharmacologic action of the drug; it can be elicited by minute doses of the drug; it usually occurs days after the initial administration of the drug; it includes symptoms that are generally associated with allergy; it reappears on challenge with the drug, with progressive shortening of the latency period before symptoms appear; and similar reactions are observed with structurally similar drugs. The detection of IgE directed against a suspected drug is useful in establishing an immunologic basis for the symptoms; the presence of antibodies of other classes that react with the drug or a cell-mediated immune response does not necessarily correlate with symptoms.

Although many in vitro assays can detect sensitivity to a drug, none are clinically reliable. In contrast, skin tests for specific drugs such as penicillin and its derivatives have diagnostic and predictive value. The reagents for the penicillin skin test include penicilloyl polylysine, which is a synthetic penicillin derivative that is used to measure sensitivity to the major antigenic determinant, and modified forms of benzyl penicillin G, which can help identify sensitivity to minor antigenic determinants. Patients with a positive skin test are at risk for an immediate hypersensitivity reaction to penicillin; those with a negative skin test are unlikely to have a serious immediate hypersensitivity reaction. Skin testing for most other drugs is unreliable because correlation between a positive test and clinical conditions is lacking.

If a drug is suspected of causing a drug allergy, administration should be stopped. Symptoms should subside within 1 or 2 days, although they may take a week to disappear. In severe cases, the drug may be eliminated faster by the administration of large amounts of fluids, diuretics, or laxatives. If anaphylaxis is present, treatment should be instituted immediately (see below). Corticosteroids have been useful for Arthus-type reactions, such as serum sickness and polyarteritis, as well as for manifestations of delayed hypersensitivity (e.g., maculopapular rash). Large daily doses of prednisone (40 to 60 mg) can be administered for several days and then stopped without the dose being tapered. If a drug that has caused an allergic reaction must be used, the patient can be desensitized first; the drug can then be safely administered. Intravenous or oral desensitization should be carried out only by qualified personnel in a hospital, where immediate treatment can be instituted if a reaction should occur.

Systemic anaphylaxis (the word means "the opposite of protection," from the Greek ana, meaning back, and phylaxis, meaning protection), the quintessential manifestation of IgE antibody-mediated immediate hypersensitivity, is an acute generalized somatic reaction. The first report of anaphylaxis, recorded in hieroglyphics in 2640 B.C., described the sudden death of an Egyptian pharaoh after a wasp sting. The cutaneous, respiratory, cardiovascular, and gastrointestinal systems are most commonly involved, probably in large part because these organs have a high density of mast cells. Clinical reactions vary widely in severity, ranging from mild pruritus and urticaria to vascular collapse and death. An increasing number of substances, including proteins, polysaccharides, and haptens, have been found to be capable of causing anaphylaxis.

Three pathways by which exposure to a foreign substance can lead to an anaphylactic response are known. In the first, the exposure of a susceptible person to a foreign substance results in the generation of IgE antibodies, which bind avidly to high-affinity receptors on mast cells and basophils. On subsequent reexposure to the allergen, the binding of antigen to cell-bound, homocytotropic specific IgE results in noncytotoxic cellular degranulation and the release of a variety of preformed and newly generated vasoactive and inflammatory mediators. In the second pathway, immune complexes or other agents activate the complement cascade, thereby generating anaphylatoxins (the complement protein fragments C3a and C5a) that, in turn, trigger the release of mast cell and basophil mediators. The third mechanism involves the IgE antibody-independent and complement-independent release of mast cell and basophil mediators induced by certain agents (e.g., opiates, mannitol, radiocontrast media, and NSAIDs) and by physical exercise. When IgE antibody is not part of the pathogenesis of anaphylaxis, the response is often defined as an anaphylactoid reaction. The signs, symptoms, and clinical import of anaphylactoid reactions are no different from those of IgE antibody-mediated anaphylaxis.

After exposure to an offending agent, the symptoms of anaphylaxis can begin within seconds or can take as long as 1 hour to appear; in severe reactions, symptoms usually occur within 5 to 10 minutes. Simultaneous involvement of multiple organ systems is typical. Initial manifestations are variable but include one or more of the following signs and symptoms: skin erythema, pruritus, generalized flushing, a sense of impending doom, nausea, vomiting, crampy abdominal pain, light-headedness, shortness of breath, and a lump in the throat. An urticarial rash is the most common manifestation of anaphylaxis; it usually lasts less than 24 hours. Angioedema of the skin can also occur, either alone or in combination with urticaria. The respiratory tract is involved in 70% of cases of fatal anaphylaxis. The early stages of upper airway edema are accompanied by hoarseness and stridor. Angioedema of the epiglottis and larynx can cause mechanical obstruction and, ultimately, death by suffocation. The patient may experience shortness of breath, chest tightening, and wheezing. Primary vascular collapse occurs in about 24% of cases of fatal anaphylaxis and is frequently associated with acute myocardial ischemia and ventricular arrhythmias. Gastrointestinal manifestations can include nausea, vomiting, abdominal pain, tenesmus, and diarrhea. Uterine cramping may also occur.

