Allergic Disorders

Allergic illnesses have a significant impact that allergic diseases have on children's health and quality of life. Allergic diseases, including asthma, are among the major causes of chronic illnesses in the United States, affecting approximately 50 million patients or as many as one in five children. The economic impact is enormous; asthma alone is estimated to cost more than 6.2 billion dollars of health care expenditures annually. Of all the chronic illnesses, allergic respiratory problems, including allergic asthma, is the most common cause of school absenteeism. Even though allergic disease usually is not fatal, death can result as a consequence of allergic anaphylaxis related to medication, food, or insect venom allergy or from a complication of asthma. Therefore, the pediatrician must be capable of diagnosing allergic disease so as to institute appropriate management. This review will emphasize those clinical diagnostic features ascertained by history and physical examination as well as the appropriate laboratory studies useful in the diagnosis of respiratory (inhalant) and gastrointestinal (food) allergy.

General Features of Allergic Diseases

Allergic diseases are immunoglobulin E (IgE)-mediated immunologic illnesses that can affect any of the body's major organ systems either individually or collectively. Typically, children are not born having allergies because maternal IgE normally does not cross the placenta. In rare instances, neonates and young infants who apparently were sensitized in utero have been born with specific IgE to foods and had allergic reactions to those foods. Development of an allergy requires a familial predisposition and repeat exposure to an allergen (antigen) that provokes specific IgE antibody.

Epidemiologic surveys indicate that the familial trait for allergy is inherited as autosomal recessive. Whereas the frequency of positive allergy skin tests is similar in boys and girls, asthma is twice as common in males as in females prior to adolescence, but it appears equal in prevalence thereafter. A specific immune response gene has been identified for IgE antibody synthesis in rodents, but it has not yet been demonstrated conclusively in humans. With the recent advances in molecular genetics, it is anticipated that the genetic basis of allergy will be understood better in the near future.

Allergens sensitize by several potential routes and are categorized as inhalants, ingestants, injectants, and contactants (Table 1). It is important for the physician to define the route by which any specific allergen provokes clinical allergy in individual patients. Of the inhalant IgE-mediated allergies, allergic rhinitis is by far the most common, affecting approximately 15% of all children. Asthma, of which 80% has an allergic inhalant basis, occurs in more than 5% of children. Gastrointestinal (ingestant) allergy typically is associated with food allergy; however, ingestants also may provoke urticaria and atopic dermatitis and less often may trigger respiratory symptoms. Anaphylaxis is a systemic generalized allergic response consisting of hypotension, urticaria, and angioedema as well as upper and lower airway obstruction; it can be caused by severe allergic reactions to foods (ingestant), insect venom stings (injectant), or

medications (ingestant, injectant, or contactant).

Although incriminated anecdotally as the cause for hyperactivity, poor school performance, learning disabilities, or abnormal child behavior, there are no definitive, appropriately controlled studies that document an IgE allergic etiology for these predominantly psychosocial or educational problems. The possibility that overgrowth of a yeast such as Candida is important in the pathogenesis of allergy never has been substantiated. The concept of such a candidal syndrome in the context of abnormal child behavior has no validity, and antifungal therapy in the absence of overt clinical candidal infection should be discouraged.

Inhalant Allergy

Microscopic inhaled airborne allergens are responsible for most respiratory allergy (Table 2). In temperate climates, seasonal allergic rhinitis is induced by tree pollens in the early spring, grass pollens in the late spring and early summer, and ragweed in the late summer and early fall. Because of geographic differences in the US, clinicians must become familiar with the pollination patterns in their individual regions. Hay fever is an inappropriate term for allergic rhinitis because these patients neither are allergic to hay nor have fever. Flowering vegetation, such as roses and fruit blossoms, rarely cause allergy because these pollens are too heavy to become airborne; their germination is facilitated by bees and other insects. Fungi (mold) spores may be important outdoor aeroallergens in humid climates throughout the year, but their numbers decrease once there is significant frost in temperate climates. Fungi can be important indoor perennial allergens in damp environments. In perennial allergic rhinitis, house dust, animals, and molds all may be significant indoor inhalant allergens. The principal allergens in house dust are the cuticles and feces of the microscopic house dust mite Dermatophagoides. Animal allergens, such as epidermal danders, salivary proteins, urinary proteins, feces, and feathers, especially from pets such as cats, dogs, and birds are important because about 50% of households in the US have indoor animal pets. Food allergens are of lesser importance in the etiology of allergic rhinitis but cannot be ignored, especially in young children. Patients can be sensitive to one or multiple allergens. Certain individuals react to miniscule amounts of inhaled allergens, while others tolerate a large allergen dose before developing symptoms.

