Laboratory tests for diagnosis of food allergy: advantages,disadvantages and future perspectives

Numerous biological tests point to the diagnosis of food sensitization: detection of specific IgEs by Rast techniques, multi-detection assays, immunoblotting, screening of basophil activation (BAT or FAST), assays for leukotriene LTC4 release (CAST), measurement of plasma histamine, serum tryptase, serum ECP, urinary EDN, completed by mannitol-lactulose test evaluating intestinal permeability, assay of fecal IgEs, Rast for specific IgG4. Primary screening for anti-food IgEs by multi-detection assays seeks justification from insufficient clinical data and false positive tests are common in patients sensitized to pollens or latex, on account of in vitro cross reactivities (CR). Multiple CR explain positive Rast to vegetal food allergens in such patients. Biological tests should not be performed as the first line of diagnosis. In vivo sensitisation is assessed by positive prick-tests, demonstrating the bivalence of allergens, as well as the affinity of specific IgEs, two conditions necessary to bridge membrane bound specific IgEs, leading to the release of mediators. Prick-tests are closer to clinical symptoms than biological tests. However, the diagnosis of food allergy is based on standardised oral challenges. Exceptions are high levels of specific IgEs to egg (> 6 kUl/l), peanut (> 15 kUl/l), fish (> 20 kUl/l) and milk (> 32 kUl/l), reaching a 95% predictive positive value. Rast inhibition tests are useful to identify masked allergens in foods. Research developments will have impact on the development of new diagnostic tools: allergen mixes reinforcing a food extract by associated recombinant major allergens, multiple combination of recombinant allergens (chips) or tests with synthetic epitopes aimed a the prediction of recovery. Laboratory tests take place in the decision free for the diagnosis for the food allergy and the follow-up of the levels specific IgEs is a tool to assess outcome and contributes to predict recovery or persistent allergy. Up to now the significance of positive laboratory tests showing the implication of IgEs is at the crossroads of the allergist's and biologist's expertise.     

Adult food allergy

Adult food allergy is estimated at approximately 3.2% worldwide. The persistence of childhood food allergy is unusual, peanut allergies excepted. Once established in adults, food allergy is rarely cured. Factors favoring the acquisition of allergy could be sensitization to pollens, occupational sensitization by inhalation, drugs (such as tacrolimus), and sudden dietary changes. Severe anaphylaxis and oral allergy syndrome are frequent. The fatality risk is estimated at 1% in severe anaphylaxis. Risk factors for severe anaphylaxis are agents causing increased intestinal permeability, such as alcohol and aspirin. β-blockers, angiotensin-converting enzyme (ACE) inhibitors, and exercise are other factors. Gastrointestinal food allergy remains, to a large extent, undiagnosed in adults. Food allergens are mainly fruit and vegetable, related to pollen sensitizations, or to latex allergy. Wheat flour allergy is increasing. The diagnosis relies on prick skin tests, detection of specific IgEs, and standardized oral challenges. Strict avoidance diets are necessary. Specific immunotherapy to pollens may be efficient for cross-reactive food allergies.     

Baked Egg and Milk Exposure as Immunotherapy in Food Allergy

Baked milk and egg have the potential to act as a form of oral immunotherapy (OIT). Clinical studies have shown that a majority of milk- and egg-allergic children can tolerate these allergens modified in baked form, and immunologic changes reported in subjects ingesting baked milk and egg mirror those seen in food allergy OIT trials. In addition, several studies have indicated that resolution of milk and egg allergies occur sooner in populations regularly ingesting baked milk and egg. Oral food challenges remain the best method for determining tolerability of baked milk and egg since baseline characteristics and diagnostic testing have not been reliable predictors. In this review, we explore the tolerability of baked milk and egg and their potential as OIT treatment for milk and egg allergy.     

Définitions des termes utilisés en allergologie alimentaire chez l’enfant

In so far as there are no recent medical references that specify terms used in allergy, and particularly terms dealing with food allergy, it seemed to us that it would be of use to compile a glossary that would be helpful in daily practice. The defined terms (plus comments) have been retained according to sequences that correspond to steps in a food allergy work-up. The following terms are entered successively in this review: atopic dermatitis; SCORAD; asthma; pulmonary function tests; medications for children; symptoms and severity of food allergies; immediate skin tests; intradermal tests or “atopy patch-tests”; allergen-specific and total serum IgE levels; oral provocation test; labial provocation test; other tests used in allergy work-ups; allergy, hypersensitivity, atopy; allergens, allergies, sensitizations, allergic cross-reactions; treatment of an allergic reaction.     

