Mitchell H. Grayson MD1
Phillip E. Korenblat MD, FACP2
1Instructor, Department of Medicine, Division of Allergy/Immunology, Washington University School of Medicine
2Professor of Clinical Medicine, Washington University School of Medicine
Mitchell H. Grayson, M.D., is a current recipient of grant/research support and/or member of the speakers' bureaus for Genentech, Merck & Co., Inc., and Novartis.
Phillip E. Korenblat, M.D., F.A.C.P., is a current recipient of grant/research support, a consultant, and/or a member of the speakers' bureaus for the following companies: AstraZeneca, Aventis, Genentech, GlaxoSmithKline, Merck & Co., Inc., Novartis, and Schering.
By definition, allergy is an untoward physiologic event mediated by immune mechanisms, usually involving the interaction of an allergen with the allergic antibody, IgE. Common illnesses mediated in this manner include allergic asthma and rhinitis, Hymenoptera hypersensitivity, and certain other causes of anaphylaxis. In addition, a significant proportion of drug, food, and skin reactions are allergic in origin.
Allergic diseases in general, and asthma in particular, have been increasing in prevalence in high-income societies.1 Although there are undoubtedly many reasons for this increase, one is described in the so-called hygiene hypothesis, which posits that greater exposure to infectious agents (and bacterial endotoxins in particular) early in life reduces the likelihood of subsequent allergy.2 This hypothesis, which requires further proof of causality, acknowledges an etiologic role for both genetic and environmental factors in allergy: a child with a hereditary predisposition to atopy is more likely to develop clinical allergy if raised in a relatively aseptic environment.
In allergic illnesses, the importance of a careful and thorough medical history cannot be overstated. The clinician must dissect the allergic reaction to understand the nature of the event and identify the antigen that was responsible for the reaction. Formal diagnosis of allergy has three elements: characterization of the allergic reaction, correlation with antigen exposure, and demonstration of IgE specific for the suspected allergen. The history is essential for the first two elements, and for practical purposes, the history can sometimes obviate the third element.
The history should begin with a review of the patient's symptoms and their temporal pattern. If the presenting symptoms include wheezing, the clinician should remember the time-honored statement that all that wheezes is not asthma. Furthermore, all that is asthma is not allergy [see 14:XIX Asthma].
The presenting symptoms must match the set of features that characterize the suspected allergic illness. For example, patients with perennial allergic rhinitis typically present with sneezing, rhinorrhea, nasal itching, and nasal congestion. Postnasal drainage is not the only symptom of this disease, so postnasal drainage alone—even with evidence of antigen exposure and the presence of specific IgE antibodies—typically would not support the diagnosis of allergic rhinitis.
A central aspect of the history is to establish a link between the time and site of exposure to the presumed allergen and the development of allergic symptoms. Seasonal allergic events are often so characteristic that the diagnosis can be made solely on the basis of the presenting symptoms and their correlation with environmental exposure to the allergen; laboratory evidence may not be needed for the diagnosis. Similarly, symptoms that develop immediately after exposure to animals or their dander often do not need additional supporting evidence for diagnosis.
In the United States, the presence of airborne pollen may vary both temporally and geographically.3 In general, early spring is characterized by the presence of tree pollen, and late spring is accompanied by grass pollen. Ragweed and other weed pollens are prevalent in the fall, usually until the first hard frost. Mold spores can be found indoors year-round, except possibly in very dry areas. Outdoor mold spores peak during the summer and fall months, and they diminish when snow covers the landscape [see Table 1]
Table 1 Inhaled Aeroallergens That Cause Rhinitis, Conjunctivitis, and Asthma
Illnesses such as asthma or rhinitis that occur on a perennial basis, if allergic, should correlate with environmental exposure to a perennial allergen (e.g., dust mites, indoor mold spores, animal dander, or cockroach antigen). Such exposure most often takes place in the household, but the possibility of exposure to allergens in the workplace should not be forgotten. It should be noted that in some warm climates (e.g., that of the southern United States), the pollen season may be nearly year-round and, thus, may be a cause of perennial symptoms.
