Diagnosis and management of food allergy.

Food allergy affects 8% of children under 3 years of age and roughly 2% of the adult population. Major targets include cutaneous, gastrointestinal, and respiratory organs. Clinicians must recognize the spectrum of food allergy in order for these patients to be diagnosed accurately and managed. IgE-mediated reactions can progress rapidly, and severe reactions are often associated with refractory bronchoconstriction. IgE-mediated allergic patients should be equipped with education, an emergency action plan, and injectable epinephrine to aggressively treat food-induced reactions and prevent fatalities.

Allergenic cross-reactivity of foods and characterization of food allergens and extracts.

OBJECTIVE: The intent of this review article is to familiarize the reader with the clinical implications of cross-allergenicity among foods, the allergens involved in the oral allergy syndrome, and the progress to date in the identification of major food allergens. DATA SOURCES: English language papers identified through a Medline search and bibliographies of the identified papers. STUDY SELECTION: Reference were selected that provided historical background or contributed significantly to our current understanding of the objectives. RESULTS: (1) Cross-allergenicity in food families is commonly demonstrated in vitro or by skin testing, but oral challenge results indicate that clinically relevant food allergy is usually specific, and dietary restrictions of entire food families are rarely needed. (2) Patients with pollinosis and the oral allergy syndrome have IgE binding that cross-reacts secondarily to binding of highly homologous proteins found in various unrelated plants (pollens) and foods. (3) Identification and characterization of several major food allergens from codfish, milk, egg, peanut, soybean, and shrimp have been accomplished. (4) Commercial food allergy extracts are currently non-standardized and not well characterized. CONCLUSIONS: Accurate diagnosis of food allergy is essential because of the potential for serious adverse reactions, but this fact should not lead to the unnecessary prescription of overly restricted diets based solely on results of in vitro or skin testing. The further identification of major allergenic components of food and the identification of specific IgE antibodies to these allergens should make the clinical approach to the treatment, understanding, and diagnosis of food hypersensitivity easier.

Sleep disturbances in children with atopic dermatitis.

OBJECTIVES: To test hypotheses based on clinical impressions that children with atopic dermatitis (AD) have frequent sleep-related problems, including difficulty falling asleep, night waking due to itching and scratching, and daytime symptoms of tiredness and irritability. DESIGN: Sleep habits and behaviors were assessed using the Child Sleep Behavior Scale (a 22-item Likert-type questionnaire for parents) in children with AD compared with normative data for age. Twelve questions were added to the questionnaire to address sleep-related habits relevant to night time pruritus, and to assess daytime behavioral symptoms of inadequate sleep. SETTING: Tertiary care center. PATIENTS: Fifty-nine children between ages 5 and 12 years meeting criteria for AD representing a referral population to a regional center. RESULTS: Compared with normative data, children with AD showed notable differences for nine of the 22 items on the sleep questionnaire, including the following: greater difficulty falling asleep, frequent night waking, less total sleep, and greater difficulty awakening for school. The children with AD also reported frequent daytime tiredness and irritability, and the severity of AD symptoms showed moderate correlations with sleep problems and with daytime behaviors suggestive of inadequate sleep. Difficulty falling asleep and night waking correlated with daytime behavior and discipline problems. CONCLUSIONS: Children with AD often have disrupted sleep and daytime behavioral difficulties associated with insufficient sleep. Improved sleep may be an important treatment focus in the clinical management of children with AD.

Allergenicity and antigenicity of chicken egg ovomucoid (Gal d III) compared with ovalbumin (Gal d I) in children with egg allergy and in mice.