Changes in prevalence and characteristics of IgE-mediated food allergies in children referred to a tertiary care center in 2003 and 2008

Although epidemiological trends in peanut allergy have been determined, there are limited data for changes in prevalence and clinical characteristics for other common food allergens. This study was performed to determine the trends in prevalence and clinical characteristics of physician-diagnosed pediatric food allergy (FA) at a large urban-based tertiary care center from 2003 to 2008. The electronic medical record system was searched to identify all unique patients with FA as a diagnosis for 2003 and 2008. Included patients had either a definite clinical reaction on ingestion and (1) a positive specific IgE or skin-prick test or (2) food-specific IgE of >90% specificity. Patients with allergies to cow's milk, eggs, fish, peanuts, sesame, shellfish, soy, tree nuts, and wheat were included. The percentage of FA clinic patients increased from 3 to 8% over 5 years. The severity of initial reactions to food also increased from 2003 to 2008 (p < 0.05). Mean initial food-specific IgE decreased from 52 kU/L in 2003 to 40 kU/L in 2003 (p = 0.002). The age at diagnosis decreased from 2003 to 2008 for cow's milk (2.64-1.36 years; p < 0.05) and fish (5.10-2.86 years; p < 0.05) allergies. Peanuts and shellfish were associated with anaphylaxis and severe symptoms in 2008. Clinical characteristics of food-allergic reactions in this large tertiary care center worsened in severity over 5 years and reactions were associated with a lower specific IgE at presentation for peanut and shellfish allergy. Clinical presentation of FA may change over time and this phenomenon warrants study to determine contributory factors.     

Cellular allergen stimulation test (CAST) 2003, a review.

Specific diagnosis of immediate type allergies, such as rhinoconjunctivis, asthma, urticaria/angioedema and anaphylaxis, particularly when IgE-mediated, traditionally rests on prick and/or intradermal skin tests and, since about 30 years, on the determination of allergen specific IgEs. Some cellular tests, i.e. tests determining the reactivity of blood cells in vitro, particularly basophils, to allergens, have been available for many years. The determination of histamine release has been widely used in allergy pathophysiological research but its routine application in allergy diagnosis has been restricted to few groups. Basophil degranulation, as determined by microscopic examination, was promoted by some groups in the 1980's but has been largely abandoned since around 10 years ago; an alternative cellular test, based on the determination of sulfidoleukotrienes (LTC4, LTD4, LTE4) produced by IL-3 primed basophils stimulated by allergens in vitro, has been proposed. This test became available commercially in 1993 under the name of CAST (Bühlmann Laboratories, Allschwil, Switzerland). The CAST assay has been used in allergy diagnosis in a variety of indications, such as inhalation allergies, allergies to insect venoms, foods, occupational allergens and various drugs. A large number of reports on CAST diagnostic value, however, have been anecdotal. A meta-analysis of validated and well controlled studies encompasses 37 studies, 1614 patients and 1145 controls. This should definitely establish the value of this diagnostic test, particularly in instances where other in vitro or in vivo diagnostic tests are not reliable, such as food or drug allergies, as well as in non-IgE-mediated immediate hypersensitivity reactions. However, a number of questions about the CAST diagnostic assay are still open or have not been systematically explored. This may explain, in addition to the practical limitations inherent to all allergy cellular tests, why CAST has not yet become a very widely used assay worldwide, having gained broad acceptance in some countries but not in others.     

Meeting the nutritional needs of the low-birth-weight infant

Approximately 5% of young children and 3-4% of adults exhibit adverse immune responses to foods in westernized countries, with a tendency to increase. The pathophysiology of food allergy (FA) relies on immune reactions triggered by epitopes, i.e. small amino-acid sequences able to bind to antibodies or cells. Some food allergens share specific physicochemical characteristics that allow them to resist digestion, thus enhancing allergenicity. These allergens encounter specialized dendritic cell populations in the gut, which leads to T-cell priming. In case of IgE-mediated allergy, this process triggers the production of allergen-specific IgE by B cells. Tissue-resident reactive cells, including mast cells, then bind IgE, and allergic reactions are elicited when these cells, with adjacent IgE molecules bound to their surface, are re-exposed to allergen. Allergic reactions occurring in the absence of detectable IgE are labeled non-IgE mediated. The abrogation of oral tolerance which leads to FA is likely favored by genetic disposition and environmental factors (e.g. increased hygiene or enhanced allergenicity of some foods). For an accurate diagnosis, complete medical history, laboratory tests and, in most cases, an oral food challenge are needed. Noticeably, the detection of food-specific IgE (sensitization) does not necessarily indicate clinical allergy. Novel diagnostic methods currently under study focus on the immune responses to specific food proteins or epitopes of specific proteins. Food-induced allergic reactions represent a large array of symptoms involving the skin and gastrointestinal and respiratory systems. They can be attributed to IgE-mediated and non-IgE-mediated (cellular) mechanisms and thus differ in their nature, severity and outcome. Outcome also differs according to allergens.     