Because of the dramatic nature of a systemic anaphylactic reaction, the diagnosis is usually obvious. When only a few symptoms are present, however, it is difficult to exclude vascular, cardiac, or neurologic conditions. Conditions to consider in the differential diagnosis include pulmonary embolism, acute myocardial infarction, cardiac arrhythmia, foreign-body aspiration, acute asthma, hereditary angioedema, seizure disorder, and vasovagal reaction. Sometimes, it is not possible to clinically differentiate between an IgE-mediated reaction and a nonimmunologic, toxic, or idiosyncratic reaction.

As is true for all allergic conditions, avoidance of the offending allergen and institution of appropriate preventive measures for persons at high risk are the mainstays of therapy. Despite attempts to prevent or anticipate such reactions, serious, usually unexpected, anaphylactic (or anaphylactoid) reactions may occur. As part of the general approach to the patient with anaphylaxis, there should be a rapid assessment of the history, extent, and severity of the reaction; discontinuance or limitation of the absorption of the offending agent; close monitoring of clinical cardiopulmonary parameters; and maintenance of adequate airway and peripheral tissue perfusion.

Epinephrine is the drug of choice for the treatment of systemic anaphylaxis because of its ability to inhibit the release of mast cell and basophil mediators and to counteract mediator-induced vasodilatation and bronchoconstriction . Epinephrine is administered subcutaneously as a 0.3 to 0.5 ml injection of a 1:1,000 dilution (0.3 to 0.5 mg); this dose is repeated every 10 to 20 minutes as needed. In the setting of severe hypotension, epinephrine is administered intravenously as a continuous drip (1 ml of a 1:1,000 dilution in 500 ml of 5% dextrose in water at a rate of 0.5 to 5.0 mg/min [0.25 to 2.5 ml/min]). Other secondary pharmacologic measures include both an H₁ receptor blocker (diphenhydramine, 50 mg intravenously, intramuscularly, or orally) and an H₂ receptor blocker (cimetidine, 300 mg intravenously or orally) and corticosteroids (methylprednisolone, 50 mg intravenously). For persistent bronchospasm, an inhaled beta-adrenergic agonist bronchodilator and aminophylline may be added to the regimen. Supplemental oxygen is administered for the treatment of hypoxemia. Intubation or tracheostomy may be necessary. Hypotension requires the administration of intravenous normal saline (1 L every 20 to 30 minutes) and often dopamine, 5 to 20 mg/kg/min, or norepinephrine, 2 to 12 mg/min.

Radiocontrast media can cause mild to severe anaphylactoid reactions by a nonimmunologically mediated release of mast cell and basophil mediators. The use of radiocontrast agents with relatively low osmolality has reduced the incidence of these reactions to less than 1%. Fatal reactions occur once in every 20,000 procedures. On reexposure, there is a 15% to 35% risk of reaction recurrence. If a repeat radiocontrast study must be performed in such a patient, the use of low-osmolality dye and pretreatment with prednisone (50 mg 13 hours, 7 hours, and 1 hour before the procedure) plus diphenhydramine (50 mg intramuscularly 1 hour before the procedure) is recommended.

Products that contain processed natural rubber latex, such as rubber gloves, condoms, catheters, dental dams, balloons, and sporting equipment, can induce T cell-mediated allergic responses, IgE antibody-mediated allergic responses, or both. The clinical manifestations of T cell-mediated latex allergy include local erythema, edema, and eczema, which occur 4 to 48 hours after contact with the allergen. The signs and symptoms of IgE-mediated sensitivity to natural rubber latex are an itchy rash, wheezing, tachycardia, abdominal pain, and diarrhea. They generally occur within minutes after exposure.

Natural latex, a milky sap collected by tapping the commercially cultivated tree Hevea brasiliensis, contains the rubber precursor molecule, cis-1,4-polyisoprene, and a variety of lipids, carbohydrates, and proteins. The protein component that attaches to the polyisoprene matrix contains the allergens that are capable of inducing IgE antibodies. After chemical additives prevent coagulation, latex is separated into liquid and solid phases. In the next processing stage, compounding, various chemical accelerators and antidegradants are added; these chemicals induce T cell-mediated immune responses. Accelerators such as thiurams, carbamates, and mercaptobenzothiazoles control the rate and completeness of the vulcanization, the heat-catalyzed cross-linking of isoprene units in the presence of sulfur. In the manufacture of latex gloves, the heat applied during vulcanization solubilizes residual protein, which then migrates to the surface of the gloves, where it comes in contact with the wearer's hands. Although the cornstarch powder used as a donning lubricant can absorb allergens, the cornstarch itself is not a sensitizer.