Allergic reactions to ingested substances typically include skin eruptions, abdominal discomfort, or respiratory symptoms. Severe and life-endangering reactions involving the cardiovascular or respiratory system, or both, may also occur. The list of ingested substances said to cause allergic reactions is seemingly endless. However, foods (particularly peanuts, tree nuts, shellfish, and seeded fruits) and medications are the most common triggers of this type of allergic reaction [see 6:XVI Food Allergies]. Again, the history is essential to establishing a particular substance as the probable cause of an allergic reaction.
The family history is important. Allergic predisposition is genetically mediated, so patients with allergies often report that family members have similar problems. However, in a patient who has both a personal and a family history of angioedema, the disorder may be inherited but not allergic: hereditary angioedema results from the absence of the C1 esterase inhibitor.
The physical examination of a patient with a suspected allergic illness requires an in-depth focus on the involved organ system or systems. In atopic dermatitis, the skin findings may include patches of lesions that are pruritic, erythematous, papular, scaling, crusting, vesicular, or lichenified—qualities that may occur alone or in combination. Lesions are usually characterized by periodic exacerbations, and it is important to examine these lesions for pyogenic infections.
The distribution of allergic dermatitis lesions varies with the age of the patient. In infants, the dermatitis begins to appear by the sixth to eighth week of life. At this age, the eruptions ordinarily involve the scalp, face (especially the cheeks), ears, and extensor surfaces of the extremities. The trunk, buttocks, and anogenital regions may also be involved. The dermatitis may continue into childhood. Alternatively, allergic dermatitis may first develop at about 2 years of age. Dermatitis in childhood is often found in the antecubital and popliteal fossa, on the neck, and at the flexor and extensor areas of the wrist. In adolescents and adults, the lesions frequently involve the neck and the flexural areas but may occur anywhere on the skin.4
Typical urticarial lesions are pruritic, transient (individual lesions resolve within 24 hours), erythematous, and raised; they comprise a wheal with a surrounding erythematous flare. Urticaria can be confused with skin lesions of vasculitis. The presence of hemorrhage or a lesion that lasts longer than 24 hours should raise the specter of urticarial vasculitis. Skin biopsy may be required to differentiate urticarialike lesions.
The hallmarks of allergic rhinoconjunctivitis are bilateral erythema and edema of the conjunctiva, watery ocular discharge, and, often, mild periorbital edema.5 Allergic shiners (bluish discoloration just below the eye orbits) may be observed. Patients with allergic rhinitis may also have an extra fold in the lower eyelids (Dennie-Morgan lines). On the exterior portion of the nose, a crease may be present as a result of continued upward rubbing of the tip of the nose (the so-called allergic salute). Examination of the nasal cavity often reveals watery secretions and edematous, bluish nasal turbinates that partially occlude the nasal passages [see 6:XII Allergic Rhinitis, Conjunctivitis, and Sinusitis]. Translucent nasal polyps may be observed, but these are not necessarily a hallmark of allergy; they can be seen in both allergic and nonallergic patients.
The chest examination often may reveal no abnormalities. However, a methodical examination is warranted. The clinician should observe specifically for cyanosis and the use of accessory muscles for respiration. In addition, auscultation is indicated for a prolonged expiratory respiratory phase or for inspiratory and expiratory wheezing. If wheezing is present, it is important to confirm that the sounds emanate from the lungs and not the trachea. All too often, extrathoracic obstruction is missed on the physical examination.
Although cardiovascular findings are not commonly associated with allergic diseases, it is important to remember that hypotension, tachyarrhythmia, and—particularly if the patient is using a beta-adrenergic blocking medication—bradycardia may be seen in cases of anaphylaxis.
Assays of IgE
Because allergic diseases result from the interaction of an allergen with specific IgE, analysis for specific IgE in a patient with clinical allergy is a major diagnostic consideration. Specific IgE can be identified both by in vivo methods (skin testing) and in vitro methods (e.g., radioallergosorbent testing [RAST]).6
The most rapid and sensitive test for allergy is skin testing. This in vivo method depends on mast cell-bound or basophil-bound IgE specific for the allergen being tested. Because a positive test requires degranulation of mast cells or basophils and subsequent histamine release, antihistamines will interfere with the outcome. In general, patients should discontinue antihistamines 1 week before skin testing, although certain antihistamines can be discontinued 3 days beforehand [see Table 2]. Corticosteroids do not inhibit this immediate-phase response, and hence, their use is not a contraindication for skin testing.
