Primary prevention of food allergy in 2021: Update and proposals of French-speaking pediatric allergists.

During the past years, there has been an alarming increase in cases of food allergy and anaphylaxis in ever-younger children. Often, these children have multiple food allergies and food sensitizations, involving allergens with high anaphylactic potential, such as peanuts and nuts, which have a major influence on their quality of life and future. After reviewing the current epidemiological data, we discuss the main causes of the increase in food allergies. We analyze data from studies on the skin barrier and its fundamental role in the development of sensitization and food allergies, data on the tolerogenic digestive tract applied in particular to hen eggs and peanuts, as well as data on the prevention of allergy to cow milk proteins. In light of these studies, we propose a practical guide of recommendations focused on infants and the introduction of cow milk, the management of eczema, and early and broad dietary diversification including high-risk food allergens, such as peanut and nuts while taking into account the food consumption habits of the family.

EAACI Molecular Allergology User's Guide.

The availability of allergen molecules ('components') from several protein families has advanced our understanding of immunoglobulin E (IgE)-mediated responses and enabled 'component-resolved diagnosis' (CRD). The European Academy of Allergy and Clinical Immunology (EAACI) Molecular Allergology User's Guide (MAUG) provides comprehensive information on important allergens and describes the diagnostic options using CRD. Part A of the EAACI MAUG introduces allergen molecules, families, composition of extracts, databases, and diagnostic IgE, skin, and basophil tests. Singleplex and multiplex IgE assays with components improve both sensitivity for low-abundance allergens and analytical specificity; IgE to individual allergens can yield information on clinical risks and distinguish cross-reactivity from true primary sensitization. Part B discusses the clinical and molecular aspects of IgE-mediated allergies to foods (including nuts, seeds, legumes, fruits, vegetables, cereal grains, milk, egg, meat, fish, and shellfish), inhalants (pollen, mold spores, mites, and animal dander), and Hymenoptera venom. Diagnostic algorithms and short case histories provide useful information for the clinical workup of allergic individuals targeted for CRD. Part C covers protein families containing ubiquitous, highly cross-reactive panallergens from plant (lipid transfer proteins, polcalcins, PR-10, profilins) and animal sources (lipocalins, parvalbumins, serum albumins, tropomyosins) and explains their diagnostic and clinical utility. Part D lists 100 important allergen molecules. In conclusion, IgE-mediated reactions and allergic diseases, including allergic rhinoconjunctivitis, asthma, food reactions, and insect sting reactions, are discussed from a novel molecular perspective. The EAACI MAUG documents the rapid progression of molecular allergology from basic research to its integration into clinical practice, a quantum leap in the management of allergic patients.

Cross-reactivity to fish and chicken meat - a new clinical syndrome.

BACKGROUND: Fish is one of the most allergenic foods. While clinical cross-reactivity among different fishes is a widely accepted feature of fish allergy, associations with other food allergies are not well understood. This study aims at analyzing the relevance of clinical cross-reactivity between fish and chicken meat in patients with allergy to chicken meat without sensitization to hen's eggs. METHODS: Patients with food allergy to fish and chicken meat (n = 29) or chicken meat only (n = 7) were recruited. IgE-reactive chicken proteins were identified (Edman, MS analysis) and quantified (ELISA). Allergens were used in IgE ELISA and skin testing. RESULTS: Chicken parvalbumin and two new allergens, aldolase and enolase, were identified at 12, 40, and 50 kDa, respectively. They were recognized by sIgE of 61%, 75%, and 83% of all patient sera which were in the majority of the cases positive for the fish homologues as well. Fish and chicken meat allergens were highly cross-reactive while high inhibition rates with fish or chicken allergens correlated with the patients' primary sensitization to fish or chicken. In cooked or roasted foods, enolase and aldolase were detectable in chicken breast while parvalbumin was detectable in chicken legs and wings. CONCLUSIONS: Fish and chicken meat are cross-reactive foods; both fish-allergic and chicken meat-allergic patients might be at risk of developing a food allergy to chicken meat or to fish, respectively. This clinical phenomenon is proposed to be termed 'fish-chicken syndrome' with cross-reactive allergens involved being parvalbumins, enolases, and aldolases.

Two galactose-α-1,3-galactose carrying peptidases from pork kidney mediate anaphylactogenic responses in delayed meat allergy.