In addition to allergens, viral infections, aerosolized cosmetics, cigarette smoke, industrial fumes, and changes in temperature, humidity, and barometric pressure contribute to exacerbation of both upper and lower respiratory tract symptoms in the allergic child. Psychologic and social stresses also can enhance symptoms. The importance of these additional contributory factors varies greatly from patient to patient but should not be ignored when evaluating any individual.

Symptoms of nasal allergy consist of frequent sneezing, nasal pruritus, watery rhinorrhea, and often, nasal obstruction. Patients also may complain of red, itchy eyes as well as itchy throat and ears. If there is nasal obstruction, the patient will be a mouth breather and snoring can be a bedtime symptom; smell and taste also may be lost. Increased symptoms frequently are noted with increased exposure to the responsible allergen, such as after cutting grass or sleeping on a feather pillow.

When an allergic reaction develops, clear nasal secretions will be evident, and the nasal mucous membranes will become edematous without much erythema. The mucosa appear boggy and blue-gray. With continued exposure to the allergen, the turbinates will appear swollen and can obstruct the nasal airway. Conjunctival edema, itch, tearing, and hyperemia are frequent findings in patients who have associated allergic conjunctivitis. Patients who have allergic rhinitis, particularly children who have significant nasal obstruction and venous congestion, also may demonstrate edema and darkening of the tissues beneath the eyes. These so-called "shiners" are not pathognomonic for allergic rhinitis because they also can be seen in patients who have chronic rhinitis and/or sinusitis. Thick, purulent secretions indicate the presence of infection, including the possibility of sinusitis.

DIAGNOSTIC TESTS

Nonspecific Allergy Tests

Many pediatricians believe in the need for a screening test for allergy. Blood eosinophilia and total serum IgE levels have been proposed as screening tests, but they have relatively low sensitivity and should be used selectively (Table 3). The nasal secretions or sputum of patients who have a respiratory allergy contain increased numbers of eosinophils, which forms the basis of a useful nonspecific test, although not one that will identify any specific allergen etiology. Eosinophilia may not be present in patients who have not been exposed to allergens recently or who have a superimposed upper respiratory tract infection. Both systemic and inhaled steroids can reduce eosinophilia in secretions significantly; antihistamines have no direct effect on eosinophils.

The usefulness of nasal eosinophilia as a diagnostic test depends in large part on the technique used to obtain the specimens to prepare the slides for examination. Patients should expel nasal secretions onto wax paper or parafilm; secretions then are spread on a microscope slide, stained, and eosinophils counted under a microscope. It is difficult to quantify nasal eosinophilia accurately, although a finding of more than 3% eosinophils on stained smear of expelled nasal or bronchial secretions is considered increased. Because cotton or nylon nasal swabs trap secretions, they are not recommended for collecting secretions, except in the young child who will not or cannot expel secretions by blowing the nose. Peripheral blood eosinophilia is observed in allergic asthma but less commonly in allergic rhinitis. Blood eosinophilia is more frequent in atopic dermatitis and other conditions, such as parasite infection.

Total serum IgE is elevated in about 60% of patients who have allergic asthma but only in 30% of those who have allergic rhinitis. Unfortunately, commercial laboratories have promoted tests of total serum IgE excessively, but its usefulness in screening for allergy is limited to positive tests only because more than 60% of patients who have nasal allergy will have normal levels of total serum IgE.

Specific Inhalant Allergy Tests

Laboratory confirmation of the presence of IgE antibodies to specific allergens such as dust mites, pollens, or animals is very helpful

in establishing a specific allergic diagnosis, especially if the history of exposure to a specific allergen is not clear-cut. It may be necessary to test for specific allergens to convince the family and patient of an allergic diagnosis and to reinforce the importance of environmental control.