Épidémiologie de l’allergie alimentaire

The epidemiology of food allergy normally relies on surveys using questionnaire in general populations and studies on cohorts and through professionals in allergy clinics, sometimes completed by prick-tests, specific IgE assays and/or oral challenges. Complementary data are supplied by specialized medical networks. In European countries, the prevalence of food allergy in the pediatric population is about 4.7%, and in adults it is about 3.2%. Striking disparities characterize the response to questionnaires in EU countries. Life-threatening anaphylaxis occurs in 1/10,000 inhabitants, fatal anaphylaxis in 1/1 million inhabitants. A drastic increase of life-threatening and lethal anaphylaxis has been noted in the UK and Australia over the past ten years. In France, there has been an increase of 28% between 2001 and 2006. The Allergy Vigilance Network, which includes 400 allergists, reports that this increase has occurred in the pediatric population. The prevalence of food allergies depends on age and consuming habits. Milk, egg, peanut and tree-nuts are at the top of the list in children. Prunoïdeae, latex-group fruits, Apiaceae, wheat and tree-nuts are the most important food allergens in adults. Peanut and tree nuts are the main offending allergens in severe anaphylactic cases. Since 2002 the Allergy Vigilance Network in France and Belgium has been identifying newly-appearing dangerous allergens. Molluscs, lupine flour and cashew nuts are the most common on this list and labelling these foods is now compulsory. Goat and sheep milk proteins (14 cases), buckwheat (25 cases) and wheat isolates are not yet required to be labelled. The danger of anaphylaxis to goat and sheep proteins (two deaths out of 14 cases) is due to the likelihood of their being masked allergens, for which reason the EU Scientific Agency should be made aware of the necessity of required labelling of foods containing these substances.     

The problems of the child with food allergies

In France, about 20% of schoolchildren are suffering from allergic diseases. Food allergy (FA) is steadily increasing for the last 20 years. Actually, 400,000 children are suffering from FA. Prevalence has increased this last decade. Frequency is estimated about 10% and increased twofold within 5 years. In France, the most common food allergens are: hen's egg (35%), peanut (24%), cow's milk (8%), mustard (6%), and fish (4%). Other food allergens as hazelnut, kiwi, wheat, sesame, seafood, and lupin. Cross reactivities to exist between fruits, vegetables pollen, latex and are more and more frequent. Multiple food allergies have recently been described.     

"Atopy patch tests" in the diagnosis of delayed food hypersensitivity

The prevalence of atopic diseases is increasing worldwide. Food allergies are the earliest manifestation of atopy. Atopic eczema affects about 18% of infants in the first 2 years of life and the main cause is allergy to multiple foods. A strong association has been shown between atopic eczema and IgE mediated allergy to milk, egg or peanut, but more than two-thirds of patients intolerant to food proteins have no evidence of IgE sensitization to the relevant food protein. Recently, patch testing with proteins has been found to be helpful in diagnosing food allergy in cases where skin prick tests and estimation of specific antibodies have failed. The methodology of atopy patch test (APT) is unstandardized, and contradictory results have been reported. In contrast to the more standardized APT methodology with aeroallergens, the sensitivities and specificities of food allergens can easily be estimated with food challenge tests. With multiallergic children adding of APTs to the skin prick tests and specific antibody estimation tests give more information for planning a wide enough elimination diet to get the skin and gastrointestinal tract symptomless in order to perform the challenge test which remains the only reliable test for food allergy. Standardization of the APT materials and reading procedure will add to the reliability of this new test method.     