BACKGROUND: Serum IgE antibodies directed at galactose-α-1,3-galactose (α-Gal) are associated with a novel form of delayed anaphylaxis occurring upon consumption of red meat or innards. Pork kidney is known as the most potent trigger of this syndrome, but the culprit allergens have not yet been identified. The aim of this study was the identification and characterization of pork kidney proteins mediating delayed anaphylactic reactions through specific IgE to α-Gal. METHODS: A cohort of 59 patients with specific IgE to α-Gal was screened by immunoblot for IgE-reactive proteins in pork kidney. Proteins were identified by peptide mass fingerprinting. Isolated proteins were assayed in ELISA and ELISA inhibition, basophil activation and skin prick test. RESULTS: Several IgE-binding proteins of high molecular weight (100- >200 kDa) were detected in pork kidney extracts by immunoblot using patient sera and an anti-α-Gal antibody. Two major IgE-binding proteins were identified as porcine angiotensin-I-converting enzyme (ACE I) and aminopeptidase N (AP-N). Reactivity of patient sera and anti-α-Gal antibody to both proteins was abolished by carbohydrate oxidation. The α-Gal IgE epitopes were resistant to heat denaturation. Pork kidney extract, isolated ACE I, and AP-N were able to activate patient basophils and elicit positive responses in skin prick tests. CONCLUSION: Two cell-membrane proteins carrying α-Gal epitopes were identified in pork kidney. For the first time, isolated meat proteins were shown to induce basophil activation in patients with delayed anaphylaxis to red meat providing further confirmation for the clinical relevance of these α-Gal-carrying proteins.

Identification of enolases and aldolases as important fish allergens in cod, salmon and tuna: component resolved diagnosis using parvalbumin and the new allergens.

BACKGROUND: The majority of fish-allergic patients are sensitized to parvalbumin, known to be the cause of important IgE cross-reactivity among fish species. Little is known about the importance of fish allergens other than parvalbumin. OBJECTIVE: The aim of this study was to characterize hitherto undefined fish allergens in three commonly consumed fish species, cod, salmon and tuna, and to evaluate their importance for in vitro IgE-diagnosis in addition to parvalbumin and fish gelatin. METHODS: Sixty-two patients were diagnosed by clinical history, skin prick tests and specific IgE to fish extracts. Two new fish allergens from cod, salmon and tuna were identified by microsequencing. These proteins were characterized by immunoblot, ELISA and mediator release assay. Purified parvalbumin, enolase, aldolase and fish gelatin were used for quantification of specific IgE in ELISA. RESULTS: Parvalbumin and two other allergens of 50 and 40 kDa were detected in IgE-immunoblots of cod, salmon and tuna extracts by most patient sera. The 50 and 40 kDa proteins were identified as beta-enolase and fructose-bisphosphate aldolase A respectively. Both purified enzymes showed allergenic activity in the mediator release assay. Indeed, 72.6% of the patients were sensitized to parvalbumin, 20% of these had specific IgE to salmon parvalbumin only. IgE to enolases were found in 62.9% (0.5-95.0 kUA /L), to aldolases in 50.0% (0.4-26.0 kUA /L) and to fish gelatin in 19.3% (0.4-20.0 kUA /L) of the patients. Inter-species cross-reactivity, even though limited, was found for enolases and aldolases by IgE-inhibition ELISA. CONCLUSIONS AND CLINICAL RELEVANCE: Fish enolase and aldolase have been identified as important new fish allergens. In fish allergy diagnosis, IgE to enolase and aldolase are especially relevant when IgE to parvalbumin are absent.

Anaphylaxis to pork kidney is related to IgE antibodies specific for galactose-alpha-1,3-galactose.

BACKGROUND: Carbohydrate-specific IgE antibodies present on nonprimate mammalian proteins were incriminated recently in delayed meat anaphylaxis. The aim of this study was to explore whether anaphylaxis to mammalian kidney is also associated with galactose-α-1,3-galactose (αGal)-specific IgE. METHODS: Fourteen patients with anaphylaxis to pork or beef kidney underwent prick tests to meat and kidney. Some patients also underwent skin tests to Erbitux(®) (cetuximab). IgE antibodies to αGal, swine urine proteins, beef and pork meat, serum albumin proteins, cat, and rFel d 1 were measured by ImmunoCAP(®). The αGal levels were estimated in meats and kidney by ELISA inhibition assay. Cross-reactivity between αGal and pork kidney was studied with the ImmunoCAP(®) inhibition assay. RESULTS: Among the 14 patients, 12 presented with anaphylactic shock. Reactions occurred within 2 h from exposure in 67% of patients. Associated risk factors were observed in 10 cases, and alcohol was the main cofactor. Three patients underwent an oral challenge to pork kidney, and anaphylaxis occurred after ingestion of small quantities (1-2 g). Prick tests to kidney were positive in 54% of patients. All tested patients showed positive skin tests to Erbitux(®). All patients tested positive for IgE to αGal, with levels ranging from 0.4 to 294 kU/l. IgE binding to αGal was inhibited by raw pork kidney extract (mean, 77%; range, 55-87%), which showed a high amount of αGal determinants. CONCLUSIONS: Pork or beef kidney anaphylaxis is related to αGal IgE. Its peculiar severity could be due to an elevated content of αGal epitopes in kidney.

Prevalence of sensitisation to oilseed rape and maize pollens in France: a multi-center study carried out by the Allergo-Vigilance Network.

