Approach to Diagnosis
- •A diagnosis of allergy should not rely completely on laboratory testing but should be based on correlations between patient history, clinical symptoms, and laboratory test results.
- •Obtaining an accurate patient history is a crucial first step in diagnosing allergic disease.
- •A family history of atopic disease increases risk for allergic disease. Patient history should include the nature of the patient’s symptoms (frequency and severity) and potential allergen exposures, such as seasonal (e.g., pollen from trees or grasses), perennial (e.g., dust mites, cockroaches), food (e.g., peanuts, tree nuts, egg, raw fruits), environmental (e.g., pets, pollutants, cockroaches, molds, fungi), drug (e.g., penicillin), and occupational (e.g., flour, latex, paints) allergen exposures.
History and Physical Examination
- •Skin should be examined for possible urticaria angioedema, or atopic dermatitis.
- 1.Urticarial lesions typically consist of small, pink, raised, irregular wheals and may be associated with angioedema.
- 2.Angioedematous lesions are most often found on the face and acral areas.
- 3.Atopic dermatitis is prominent over the trunk and face during infancy, and a typical flexural distribution is observed in childhood. Signs of atopic dermatitis include flexural papillae, thickening of skin due to hyperkeratinization, excoriations, and lichenification.
- •The eyes should be examined for signs of excessive tear production, injection and swelling of the palpebral conjunctivae, and swollen or darkened periorbital tissues. “Cobblestone papillae” may be present.
- •Internal inspection of the nasal mucosa should be focused on deviations or perforations of the nasal septum, nasal patency, presence of polyps or foreign bodies, mucosal appearance, and presence and nature of secretions.
- 1.Decreases in nasal patency caused by swelling of the lower turbinates are often observed.
- 2.In allergic patients, the nasal mucosa typically appears pale, watery, edematous, and bluish, and secretions are clear and watery to mucoid in nature.
- •In patients with acute asthma, clinical examination can help detect wheezing, prolonged expiration, tachypnea, and shortness of breath. Extremities should be checked for cyanosis.
- 1.Chronic hyperinflation (increased diameter or barrel chest) can be seen in chronic asthma.
- 2.Wheezing, if unilateral, may suggest a foreign body or tumor. Wheezing may only be present during expiration (mild or moderate asthma) or during both inspiration and expiration (severe asthma), or it may be absent (when airflow is severely limited or when it predominantly affects the small airways).
- •Anaphylaxis is a systemic event and affects many organs.
- 1.Signs of anaphylaxis generally include flushing and presence of urticaria and angioedema.
- 2.Hoarseness caused by upper airway obstruction from angioedema of the tongue, oropharynx, or larynx, or wheezing secondary to asthma, may be observed.
- 3.Other symptoms may include pruritus, chest tightness, cough, wheezing, rhinitis, sneezing, congestion, rhinorrhea, abdominal pain, uterine cramping, urinary and fecal urgency or incontinence, nausea, vomiting, and diarrhea.
- 4.Patients may become hypoxic, and anaphylaxis with hypotension may signal shock and cardiovascular collapse.
- •Allergic diseases are often associated with increased numbers of eosinophils circulating in the peripheral blood and invading the tissues and secretions of target organs.
- •Eosinophilia, defined as the presence of >500 eosinophils/μL in peripheral blood, is the most common hematologic abnormality of allergic patients.
- •Seasonal increases in the number of circulating eosinophils may be observed in sensitized patients after exposure to allergens such as tree, grass, and weed pollens.
- •The number of circulating eosinophils can be suppressed by certain infections and systemic corticosteroids.
- •In certain pathologic conditions, such as drug reactions, eosinophilic pneumonias, and eosinophilic esophagitis, significantly increased numbers of eosinophils may be present in the target organ in the absence of peripheral blood eosinophilia.
- •Increased numbers of eosinophils are observed in a wide variety of disorders in addition to allergy; eosinophil counts >1500 without an identifiable etiology should suggest one of the two hypereosinophilic syndromes.
Eosinophilia in Nasal and Bronchial Secretions
- •The presence of eosinophils in the sputum of asthmatic patients is common.