Table 2 Time Before Skin Testing to Stop Antihistamines*
Skin testing should be performed by a qualified allergist. Initial testing is performed by pricking the epidermis with a small amount of the specific allergen. In patients with IgE specific for the allergen, a wheal-and-flare response will develop at the site within 20 minutes. The areas of edema and erythema are then measured. The results are often reported as wheal size over flare size (both in millimeters) or, alternatively, identified on an arbitrary scale of 1 to 4+, correlating to the size of the wheal, the flare, or both. Histamine is used as a positive control, and because some patients develop hives in response to any strong pressure on the skin (dermatographism), saline is used as a negative control.
If the results of epicutaneous skin testing are negative but the patient's symptoms strongly suggest an allergic etiology, intradermal testing can be performed. This involves injecting 0.02 ml of a dilute allergen solution (usually a 1:100 or 1:1,000 dilution of the concentrated extract) into the dermis. As with epicutaneous testing, the skin is observed for the development of a wheal and flare within 20 minutes. Grading of the results is similar to that for epicutaneous testing.
Intradermal testing has a higher sensitivity but a lower specificity than epicutaneous testing. This means that intradermal testing produces more false positives but fewer false negatives than epicutaneous testing. Although the relevance of isolated positive intradermal tests for aeroallergens is debated, intradermal testing is crucial for the evaluation of drug and insect allergy.
Compared with epicutaneous testing, intradermal testing exposes the body to a significant antigen load and, therefore, poses a higher risk of a systemic reaction. For that reason, intradermal testing is contraindicated in patients who have not had a prior negative result on epicutaneous testing. It is not surprising that five of the six skin-testing fatalities reported from 1945 to 1987 occurred in patients who underwent intradermal testing without previous epicutaneous testing.7 Food allergens should never be used for intradermal testing, because they are associated with a high rate of false positive irritant responses. Furthermore, some foods (e.g., peanuts and shellfish) are such potent antigens that they could provoke severe systemic reactions if injected intradermally.
Inaccurate or incorrect skin-testing results can occur for a variety of reasons. For example, the use of low-potency extracts can lead to false negative results, as can certain patient factors, such as (1) age (wheals are small in infants, increase until age 50, and then decline), (2) race (whites produce smaller wheals than African Americans8), and (3) antihistamine use (including drugs with antihistaminic properties, such as tricyclic antidepressants). In addition, skin-testing results depend on vascular leak; medications such as adrenergic agents can inhibit this response, leading to false negatives. False positives most often result because of irritant reactions, dermatographism, or a nonspecific reaction from a nearby strong reaction (a so-called bystander reaction).
RAST and other in vitro tests measure the concentration of nonspecific and allergen-specific IgE in the patient's serum. Because these tests do not depend on IgE-mediated histamine release for their interpretation, they are not adversely affected by the use of antihistamines and other medications (except for anti-IgE, omalizumab [see below]). Although there are circumstances in which high levels of nonspecific IgE can be found, determination of nonspecific IgE is generally of little value, because IgE concentrations vary substantially and there is significant overlap between patients with atopic disease and patients with non-atopic disease. However, the determination of allergen-specific IgE can be useful, especially in patients in whom skin testing cannot be performed (e.g., because of skin disease or inability to stop using antihistamines).
RAST is the most common method of determining allergen-specific IgE in the serum [see Figure 1]. This test involves adding the patient's serum to a solid phase (usually a disk) coated with the allergen to be tested. Antibodies in the patient's serum that are specific for the allergen will bind to the solid phase. After the disk is washed, to remove the unbound antibodies to other allergens, antibodies against human IgE that have been tagged with a radioactive isotope are added. The disk is then washed again, to remove unbound tagged anti-IgE. The level of radiation that is present after washing the disk is directly proportional to the quantity of allergen-specific IgE in the patient's serum. Comparing these values with known standards allows for the determination of allergen-specific IgE. Gaining in popularity is the CAP-RAST system, which is a test for specific IgE that incorporates a solid phase consisting of an encapsulated hydrophilic carrier (in the shape of a cup or “CAP”) to which antigen is covalently bonded. This allows for better allergen attachment and much more accurate quantification of specific IgE than can be obtained with traditional RAST testing. Furthermore, CAP-RAST testing is usually performed with fluorescently labeled anti-IgE, as opposed to the radiolabeled anti-IgE in traditional RAST testing. Although the CAP-RAST method is different from traditional RAST testing, some laboratories may refer to both of these modalities as RAST tests.