Exposure to latex allergen can occur by cutaneous, percutaneous, mucosal, and parenteral routes; direct mucosal or parenteral exposure poses the greatest risk of anaphylaxis. Usually, latex allergy occurs in health care workers, workers in the rubber industry, and children with meningomyelocele (spina bifida) and urogenital abnormalities. The prevalence of IgE-mediated latex allergy in the general population is unknown; however, the risk appears to be higher in atopic persons than in nonatopic persons. Although the natural history of latex allergy remains to be completely defined, health care workers with this sensitivity tend to have occupational symptoms that progress from initial cutaneous reactions to more widespread organ system involvement and anaphylaxis.

Questions about latex allergy should become a routine part of the history taking for all patients with allergic disease. If a patient's history supports a reasonable suspicion that latex allergy is present, confirmatory testing is available. The presence of T cell-mediated sensitivity can be confirmed by performing patch testing with a standard battery of rubber accelerators and antidegradants. IgE-mediated latex sensitivity can be confirmed in vitro by RAST or in vivo by epicutaneous hypersensitivity testing. Although both testing modalities are nearly 100% specific, RAST sensitivity depends on the patient being tested and the reagent used.

Optimal treatment consists of complete avoidance of the allergen and intensive patient education about the potential sources of exposure. Persons in high-risk groups should be identified and offered diagnostic testing, especially before they undergo medical or dental procedures. Latex exposure should be avoided altogether by spina bifida patients because they are at very high risk for the development of latex allergy. Patients who have experienced an IgE-mediated latex reaction should wear a Medic Alert bracelet.

Health care institutions should provide nonlatex devices, including gloves, and latex-free areas for persons with latex allergy. In addition, the use of powder-free and latex-free gloves should be encouraged to reduce aeroallergen levels and the likelihood of sensitization. Washing, heat treatment, chlorination, and enzyme digestion to remove sensitizing allergens from the manufacturing process is also recommended.

The latter half of this century has seen the emergence of a puzzling illness of ostensible allergy or sensitivity to almost all organic and synthetic chemicals; this illness is called multiple chemical sensitivity syndrome (also called environmental illness, clinical ecological illness, total allergy syndrome, and chemical AIDS). Patients with this disorder are typically previously healthy persons who seek medical attention either because of upper respiratory symptoms or ill-defined CNS dysfunction related to living or working in a tightly sealed building served by a closed system of ventilation or because of similar symptomatology after accidental exposure to an established toxin. Despite removing themselves from the offending environment or avoiding the offending toxin, these patients have symptoms that recur, intensify, and generalize over time to involve virtually all organ systems.

The most prominent symptoms of multiple chemical sensitivity syndrome are, typically, systemic, cardiorespiratory, neuropsychological, and gastrointestinal. Although symptoms are initially caused by a single or limited number of offending substances, they are eventually precipitated by a vast array of chemically unrelated compounds at doses far below those established to cause harmful effects in the general population. In extreme cases, patients become recluses, withdrawing completely from everyday life. Despite patients' voicing of a wide array of subjective complaints, physical examination discloses no abnormalities, and these patients have functionally intact immune systems. As a group, they display no deficiency or excess in their ability to mount appropriate immune responses, and they do not suffer from an excess prevalence of allergic reactions, autoimmune diseases, unusual or opportunistic infections, or cancer. Likewise, there are no data to substantiate an infectious or toxicologic etiology for this malady. A psychiatric foundation for this illness has been proposed, but no unifying psychiatric diagnosis has been suggested.

The mechanism or mechanisms that underlie the pathogenesis of multiple chemical sensitivity syndrome are unknown; in fact, there is much controversy about whether this entity is even an organic disease process. However, there are sufficient numbers of people with clinical manifestations of this disorder to make it necessary for physicians to be able to manage them. A subgroup of practitioners known as clinical ecologists or environmental physicians, armed with untested theories of disease and unvalidated results of diagnostic testing, have provided patients with substance-avoidance strategies that often result in extremes of social isolation and severe dietary restriction. To rid the body of contaminating chemicals and create a properly balanced immune system, the clinical ecologists recommend nutritional supplementation, detoxification programs, anticandidal therapy or desensitizing injections of Candida albicans extract, intradermal or subcutaneous administration of neutralizing doses of the putative offending substances, and periodic administration of intravenous g-globulin. The efficacy of these therapies is unproved. Until a more scientific understanding of this group of patients is obtained, the physician should not focus on specific symptoms, obtain a series of diagnostic tests, or embark on unvalidated therapies; instead, persons who have this illness should be counseled in attaining short-term, modest, workable goals aimed at reducing disability and at reorienting them toward health.