- •An increased number of eosinophils in a smear of nasal mucus with Hansel stain is a more sensitive indicator of nasal allergies than peripheral blood eosinophilia and can aid in distinguishing allergic rhinitis from other causes of rhinitis.
Serum Ige Levels
- •An elevated IgE value is often found in the serum of allergic patients, because IgE is the primary antibody associated with immediate hypersensitivity reactions.
- •The presence of IgE specific for a particular allergen can be documented in vitro by the measurement of allergen-specific IgE (sIgE) levels in the serum.
- •The first test for documenting the presence of sIgE was called the radioallergosorbent test (RAST) because it used a radiolabeled anti-IgE antibody. The RAST has been replaced by an improved generation of automated enzymatic sIgE immunoassays.
- •Several new innovative high-throughput in vitro tests for measuring sIgE have recently been commercialized, such as the ImmunoCAP Immunosorbent Allergen Chip, Immuno Solid Phase Allergen Chip (VBC Genomics-Phadia), and AdvanSure AlloScreen assay, and these tests can be used in conjunction with in vivo sIgE tests for further confirmation of a diagnosis of allergy.
- •Component testing refers to diagnostic tests where sIgE is measured to specific proteins that comprise allergens (e.g., Ara h 2 from peanut, Bet v 1 from birch pollen), rather than to a mixture of the allergens extracted from the source.
- •Testing sIgE to component allergens may add additional diagnostic value by differentiating immune responses that are directed toward clinically relevant allergenic proteins.
- •The diagnosis of insect sting allergy by detection of allergen-specific IgE antibodies in serum is another application of IgE antibodies. A high level of venom-specific IgE is usually diagnostic.
- •Venom skin tests and venom-specific IgE assays correlate imperfectly. The latter produce negative results in up to 20% of skin test–positive subjects, and venom skin test results are negative for approximately 10% of persons with elevated IgE antibodies. Neither test alone can detect all cases of insect sting allergy, and each test is useful as a supplement to the other.
Allergen Skin Testing
- •Allergen skin testing is the primary in vivo procedure for the diagnosis of allergic disease.
- •Mast cells with sIgE antibodies attached to high-affinity receptors on their surface reside in the skin of allergic patients. The introduction of minute amounts of an allergen into the skin of the sensitized patient results in cross-linking of IgE antibodies on the mast cell surface, thereby triggering local mast cell activation. Once activated, these mast cells release a variety of preformed and newly generated mediators that act on surrounding tissues. Histamine is the mediator most responsible for the immediate wheal and flare reactions observed in skin testing. Examination of the site of a positive skin test result reveals a pruritic wheal surrounded by erythema. The time course of these reactions is rapid in onset, reaching a peak within 10 to 20 min and usually resolving over the next 30 min.
- •Skin testing is performed using the prick/puncture technique. With this technique, a small drop of allergen is applied to the skin surface, and a tiny amount is introduced into the epidermis by lightly pricking or puncturing the outer layer of skin through the drop of extract with a small needle or other device.
- •When the skin-prick test (SPT) result is negative but the history suggestive, selective skin testing (for vaccines, venom, drugs, and aeroallergens) using the intradermal technique may be performed. This technique involves using a 26-gauge needle to inject 0.01 to 0.02 mL of an allergen extract diluted 1,000- to 10-fold into the dermis of the arm.
- •Intradermal skin tests are not recommended for use with food allergens because of the risk of triggering anaphylaxis.
- •Irritant rather than allergic reactions can occur with intradermal skin testing if higher concentrations of extracts are used.
- •Although skin-prick testing is less sensitive than intradermal skin testing, positive SPT results tend to correlate better with clinical symptoms.
- •The below table summarizes the relative advantages of prick and intradermal tests.
Relative Advantages of Prick and Intradermal Tests
From Burks AW et al: Middleton’s allergy principles and practice, ed 9, Philadelphia, 2020, Elsevier.
|Advantages||Prick Test||Intradermal Test|
|Interpretation of positive and negative reactions||++++||++|
|Detection of IgE antibodies||Yes||Yes|
|Testing of infants||Yes||Difficult|
+, Mild; ++, moderate; +++, high; ++++, very high.