Figure 1. Radioallergosorbent Test
The radioallergosorbent test (RAST). A solid-phase disk coated with the test allergen is incubated with the patient's serum. IgE and IgG antibodies to the test allergen (E1 and G1, respectively) will bind with the allergens on the disk, whereas IgE and IgG antibodies to other allergens (E2 and G2, respectively) will remain free in the serum. After the free antibodies have been washed away, the disk is incubated with antibodies against human IgE that have been labeled with a radioactive or a fluorescent tracer. The tagged anti-human IgE antibodies will then bind IgE attached to the disk; a second washing then removes any unbound tagged antibody. The level of radioactivity or fluorescence is then proportional to the amount of specific IgE against the antigen (E1). IgG against the antigen (G1) does not react with the tagged antibody and therefore is not counted in this test.
Although RAST results generally correlate with allergic sensitivity, RAST is more likely than skin testing to produce false positive results. As such, the sensitivity of RAST is lower than that of skin testing. Therefore, skin testing is still the preferred method of identifying the allergens to which a person is sensitive.
INTERPRETATION OF IGE TEST RESULTS
Regardless of the modality used to test for IgE, all results must be correlated with the clinical findings. Only tests whose results fit with the patient's symptoms should be considered relevant for explaining those specific symptoms. In other words, a positive result is useful for therapeutic intervention only if the patient has symptoms when exposed to the allergen, and a negative test is useful only if the patient has no symptoms on exposure to the allergen. An example would be a patient who has a positive skin test to a tree pollen yet has no symptoms in the spring but instead has symptoms in the fall, in a region devoid of tree pollen at that time of the year. Even if tests for weeds and molds were negative, this seasonality of symptoms would still suggest that a fall pollen or untested mold spore is to blame for the symptoms rather than trees, as the testing would suggest. A positive skin test in the absence of exposure or symptoms, however, does not mean that the patient will not develop symptoms to the antigen at some time in the future. In general, the clinician should use the clinical history to guide all testing modalities, rather than using the testing to try to identify unknown triggers.
The most effective therapeutic intervention for atopic disease is complete removal of the offending allergen or allergens from the patient's environment [see Table 3]. For example, environmental control for a patient who is allergic to dust mites would include encasing the pillows and mattress in dust-mite-proof covers, washing all bedding in hot (> 130° F) water weekly, and lowering the ambient humidity in the house to below 45%. Some authorities also recommend the removal of bedroom carpet as an additional control for dust-mite exposure; this recommendation is controversial, however. For pet-allergic patients, the pet should be removed from the household or, at a minimum, should be kept out of the bedroom at all times. Pollen-sensitive individuals will benefit from staying in air-conditioned environments during the time of year when the offending pollen is prevalent.
Table 3 Environmental Control for Allergy Management
Although environmental control measures constitute the primary treatment for atopic disease, such interventions are sometimes impossible to carry out or do not completely eliminate the allergen and, therefore, do not fully resolve the disease. This is the point at which pharmacotherapy should be added. The medications used in allergic disease are targeted to various components of the allergic cascade [seeFigure 2]. These medications include antihistamines and decongestants, anti-IgE, long-acting and short-acting bronchodilators, corticosteroids (both topical and systemic), leukotriene receptor antagonists, and theophylline. Although cromolyn and nedocromil sodium have an established tradition of use and favorable safety profiles, their minimal efficacy does not justify their inclusion on this list.