When attempting to generate mouse monoclonal antibodies to hen's egg ovalbumin, injection of commercially purified ovalbumin resulted in monoclonal antibodies, which when assayed against commercially purified ovalbumin (Gal d I) or ovomucoid (Gal d III), appeared to be specific to both. With the use of high-performance liquid chromatography (HPLC)-repurified ovalbumin and ovomucoid in assay procedures, monoclonal antibodies generated by commercially purified ovalbumin were found to be specific for ovomucoid only. To clarify this phenomenon, mice were serially injected with commercially purified ovalbumin or HPLC-repurified ovalbumin. It was found that most of the antibody response to commercially purified ovalbumin was directed against the minor (< 1%) ovomucoid contaminant and that HPLC-repurified ovalbumin failed to produce antibodies to ovomucoid. Commercially purified ovomucoid resulted in only minimal amounts of antibodies to ovalbumin. Thus when commercially purified ovalbumin is used both for immunization and immunoassay, most of the antibodies produced are actually against the small amount of ovomucoid contaminant, and not ovalbumin. To determine whether ovomucoid is the major antigenic and allergenic egg white protein in human beings, one group of 18 children with egg allergy were skin prick tested with half-log dilutions of egg white extract and diethylaminoethyl cellulose (DEAE)-repurified ovomucoid, ovalbumin, and lysozyme. Ovomucoid mean wheal diameters were significantly greater than wheal diameters in response to ovalbumin, lysozyme, and egg white extract at the three most concentrated of five dilutions tested: 0.01, 0.03, and 0.1 mg/ml (p < 0.01). Serum ovomucoid-specific IgE and IgG antibody concentrations to DEAE-repurified ovomucoid were significantly greater than that to DEAE-repurified ovalbumin (p < 0.05). In a second study, 10 patients with egg allergy and persistent egg hypersensitivity were compared with 11 patients with egg allergy in whom clinical tolerance to egg developed. IgE antibodies to repurified ovomucoid were significantly greater in patients with persistent egg hypersensitivity compared with patients in whom clinical tolerance developed at the time of both initial and follow-up food challenges. In contrast, there were no significant differences in IgE antibody concentrations to repurified ovalbumin in either group at any time. These results suggest that ovomucoid is the immunodominant protein fraction in egg white and that the use of commercially purified ovalbumin has led to an overestimation of the dominance of ovalbumin as a major egg allergen and antigen in human beings.

Respiratory reactions provoked by double-blind food challenges in children.

A total of 320 children with atopic dermatitis undergoing double-blind, placebo-controlled food challenges (DBPCFC) for the evaluation of food hypersensitivity were monitored for respiratory reactions. The patients, ages 6 months to 30 yr, were highly atopic (median IgE; 3,400 IU/ml) and had multiple sensitivities to foods and aeroallergens. Fifty-five percent of the patients had asthma; 45% presented with both asthma and allergic rhinitis. Food hypersensitivity was confirmed by DBPCFC in 205 (64%) of the 320 patients evaluated, and 121 (59%) of these 205 patients experienced respiratory reactions, including nasal, laryngeal, and/or pulmonary symptoms in 34 (17%). To assess the degree of pulmonary dysfunction developing during food hypersensitivity reactions, especially those including lower respiratory symptoms, 88 of these patients were monitored with spirometry during positive and negative DBPCFC. Of these patients, 13 (15%) developed lower respiratory symptoms, including wheezing, during DBPCFC; however, only six patients had a > 20% decrease in FEV1. We conclude that respiratory symptoms are commonly provoked in children with atopic dermatitis during DBPCFC, but significant bronchopulmonary obstruction is not frequently observed.

Fish hypersensitivity. II: Clinical relevance of altered fish allergenicity caused by various preparation methods.

In double-blind, placebo-controlled, oral food challenges with fish, a 12-fold higher false-negative rate was found compared with other food antigens. In an effort to elucidate this discrepancy, cooked lyophilized fish extracts (used in double-blind, placebo-controlled, oral food challenges) were compared with cooked, nonlyophilized fish extracts (used in open challenges) by sodium dodecyl sulfate-polyacrylamide gel electrophoresis, immunoblot, and ELISA-inhibition assays. Altered fish allergenicity as a result of food processing was examined with canned tuna and salmon. Forty-five children and young adults with food allergies, including 18 patients with IgE-mediated hypersensitivity to fish, were challenged with canned tuna. All 45 challenges with canned tuna were negative. Two of these patients are allergic to salmon and also have negative reactions to challenges with canned salmon. In vitro investigation by sodium dodecyl sulfate-polyacrylamide gel electrophoresis of tuna and salmon extracts revealed a striking loss of definable protein fractions in the canned fish extract when compared with raw and cooked fish extracts, and immunoblot analyses demonstrated minimal IgE-specific binding to the canned fish extracts. In addition, decreased allergenicity of the canned tuna and salmon was demonstrated by ELISA-inhibition assay and by negative oral challenges with canned salmon in two patients allergic to salmon. Collectively, these findings suggest that some of the major allergens responsible for IgE-mediated food allergy to fish are more labile than previously recognized.

Fish hypersensitivity. I. In vitro and oral challenge results in fish-allergic patients.