Food allergy in gastroenterologic diseases： Review of literature

INTRODUCTION Food allergy is recognized as a common worldwide prob- lem, and, like other atopic disorders, its incidence seems to increase. Moreover, food-related allergic disorders are the leading cause of anaphylactic reactions treated in the emer- genc…     

Egg and milk allergy in asthmatic children: assessment by immulite allergy food panel, skin prick tests and double-blind placebo-controlled food challenges

There is a perception that asthmatic symptoms may be worsoned by ingestion of certain foods. This study aimed to investigate whether ingestion of cow's milk or egg might induce respiratory symptoms in asthmatic children. Fifty asthmatic children aged 1.5 to 6 years old, with positive Immulite Food Panel FP5 test results were included in the study. Fifty healthy children within the same age group were accepted as control group. Total serum IgE levels were measured and skin prick tests for food allergens including milk and egg were performed. All of the subjects underwent oral, double-blind, placebo-controlled challenge with fresh egg and cow's milk powder. Two medical histories were confirmed by double-blind, placebo-controlled challenge in 9 patients (22.2%). Skin prick tests were positive in 9 patients (18%) with milk and 18 patients (36%) with egg antigen. Two children experienced wheezing, one after ingesting milk and the other after egg challenge (4%). In the control group no positive reactions were seen with egg or milk challenges. Our findings confirm that food allergy can elicit asthma in children, but its incidence is low, even with major allergens such as egg and milk. History, specific IgE determinations and skin prick tests are not reliable in diagnosing food reactions. Since any diet can cause rapid deficiencies in infancy, diet restrictions must not be applied, without performing double-blind, placebo-controlled challenge.     

IgE-mediated food allergy--extensive review of the literature

Adverse reactions to food, i.e. food allergy and intolerance have gained considerable attention. This overview focuses on the diagnosis and management of IgE-mediated food allergy that is believed to be responsible for most immediate-type food-induced hypersensitivity reactions. Clinically, these reactions are characterised by a variety of signs and symptoms that occur within minutes or hours after consumption of the offending food. Reactions may be limited or more generalised with involvement of the skin, nose, eyes, and/or lungs. In more severe cases, cardiovascular symptoms including hypotension, shock, cardiac dysrhythmias and death can occur. In food-allergic individuals, IgE is produced against naturally occurring food components, primarily glycoproteins that usually retain their allergenicity after heating and/or proteolysis. While adults tend to be allergic to fish, crustaceans, peanuts and tree nuts, children tend to be allergic to cow's milk, egg white, wheat and soy more frequently. "Emerging" food allergens include tropical fruits, sesame seeds, psyllium, spices and condiments. These allergies frequently represent a cross-allergy to an allergen derived from another source, e.g. pollens or natural rubber latex. The evaluation of IgE-mediated food allergy relies on a careful history, physical examination, appropriate skin testing or in vitro testing with food extracts, and/or double blind, placebo-controlled food challenges. Avoidance remains the mainstay of therapy. However, allergens may be "hidden" and labelling can be non-precise or misleading, thereby severely hampering prevention. Patients with severe allergies should keep at hand an emergency kit with adrenaline, an antihistamine and an injectable rapid onset-of-action corticosteroid. At present there is no evidence to support the use of immunotherapy, except for research purposes. Production of "hypoallergenic" food is hampered by incomplete methods for assessing the allergenic potential of such novel foods.     

Allergies alimentaires précoces du nourrisson de 6 à 18 mois : étude de 69 cas

We report our findings on a group of 69 children without cow’s milk allergy who had one or several other food allergies between 6 and 18 months of age. Their initial symptoms were of moderate to severe intensity: 61 (88.5%) of them had had systemic symptoms, including angioedema (52%), generalized urticaria (36%), laryngeal edema (13%) and asthma (10%). In 11.5% of the patients, the first sign was severe acute eczema that did not respond to the usual treatment. The most important allergens, those identified with skin tests, serological assay for specific IgE antibody and labial or oral challenge tests, were egg (60.2%), peanut (50%), fish (10.3%) and cashew nut (5.8%). An atopic background was present in 90% of these infants. Of those allergic to eggs, 53% subsequently had no reaction to this food, whereas only one child allergic to peanuts and none of those allergic to cashew nuts or fish became symptom-free. Forty-three percent of the infants suffered from multiple food allergies, and asthma had developed in 33 (48%) of them. In conclusion, the early onset of food allergy and the presence of multiple sensitivities in this group of patients pointed to the seriousness and the unfavorable evolution of their allergic condition.     