Although skin testing might be performed in any child at any age, children less than 1 year of age may not mount a positive reaction. Often, the child who has seasonal respiratory allergy will not manifest a positive test until after two seasons of exposure. Clinicians should use allergens for skin testing selectively and employ only common allergens of potential clinical importance. The most useful allergens for which to test in the child who has perennial inhalant allergy are house dust mites (Dermatophygoides), animal danders, and fungi (molds) (Table 2). Allergens important in the diagnosis of seasonal allergic rhinitis are weeds, grasses, and tree pollens. These allergens vary not only by season of year but by geographic distribution. Therefore, allergens used for skin testing must be individualized and should be selected on the basis of prevalence in the local area and the home and school environment.

IgE antibody can be tested via two methods: in vivo skin testing and in vitro serum testing (Table 3). Their advantages and disadvantages are outlined in Table 4. For most patients, skin tests that are performed properly offer the best available method for detecting the presence of allergen-specific IgE. The prick, also called the puncture or epicutaneous skin test, is preferred; scratch testing has been abandoned as too traumatic. If prick tests are negative and allergy is highly suspect, then intradermal testing, which is more sensitive, may be employed. Skin tests are both 10% to 20% more sensitive and less expensive on a per test basis than are in vitro serum tests.

The in vitro serum tests employ specific antisera, and the allergen antibody reactions are amplified as a radioimmunoassay (RAST), fluorescent immunoassay (FAST), or an enzyme-linked immunosorbent assay (ELISA). Each of these techniques is comparable when performed properly. In vitro tests are acceptable substitutes for skin tests in the following circumstances: 1) The patient has abnormal skin, such as dermatographism or extensive dermatitis, 2) The patient cannot or did not discontinue antihistamines or other interfering medications, 3) The patient is very allergic by history, and anaphylaxis is a possible risk, and 4) The patient is noncompliant regarding skin testing. The results of either skin tests or in vitro assays depend very much on the quality of the allergen and the competence with which the test is performed.

Although the quality of allergens is improving, there is need for more and better standardization. Both skin testing and in vitro assays have been criticized for lack of good quality control. Skin testing should not be an occasional test for the inexperienced and obviously never should be delegated to an inadequately trained or unsupervised assistant. Board certified allergy and immunology specialists are best qualified to correlate patient histories with tests results. Quality control also has been a major problem for in vitro serum IgE antibody tests. Compulsory participation in quality control programs, such as that offered by the College of American Pathologists and mandated by the Clinical Laboratory Improvement Act, eventually will lead to better quality and standardization of in vitro serum IgE tests.

Positive tests for allergen-specific IgE do not diagnose allergy; they only indicate the presence of IgE molecules that have a particular immunologic specificity. Whether the specific IgE antibodies are responsible for clinically apparent disease must be determined

by a well-trained physician. The ultimate standard for the diagnosis of allergic disease remains the combination of: a positive history, the presence of specific IgE antibodies, and demonstration that the symptoms are the result of IgE-mediated inflammation.

To avoid false-negative skin tests, short-acting antihistamines should be withheld for 36 to 48 hours and long-acting antihistamines (ie, astemizole) for 4 to 6 weeks before skin tests are performed because antihistamines suppress skin testing results. The specifics of skin testing are outlined in standard allergy textbooks. Skin tests with the appropriate allergens are mandatory in all patients prior to initiation of immunotherapy with allergy extracts, and the intensity of the local wheal and flare skin reactions is a guide for determining the initial dose of allergen.

Skin testing by the multiple serial dilution (end-point titration method) is not recommended by this author because multiple skin tests increase the cost of evaluating the patient and the postulated more quantitative results have not been validated. Sublingual challenge with allergen is not a useful diagnostic test for inhalant allergy, and so-called neutralization of allergy via sublingual drops of allergen has not been substantiated. In vitro cytotoxic leukocyte test has not been documented as a useful laboratory test in controlled studies and is not recommended.

Ingestant (Food) Allergy

The evaluation of the child who is suspected of having a food allergy can be fraught with unnecessary confusion because of misuse of terms. It is important to define the clinical syndrome to enhance understanding of the medical problem. An adverse food reaction is a generic term used to describe any untoward reaction following the ingestion of a food or food additive. Adverse food reactions can be categorized into food allergy (food hypersensitivity) or food intolerance. A food allergy is an abnormal immunologic response. A food intolerance is due to a nonimmunologic mechanism, such as toxins contained in the food, metabolic disorders (eg, disaccharidase deficiencies), or idiosyncratic reactions. Lactose intolerance due to lactase deficiency, a common cause of cow milk intolerance, often is mislabeled as milk allergy. In addition, patients may experience a nonimmune adverse reaction to a constituent in food, such as monosodium gluconate added to food during processing, spices such as peppers (capsacian) added as flavoring during cooking, or preservatives. Although food additives, such as coloring or preservatives, may induce urticaria and, rarely, systemic allergy, the hypothesis that they contribute to behavior problems such as hyperactivity or other entities such as learning disabilities has never been substantiated in well-designed and controlled studies.