The purpose of this study was to determine whether patients allergic to one fish species can safely eat other fish species. Eleven atopic, food-allergic children and young adults with histories consistent with IgE-mediated fish hypersensitivity were skin prick tested to 10 fish species. Skin prick tests (SPTs) were positive to all 10 fish in eight of the 11 patients, and the remaining three patients had at least two positive fish SPTs. Positive oral challenges occurred to only one fish in seven of the patients, to two fish species in one patient, and to three fish species in two patients. One patient did not react to any of the fish tested. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis and immunoblot analyses were performed on raw and cooked protein extracts from nine of the 10 fish species used in SPTs. Several protein bands in the raw-fish extracts appeared to denature with cooking and form high molecular weight conglomerates. Immunoblot analyses with sera from documented fish-allergic patients demonstrated specific IgE binding to protein bands from fish to which patients were not clinically allergic, as determined by oral challenge. In ELISA-inhibition assays, the concentration of fish antigen required to achieve 50% inhibition was similar for fish to which the patients were clinically allergic as compared to fish to which they were clinically tolerant. SPT and in vitro evidence of IgE-specific cross-reactivity does not necessarily correlate with symptomatic fish allergy. In addition, these fish-hypersensitive patients were able to consume one or more other fish species without adverse allergic reactions.

Safety of casein hydrolysate formula in children with cow milk allergy.

The purpose of this study was to determine whether a new casein hydrolysate infant formula, Alimentum, could be administered safely to children with cow milk hypersensitivity. The formula was analyzed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and with a sensitive enzyme-linked inhibition immunoassay, and it was judged to be safe for clinical trials in children allergic to cow milk. Twenty-five such children underwent double-blind placebo-controlled oral food challenges with 10 gm of powdered cow milk and casein hydrolysate formula. All children were highly atopic and had positive skin prick reactions to cow milk. No patient reacted to placebo during a double-blind, placebo-controlled food challenge. Two patients lost their allergy to cow milk and did not react during the challenge; the remaining patients reacted with a variety of cutaneous, respiratory, and gastrointestinal symptoms within 15 to 90 minutes of challenge. All children tolerated the blinded challenge to the casein hydrolysate and were fed the hydrolysate openly without difficulty. We conclude that this casein hydrolysate is generally safe to feed to children with immediate hypersensitivity to cow milk. We recommend that all infant formulas promoted as "hypoallergenic" be tested in milk-allergic patients to assess their allergenic potential, in addition to standard nutritional evaluation and animal testing for antigenicity.

Recombinant human interferon-gamma as adjunct therapy for Aspergillus infection in a patient with chronic granulomatous disease.

The hallmark of chronic granulomatous disease (CGD) is defective killing of ingested microorganisms by phagocytic cells. Invasive aspergillosis in CGD patients is particularly virulent and has a mortality rate of approximately 50%. A patient with autosomal recessive CGD was identified who had progressive pulmonary aspergillosis that was unresponsive to conventional antifungal therapy. She was treated with recombinant human interferon-gamma (rHuIFN-gamma) and had a dramatic improvement in clinical symptoms, sedimentation rate, and radiographic scans. No consistent improvement in bactericidal function or neutrophil oxidative capacity could be demonstrated. However, serum neopterin levels, a measure of macrophage activation, increased in a dose-dependent manner with rHuIFN-gamma therapy; increased levels mirrored the improved clinical parameters. This patient's treatment illustrates the usefulness of the single-photon emission computed tomography (SPECT) gallium scan for following pulmonary inflammatory lesions in the presence of fibrosis and indicates that rHuIFN-gamma may be of benefit to CGD patients with serious infections unresponsive to conventional therapy.

Allergenicity of orally administered immunoglobulin preparations in food-allergic children.

Passive immunization by the oral administration of immunoglobulin preparations derived from bovine milk, chicken egg, and human sera has been proposed as a method for the prevention and treatment of enteric diseases. However, the allergenic potential of these proteins may be a factor limiting their widespread use for disease prevention. An in vitro study with sera from milk- and egg-allergic children was performed to determine whether these immunoglobulin preparations have allergenic potential. Protein extracts of milk, bovine immunoglobulin, egg white, human immune globulin, and five egg yolk antiviral immunoglobulin preparations were bound to nitrocellulose paper. These preparations were probed for specific IgE binding with sera from milk- and egg-allergic patients. Of 22 milk-hypersensitive patients, 16 had specific IgE binding against the bovine immunoglobulin preparation. Of 28 egg-allergic patients 15 had specific IgE binding against one or more of the egg yolk-derived antiviral chicken immunoglobulins. Control sera were negative against the milk and egg preparations. Western blot analysis confirmed that milk- and egg-allergic patients had IgE-specific antibodies for bovine and chicken immunoglobulin molecules. Therefore, the removal of contaminating proteins from milk and egg antibody preparations would be unlikely to eliminate their allergenic potential. In contrast, sera from milk- and egg-allergic patients displayed no detectable IgE binding to human immunoglobulin preparations. These data indicate that the administration of antibody preparations derived from bovine and chicken sources may lead to severe allergic reactions in milk- or egg-sensitized patients and to sensitization in some nonallergic individuals.(ABSTRACT TRUNCATED AT 250 WORDS)

Cross-allergenicity in the legume botanical family in children with food hypersensitivity. II. Laboratory correlates.