Skin Testing for Detection of sIgE
- •Detection of sIgE denotes a sensitized state (i.e., atopy or a tendency toward development of allergic disease) but is not equivalent to a clinically relevant allergic diagnosis. Many children with positive tests have no clinical symptoms on exposure to the allergen.
- •Increasingly strong test results (higher serum sIgE results or larger SPT wheal sizes) generally correlate with increasing likelihood of clinical reactivity (but not severity).
- •Neither serologic testing nor skin testing for allergy is predictive of reaction severity or threshold of reactivity.
- •The limitations of these test modalities underscore the need for a detailed medical history that can guide the selection and interpretation of test results.
- •Both serum sIgE tests and SPT are sensitive and have similar diagnostic properties. The benefits of the serologic immunoassays are that performance is not limited by presence of skin disease (i.e., active atopic dermatitis) or medication use (i.e., antihistamines). Advantages of skin testing are that they provide rapid results to the patient/family during the clinic visit, do not require venipuncture, and are less costly.
Non-IgE Tests: Inhalation Tests and Patch Tests
- •Inhalation testing of specific allergens or chemicals may help diagnose occupational allergy or asthma.
- •The bronchial provocation test most frequently performed clinically is the methacholine challenge, which causes potent bronchoconstriction of asthmatic but not of normal airways; it is performed to document the presence and degree of bronchial hyperreactivity in a patient with suspected asthma.
- •After baseline spirometry values are obtained, increasing concentrations of nebulized methacholine are inhaled until a drop occurs in lung function, specifically a 20% decrease in FEV1 (forced expiratory volume in first second of expiration), or the patient is able to tolerate the inhalation of a set concentration of methacholine, typically 25 mg/mL.
- •Patch tests are used to diagnose contact dermatitis. Patches containing potentially allergenic substances (e.g., dyes, latex, metals) are placed on the back for about 48 hr, and a reading is obtained after 72 to 96 hr.
Oral Food Challenges
- •Oral food challenges are performed to determine whether a specific food causes symptoms or whether a suspected food can be added to the diet.
- •Food challenges are generally performed when the history and results of skin tests and immunoassays for sIgE fail to clarify the diagnosis of an allergy.
- •These challenges involve the ingestion of gradually increasing amounts of the suspected food at set intervals until the patient either experiences a reaction or tolerates a normal portion (i.e., 1 serving size) of the food openly.
- •Because of the potential for significant allergic reactions, oral food challenges should be performed only in an appropriately equipped facility with personnel experienced in the performance of food challenges and the treatment of anaphylaxis, including cardiopulmonary resuscitation.
Upper Gastrointestinal Endoscopy
- •UGI endoscopy is performed to confirm the diagnosis of eosinophilic esophagitis. One or more biopsy specimens from the proximal and distal esophagus must show eosinophil-predominant inflammation. With few exceptions, 15 eosinophils/hpf (high-power field) (peak value) is considered a minimum threshold for the diagnosis.
Measurement of Serum IgE
- •Testing for IgE antibodies has limited diagnostic usefulness in adults suspected of having an allergic disease but clinically indicated in the evaluation of adults with asthmatic symptoms to characterize the phenotype of disease and to identify allergen triggers including occupational allergens.
- •Results of clinical studies of adult respiratory allergy indicate that approximately 50% of adults with allergic asthma and fewer than 5% of adults with nonallergic asthma have elevated serum IgE levels.
- •The highest IgE levels in adults typically occur in patients with allergic sensitization to several allergens and combinations of asthma, atopic dermatitis, and rhinitis.
- •Allergic bronchopulmonary aspergillosis (ABPA) is associated with marked elevation in the serum concentration of IgE. An elevated serum IgE level (more than 416 IU/mL [1000 ng/mL]) is one of the diagnostic criteria for this condition, and the level of IgE can be used to follow the course of the disease. This disease typically occurs in patients with allergic asthma, generally of long duration. The concentration of IgE in serum is elevated during times of acute pulmonary infiltration, but may fluctuate considerably during the course of the disease. A normal IgE level in a patient with active lung disease virtually excludes the diagnosis of ABPA.
- •Testing for IgE antibodies to components can also be used for determining allergy to food products.
- •Testing for IgE antibodies is also useful in the evaluation of suspected allergy to Hymenoptera venom(s).
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