Food allergy and asthma morbidity in children

BACKGROUND: Coexisting food allergy and asthma is a significant problem in the pediatric population. Studies have looked at the association between food sensitization and asthma severity. It is unknown whether specific food allergies are associated with increased asthma morbidity. OBJECTIVE: We studied the independent effect that allergy to egg, milk, fish, and peanut has on the number of hospitalizations and courses of systemic steroids in children with asthma. METHODS: We performed a medical record review to evaluate the effect food allergy to egg, fish, peanut, and milk has on asthma morbidity. We reviewed the records of 201 children aged 3 months to 14 years with the diagnosis of asthma (ICD-9 codes 493.90, 493.91, and 493.92), of which 88 had coexistent food allergy. All children in the food allergy group had food-specific IgE concentrations greater than the 95% positive predictive value. We compared the rate of hospitalizations and use of systemic steroids between children with asthma and food allergies and those without coexisting food allergy using direct-entry, multiple regression analysis. Patients were adjusted for the severity of their asthma based on symptoms documented at their first visit to the allergist according to the National Asthma Education and Prevention Program guidelines and presence of environmental allergy, eczema, smoke exposure, and gastroesophageal reflux. RESULTS: Peanut and milk allergies were both associated with increased number of hospitalizations (P=0.009, 0.016), and milk allergy was associated with increased use of systemic steroids (P=0.001). CONCLUSION: Peanut and milk allergies were associated with increased hospitalization and steroid use and may serve as early markers for increased asthma morbidity.     

Gastrointestinal allergy in adults

The prevalence of food allergy reaches 3% in the adult population. Chronic gastrointestinal allergy is a rare entity: 4.2% of food allergies in adults, and represents 3.2% of all intestinal disorders. Non-specific symptoms are the rule but eosinophilic gastrointestinal disorders are the subject of much interest. Endoscopy and biopsies of the gastrointestinal tract help the differential diagnoses. Food allergy is suspected from the patient's history leading to skin tests and laboratory tests identifying a sensitization but allergy is only confirmed by standardized challenges or eviction diets over a sufficiently long period. New types of investigations coupling oral challenges to foods to gastroenterological techniques should be studied further.     

Food allergy: a challenge for the clinician

Adverse reactions to food resulting in gastrointestinal symptoms and due to immunologic reactions (allergy) are discussed: their pathogenesis, the prevalence of food allergens and the clinical digestive expressions of food allergy in children and adults are reviewed. In IgE-mediated food allergy, the usefulness of the biological available tests is considered, mainly CAP tests, for proceeding to the diagnosis and the monitoring of the allergic disease. Finally, the best actual diagnostic tools in food allergy are considered (clinical history, skin tests, biological tests and food oral challenges), with their limitations and indications.     

Allergen Component Testing for Food Allergy: Ready for Prime Time?

Food allergies can cause life-threatening reactions and greatly influence quality of life. Accurate diagnosis of food allergies is important to avoid serious allergic reactions and prevent unnecessary dietary restrictions, but can be difficult. Skin prick testing (SPT) and serum food-specific IgE (sIgE) levels are extremely sensitive testing options, but positive test results to tolerated foods are not uncommon. Allergen component-resolved diagnostics (CRD) have the potential to provide a more accurate assessment in diagnosing food allergies. Recently, a number of studies have demonstrated that CRD may improve the specificity of allergy testing to a variety of foods including peanut, milk, and egg. While it may be a helpful adjunct to current diagnostic testing, CRD is not ready to replace existing methods of allergy testing, as it not as sensitive, is not widely available, and evaluations of component testing for a number of major food allergens are lacking.     

Food allergies

Opinion statement Food incompatibilities affect approximately 20% of the general population in Western countries. In about one quarter of the affected children and one tenth of affected adults, the incompatibility is based on an allergy, that is, on an immunologically generated incompatibility reaction. Gastrointestinal symptoms occur in a third of these cases. Food allergies are caused by IgE-dependent or Ige-independent immunologic reactions, which lead to an inflammatory reaction, in which mast cells, eosinophilic granulocytes, and other cells are involved. Both genetic and environmental causes are under consideration. New findings concerning the interaction between the innate immune system and intestinal microflora have generated innovative therapeutic concepts, including the use of probiotics to prevent food allergies. The development of recombinant allergens and varieties of allergens will improve diagnostic possibilities and bring new therapeutic options, such as hyposensitization and induction of immunologic tolerance. Food intolerances (nonimmunologic food incompatibilities often caused by specific enzyme deficiencies) must be diagnostically differentiated from food allergies.