Only two of 41 legume-allergic patients diagnosed by double-blind, placebo-controlled oral food challenge or "convincing history" of anaphylaxis had an IgE-mediated hypersensitivity reaction to more than one member of the legume family. However, extensive immunologic cross-reactivity was demonstrated among legume antigens on Immunoblot and Immunodot-blot analyses and prick skin tests. The proteins of six legumes (peanut, soybean, lima bean, pea, garbanzo bean, and green beans) were separated by sodium dodecyl sulfate-polyacrylamide gel electrophoresis, transferred to nitrocellulose, and probed with sera from six legume-allergic patients. Multiple IgE-binding bands were identified in each legume lane by the sera from each of these legume-allergic patients. In vitro cross-reactivity did not correlate with clinical hypersensitivity. All the legumes studied (except green bean) had a prominent band at 20 kd. Numerous proteins and protein subunits can be identified in each of the legumes (16 peanut, 21 soybean, 23 lima bean, 25 pea, 22 garbanzo bean, and 11 green bean protein bands) by sodium dodecyl sulfate-polyacrylamide gel electrophoresis, and it appears that legume-allergic patients' sera may recognize multiple similar fractions from each legume. A second in vitro test was performed in which the six legume extracts were bound directly onto nitrocellulose paper. These "legume" Immunodot blots were probed for specific IgE-binding activity with sera from 62 patients with positive legume prick skin tests. The legume Immunodot blots again demonstrated extensive clinically irrelevant cross-reactivity. However, this test may prove useful as a simple technique for screening food-specific IgE with minimal quantities of sera.

Spontaneous release of histamine from basophils and histamine-releasing factor in patients with atopic dermatitis and food hypersensitivity.

Patients with hypersensitivity to food documented by a double-blind, placebo-controlled oral food challenge have been reported to have a high rate of release of histamine from basophils in vitro. To determine whether patients with atopic dermatitis and food hypersensitivity had similar high rates of spontaneous histamine release in vitro, whether dietary elimination of relevant food antigens affected this release, and whether a cytokine, histamine-releasing factor, could account for it, we evaluated 63 patients with atopic dermatitis and food hypersensitivity (38 of whom had eliminated the offending foods from their diets), 20 patients with atopic dermatitis without food hypersensitivity, and 18 normal volunteers. Patients with atopic dermatitis and food hypersensitivity were found to have higher rates of spontaneous release of histamine from basophils than controls (mean +/- SE, 35.1 +/- 3.9 percent vs. 2.3 +/- 0.2 percent; P less than 0.001). Those who had eliminated the offending food allergen from the diet for an extended period had a significantly lower rate of histamine release (3.7 +/- 0.5 percent; P less than 0.001). In patients with atopic dermatitis without food hypersensitivity, the rate (1.8 +/- 0.2 percent) did not differ from that in normal controls. Mononuclear cells from persons with food allergies spontaneously produced a histamine-releasing factor in vitro that provoked the release of histamine from the basophils of other food-sensitive persons, but not from those of normal controls. Patients who adhered to a restricted diet had a decline in the rate of spontaneous generation of the factor by their mononuclear cells. The histamine-releasing factor was found to activate basophils through surface-bound IgE. We conclude that in patients with food hypersensitivity, exposure to the relevant antigens produces a cytokine (histamine-releasing factor) that interacts with IgE bound to the surface of basophils, causing them to release histamine.

Cross-allergenicity in the legume botanical family in children with food hypersensitivity.

Sixty-nine patients with one or more positive prick skin tests to legumes (peanut, soybean, green bean, pea, and lima bean) were evaluated for food hypersensitivity with in-hospital oral food challenges. Of the 280 prick skin tests to legumes performed, 130 were positive. Forty-three positive food challenges occurred in 41 patients. The prevalence of legume allergy was not statistically different in those patients (N = 36) with two or more positive legume prick skin test (64% positive) compared to those patients (N = 33) with only one positive legume prick skin test (55% positive; p greater than 0.10). Even in this selected patient population, only two patients had symptomatic hypersensitivity to two legumes. Among patients with a positive prick skin test to peanut (N = 60), the mean wheal size was larger in patients with a positive versus a negative oral food challenge to peanut (p less than 0.001). Results of oral food challenges demonstrate that clinically important cross-reactivity to legumes in children is very rare. Clinical hypersensitivity to one legume does not warrant dietary elimination of all legumes. Results of prick skin tests should not be used to determine prolonged food restriction diets.