Symptoms other than those of the gastrointestinal system can result from allergic reactions to food. Anaphylactic reactions, fatal and near-fatal, have been reported both in children and adults. Anaphylactic shock associated with exercise following ingestion of certain foods has been reported in individuals, even though neither food nor exercise alone induced anaphylaxis. Ingestion or contact with food is a common cause of acute urticaria or angioedema. Chronic (>6 weeks' duration) urticaria secondary to food allergy is much less common. Atopic dermatitis in infants and children commonly is associated with food allergy, especially from eggs, milk, wheat, peanuts, and fish.

Within 10 to 60 minutes after ingestion of a food allergen, some children may develop a pruritic, erythematous morbilliform rash. It has been postulated that repeated ingestion of the offending allergen leads to continuation of the IgE inflammatory response, which provokes the pruritus, scratching, and development of eczematous lesions of atopic dermatitis. Although not common, both upper and lower respiratory tract symptoms also have been described secondary to food allergy; however, respiratory symptoms associated with food allergy in the absence of gastrointestinal or skin symptoms is unusual.

Several gastrointestinal immune-mediated disorders have been described. Food-induced enterocolitis, generally associated with ingestion of cow milk or soy-based formula, has its onset between 1 week and 3 months of age, with vomiting and diarrhea severe enough to produce dehydration. Stools contain gross or occult blood and often are watery and positive for carbohydrate (reducing substances). When diarrhea contains gross or occult blood only and pathology is limited to the distal bowel, the condition is defined as food-induced colitis. Both syndromes improve within 72 hours of eliminating the allergen. Malabsorption syndromes have been described secondary to ingestion of cow milk, soy-based products, egg, and wheat. These patients have patchy intestinal villous atrophy when biopsied. The more extensive malabsorption enteropathy with total villous atrophy (often called celiac syndrome) is associated with sensitivity to gliadin, a component of gluten. Allergic eosinophilic gastroenteropathy syndrome can affect children and presents with postprandial nausea, vomiting, abdominal pain, diarrhea, and steatorrhea. Affected patients may have elevated serum IgE levels, positive skin tests, peripheral eosinophilia, iron deficiency anemia, hypoalbuminemia, and a specific food allergy.

The natural history of food allergy in children varies from patient to patient, and food allergies are not always life-long. Studies have shown loss of gastrointestinal food allergy in 1 to 3 years among one third of children, even though results of skin tests and RASTs may not change. The likelihood of losing a food allergy depends on the food that provokes the symptoms and the degree to which the patient maintains the allergen elimination diet. Allergy to peanuts, tree nuts, and fish and seafood appear to be more long-lasting than allergy to milk, soy, and egg.

DIAGNOSTIC TESTS FOR FOOD HYPERSENSITIVITY

The evaluation for adverse food reactions begins by attempting to define whether the patient is suffering from a nonimmunologic intolerance or from an immune reaction, which can be IgE- or nonIgE-mediated. The following must be established if possible: 1) the identity and quantity of the food allergen suspected of provoking the reaction, 2) the time elapsed between the ingestion of the suspected food and the onset of symptoms, 3) a complete description of the symptoms elicited and the duration of the reactions, 4) whether similar symptoms have occurred in the past when the food was eaten and the therapeutic measures taken, and 5) whether other factors (eg, exercise) appear necessary for symptoms to develop. Diet diaries sometimes are useful for the infant as an adjunct to the history; however, with the frequent use of processed foods and prepackaged meals, this may be difficult in the older child and adolescent. Parents are asked to keep a chronologic record of symptoms and foods ingested, generally for no longer than a week. The diary then is reviewed to correlate ingestion of specific food with the development of symptoms.

An elimination diet can be used as a diagnostic and therapeutic test when the history suggests that certain foods may be provoking the specific symptoms. Foods and all "hidden" sources of those foods suspected of inducing symptoms are eliminated from the patient's diet for 1 to 2 weeks. In chronic disorders (such as atopic dermatitis or chronic diarrhea), additional factors may be contributing to symptoms. Therefore, failure to resolve symptoms during the elimination period does not completely rule out a food hypersensitivity.