Figure 2. Mechanisms of Action of Medications Used in Allergic Diseases
Mechanisms of action of medications used in allergic diseases. Environmental control (A) minimizes exposure to the antigen to which the patient has specific IgE. If the antigen is present, it binds with specific IgE; cross-linking of the antigen-bound IgE on the surface of a mast cell or basophil starts the allergic cascade, with release of leukotrienes, histamine, cytokines, chemokines, and other mediators such as prostaglandins and proteases (not shown). Leukotriene antagonists (B) block the action of leukotrienes; antihistamines compete with histamine at H1 receptors; corticosteroids (D) inhibit the production of inflammatory cytokines and chemokines. Anti-IgE therapy (e.g., omalizumab) (E) works by directly reducing the amount of IgE in the body. It is unclear at which sites immunotherapy and cromolyn and nedocromil sodium exert their anti-inflammatory action.
Antihistamines and Decongestants
Antihistamines block the action of histamine at its receptor.9 Although there are at least four histamine receptors, most allergic symptoms have been attributed to the H1 receptor. Symptoms mediated by histamine include pruritus, nasal itching, conjunctivitis, and the wheal-and-flare response.
H1 receptor antagonists can be divided into two broad categories on the basis of their ability to cross the blood-brain barrier and cause sedation. The classic antihistamines, which cause more sedation, include over-the-counter drugs such as diphenhydramine and chlorpheniramine, as well as prescription medications such as cyproheptadine and hydroxyzine. These medications are potent antihistamines, but their usefulness is limited by their central nervous system side effects. Of particular significance is that CNS effects have been shown to last beyond the sedative effects of these medications, leading to decreased reaction time. Therefore, the recommended choice for long-term therapy is a second-generation or third-generation (active metabolite) antihistamine, which will produce minimal sedation. Examples of such agents include over-the-counter loratadine and the prescription drugs cetirizine (Zyrtec), desloratadine (Clarinex), and fexofenadine (Allegra). Also available as a nasal spray is azelastine (Astelin).
Antihistamines do not have a significant effect on nasal congestion. For intermittent congestion, a systemic decongestant may be used. Since phenylpropanolamine (PPA) was taken off the market because of its association with increased frequency of strokes, pseudoephedrine has been the only systemic decongestant available in the United States. Nevertheless, although decongestants provide some relief of the sensation of nasal fullness, they do not alter the underlying etiology.
The allergic response requires the presence of IgE. A newly approved therapeutic modality in the United States is omalizumab, a humanized anti-IgE monoclonal antibody that is administered subcutaneously on a biweekly to monthly schedule and can reduce serum unbound IgE to undetectable levels. This molecule consists of the hypervariable region from a mouse antibody against human IgE that is genetically grafted onto a human IgG molecule—hence the term humanized. Clinically, omali-zumab has been shown to significantly reduce symptom scores in patients with allergic rhinitis, as well as to relieve symptoms and modestly improve airway function in patients with moderate to severe asthma.10,11,12 This medication has the ability to block the allergic cascade at its initiation and has not been associated with significant side effects.
The appropriate end points for omalizumab therapy remain uncertain. Standard measures of allergic sensitivity are not useful in patients who are taking omalizumab: skin testing will produce negative results, and total IgE will be elevated because IgE is bound to the anti-IgE medication in circulation. Current data support continued administration for a minimum of 12 weeks. Patients with low pulmonary functions, patients who have had emergency department visits within the preceding year, and patients on high-dose inhaled corticosteroids are the most likely to respond to therapy with anti-IgE.13 The relatively high cost of this medication in the United States may limit its usefulness.
Both short-acting and long-acting bronchodilators are available for treatment of asthma. Short-acting bronchodilators relieve bronchoconstriction but have no effect on the underlying inflammatory process, whereas long-acting bronchodilators not only provide symptomatic relief of bronchoconstriction but also may have slight anti-inflammatory properties. Unfortunately, over time there is loss of potency of bronchodilators when they are used alone (subsensitivity). This loss of potency does not occur, however, when bronchodilators are combined with an inhaled corticosteroid. Given the lack of sufficient anti-inflammatory activity and the subsensitivity of bronchodilators, the recommended use of these medications is in combination with an inhaled corticosteroid rather than as monotherapy.14,15
Corticosteroids inhibit the production of inflammatory cytokines and chemokines, thus reducing the inflammation and cellular recruitment to sites of disease. These medications play a major role in the treatment of allergic disease. They may be given locally (topically) or systemically (orally).