In cases in which food hypersensitivity or intolerance is suspected but no specific foods can be incriminated, a brief trial (ie, 2 to 4 weeks) of an oligoantigenic or elemental diet may be helpful. If symptoms persist unabated during that period, it is very unlikely that food is a contributing factor. If symptoms appear to improve, further characterization of the sensitivity may be pursued by allergy skin tests or serum IgE antibody tests. These should be performed prior to initiating the elimination diet because the presence or absence of food allergen-specific IgE antibodies is useful for counseling patients. When compared with the double-blind, placebo-controlled oral food challenge (described below), prick skin tests have been found to have excellent negative predictive accuracies for IgE-mediated food allergy but poor positive predictive accuracies.

The major problem with skin testing for foods as well as with many serum IgE antibody tests for foods has been the lack of potent, stable, and pure standardized allergen solutions. At times, a few food allergens produce false-positive reactions secondary to an irritating effect on the skin. The results of food skin tests must be interpreted carefully because there may be a discrepancy between the production of clinical symptoms and positive skin tests to foods. In the practice setting, an open or single-blind oral food challenge may be used to screen for allergic reactions to food. However, in cases in which multiple food allergies are diagnosed, positive responses should be confirmed by double-blind, placebo-controlled food challenges (DBPCFCs). DBPCFCs are the gold standard for diagnosing food allergies and have been used successfully in both children and adults for examining a variety of food-related complaints. The choice of foods used in DBPCFCs is based on history, skin test (or serum IgE antibody) results, or foods suspected on the basis of elimination diets. DBPCFC testing should be performed by a specialist or an experienced clinician; it is not a procedure suited for most primary care practices. (For details see Bock 1988 in Suggested Readings.)

Diagnosis of nonIgE-mediated food hypersensitivity such as malabsorption syndromes and eosinophilic gastroenteritis is facilitated by endoscopy and intestinal biopsy prior to and after the child is placed on an elimination diet. In the malabsorption syndromes, villous atrophy may be partial or complete and often is patchy. Consequently, multiple biopsies may be required to exclude this diagnosis, especially in young children. IgA antigliadin and IgA antiendomysial antibodies can be measured to screen for celiac disease. However, this diagnosis depends on demonstrating biopsy evidence of villous atrophy and inflammatory infiltrate while the patient is ingesting gluten, resolution of biopsy findings after 6 to 12 weeks of gluten elimination, and recurrence of biopsy changes following reinstitution of gluten.

Food-induced enterocolitis and colitis syndromes may require an oral food challenge in the office or hospital. A positive challenge will provoke occult or grossly apparent blood in the stools, an increase in stool neutrophils and eosinophils over baseline, and an increase in the total peripheral blood neutrophil count of 3500 cells/mm over baseline at 6 to 8 hours after the challenge. The diagnosis of food allergy requires a careful history, physical examination, selective skin or serum IgE antibody tests in cases

of suspected IgE-mediated disorders, appropriate exclusion diets, and sometimes blinded provocation challenges. At present, there is no evidence of the diagnostic utility for the following assays: quantitation of food-specific serum IgG or IgG4 antibodies, serum food antigen-antibody complex assays, cytotoxic food testing, tests of lymphocyte activation (proliferation, interleukin-2, or leukocyte inhibitory factor studies), or sublingual or intracutaneous neutralization or provocation.

Once food allergy or hypersensitivity has been diagnosed definitively, the only proven form of therapy is strict elimination of the offending food. This requires considerable time (and ideally a dietitian) to educate the patient on spotting all forms of "hidden foods" and assuring a nutritionally sound diet. Teaching patients to read food labels is necessary to ensure good compliance with an elimination diet. Patients who have IgE-mediated food allergies also must be prepared to treat accidental ingestions; this includes using injectable epinephrine and oral liquid antihistamines. In addition, patients must be prepared to go to the nearest emergency facility for further treatment when indicated.

The role of breastfeeding and food allergen avoidance in the prevention of atopy and food allergy remains controversial. However, it appears that breastfeeding (especially when the mother avoids major allergens--milk, egg, peanut, fish--during lactation) and/or the use of hydrolyzed infant formulas can prevent some atopic dermatitis and food allergy in high-risk infants, but whether it actually prevents respiratory allergy is not yet clear.