Topical corticosteroids are capable of potent anti-inflammatory effects and are a mainstay of allergic therapy. These medications, which are inhaled for asthma or taken intranasally for rhinitis, have the ability to abrogate the inflammatory response and interfere with multiple aspects of the allergic cascade. However, unlike antihistamines, which provide rapid relief (within 1 to 2 hours), topical corticosteroids may require 3 to 5 days of therapy before full relief is realized. In rhinitis, steroids can relieve the congestion and raise the threshold for the development of symptoms to allergen exposure.16,17 Significant systemic effects are uncommon with inhaled or intranasal corticosteroids given at the usual recommended doses.
Oral corticosteroids are potent at resolving and preventing most allergic disease. Unfortunately, the usefulness of chronic systemic corticosteroid use is limited by the potentially devastating side effects of these agents, which include weight gain, abnormal fat deposition, adrenal suppression, cataracts, type 2 diabetes mellitus, and osteoporosis.
In general, oral corticosteroids are prescribed only for short bursts and do not require a taper, because therapy for less than 2 weeks is not associated with adrenal suppression. Longer courses are reserved for patients whose condition has been refractory to all other standard therapies.
Leukotriene antagonists (either receptor antagonists or 5-lipoxygenase inhibitors) also have anti-inflammatory properties.18 Leukotrienes are found at sites of allergic inflammation. Although corticosteroids affect many other inflammatory pathways, they do not seem to have a clinically significant impact on the generation and release of leukotrienes. These molecules are capable of inducing further inflammation by causing the release of additional mediators, as well as the recruitment of inflammatory cells to sites of allergic disease. Consequently, leukotriene antagonists are used in the treatment of both asthma and allergic rhinitis.19
Although generally not viewed as a major therapeutic option because of their narrow therapeutic window and significant side effects, methylxanthines still have some usefulness in asthma care. Recent asthma treatment guidelines suggest theophylline (at a serum concentration of 5 to 15 µg/ml) to be an alternative treatment in mild and moderate persistent asthma.20 The addition of low-dose theophylline (5 to 10 µg/ml) to inhaled corticosteroids has shown benefit in asthma, with a lower risk of side effects than with higher theophylline doses.21 As a result, methylxanthines remain worthy of consideration as part of the therapeutic regimen, especially in patients for whom cost is an issue.
Immunotherapy, or allergy shots, involves injecting increasing doses of the offending antigen or antigens in an attempt to attenuate the specific allergic response. Clinical trials have shown that immunotherapy is successful in treating allergic rhinitis with or without associated asthma.22,23 An immunotherapy extract is prepared on the basis of skin-testing results. The patient then receives increasing doses subcutaneously on a weekly or twice-weekly schedule for about 5 months. After this so-called build-up phase, the patient is maintained on a stable dose that is administered weekly to monthly for several years. Usually, patients achieve maximal benefit after being on the maintenance dose for 1 year. The duration of treatment is still under investigation; therefore, the discontinuance of immunotherapy must be determined on an individual basis.
Immunotherapy is usually reserved for those patients in whom environmental and pharmacologic interventions have been less than fully successful. The only patients for whom immunotherapy is almost always indicated are those who have systemic symptoms from venom (Hymenoptera) allergy. Immunotherapy is often indicated for allergic rhinitis or asthma that is clearly associated with sensitivity to specific allergens.24 It is also used in children, because some data suggest that early treatment of allergic rhinitis with immunotherapy may prevent the subsequent development of asthma.25 Because of the small but real risk of anaphylaxis, immunotherapy should be given only in a medical office or in another carefully screened location, where personnel and supplies are readily available to treat reactions. Similarly, patients with an FEV1 (forced expiratory volume in 1 second) of less than 70% of predicted or those having an asthma exacerbation should not be given immunotherapy because of the risk of developing even worse bronchospasm. Currently, there is no role for immunotherapy in the treatment of food allergies.
Standard immunotherapy (also known as conventional high-dose immunotherapy) should not be confused with other invalidated and inappropriate methods of immunotherapy. These techniques, which should be avoided, include skin-titration testing and treatment (the Rinkel method), subcutaneous provocation and neutralization, and sublingual provocation.6
Figure 1 Tom Moore.
Figure 2 Seward Hung.
Editors: Dale, David C.; Federman, Daniel D.