BACKGROUND: Oilseed rape and maize crops represent a large part of agriculture fields in European countries. OBJECTIVE: To establish the actual prevalence of sensitization to oilseed rape and maize pollen, and to determine if this is correlated to the amount of exposure as well as to the patient's history of atopy or asymptomatic atopy. METHODS: The study was conducted by 69 allergists belonging to the Allergo-Vigilance Network, in collaboration with the French Agency for Safety of food, and compiles the results of skin prick-tests using oilseed rape and maize pollens and seeds, as well as common aeroallergens. The patients were classified into 3 groups: nonatopic, asymptomatic atopy, and actual atopic diseases. RESULTS: Among the 5372 subjects studied (2515 children, 2857 adults), 62.3% had an atopic disease, 10.2% had an asymptomatic atopy, and 27.5% were non-atopic. The level of sensitization was higher in the subjects with atopic disease, as compared to those with asymptomatic atopy: oilseed rape pollen: 11.8% vs 8%, maize pollen, 26% vs 19%, oilseed rape seeds, 7.7% vs 6.9%, corn seeds: 8.3% vs 4.8% (p < 0.001). The rate of sensitization was significantly increased in those living in high crop density regions. The association of an atopic disease with a high rate of exposure yielded a higher rate of sensitization of 13.8% and 21.3% for rapeseed pollen, and 22.9% and 30.7% for maize pollen in both children and adults, respectively. CONCLUSIONS: The incidence of sensitisation to rapeseed and maize pollen is positively correlated to the level of exposure. This prevalence is higher in patients with actual atopic disease as compared to those with asymptomatic atopy. The frequency of sensitization confirms the allergenicity of these plants destined for food supply and demonstrates the importance of monitoring for respiratory allergies to these pollens, not only in workers exposed to these types of crops, but also in atopic patients living in regions that contain a high density of rapeseed and maize fields. Cross-reactivities between pollens and seeds could potentially elicit cross-reacting food allergies.

A novel immunoassay using recombinant allergens simplifies peanut allergy diagnosis.

BACKGROUND: Double-blind placebo-controlled food challenge (DBPCFC) is currently considered the gold standard for peanut allergy diagnosis. However, this procedure that requires the hospitalization of patients, mostly children, in specialized centers for oral exposure to allergens may cause severe reactions requiring emergency measures. Thus, a simpler and safer diagnosis procedure is needed. The aim of this study was to evaluate the diagnostic performance of a new set of in vitro blood tests for peanut allergy. METHODS: The levels of IgE directed towards peanut extract and recombinant peanut allergens Ara h 1, Ara h 2, Ara h 3, Ara h 6, Ara h 7, and Ara h 8 were measured in 3 groups of patients enrolled at 2 independent centers: patients with proven peanut allergy (n=166); pollen-sensitized subjects without peanut allergy (n=61), and control subjects without allergic disease (n=10). RESULTS: Seventy-nine percent of the pollen-sensitized patients showed IgE binding to peanut, despite their tolerance to peanut. In contrast, combining the results of specific IgE to peanut extract and to recombinant Ara h 2 and Ara h 6 yielded a peanut allergy diagnosis with a 98% sensitivity and an 85% specificity at a positivity threshold of 0.10 kU/l. Use of a threshold of 0.23 kU/l for recombinant Ara h 2 increased specificity (96%) at the cost of sensitivity (93%). CONCLUSION: A simple blood test can be used to diagnose peanut allergy with a high level of precision. However, DBPCFC will remain useful for the few cases where immunological and clinical observations yield conflicting results.

A non-hydrolyzed, fermented milk formula reduces digestive and respiratory events in infants at high risk of allergy.

BACKGROUND/OBJECTIVES: To determine the impact of a not hydrolyzed fermented infant formula containing heat-killed Bifidobacterium breve C50 and Streptococcus thermophilus 065 (HKBBST) on the incidence of allergy-like events during the first 2 years of life in children at high risk of atopy. SUBJECTS/METHODS: This multicenter, randomized, double-blind, controlled study included infants at high risk of atopy. Infants used HKBBST or a standard infant formula (SIF) since birth until 1 year of age, and were followed at 4, 12 and 24 months after birth. Skin prick tests (SPTs) for six foods and six aeroallergens were systematically performed and adverse events (AEs) were recorded. In case of potentially allergic AE (PAAE), allergy could be further tested by SPT, patch tests and quantification of specific IgEs. If cow's milk allergy (CMA) was suspected, an oral challenge could also be performed. RESULTS: The study included 129 children, 63 were randomized to SIF, 66 to HKBBST. The use of HKBBST milk did not alter the proportion of CMA but decreased the proportion of positive SPT to cow's milk (1.7 vs 12.5%, P=0.03), and the incidence of digestive (39 vs 63%, P=0.01) and respiratory potentially allergic AEs (7 vs 21%, P=0.03) at 12 months, and that of respiratory PAAEs at 24 months (13 vs 35%, P=0.01). CONCLUSIONS: HKBBST decreased the incidence of PAAEs in children with family history of atopy, during the first months of life and after the formula was stopped. Oral tolerance to cow's milk in infants at high risk of atopy may therefore be improved using not hydrolyzed fermented formulae.

Prospective study of sensitization and food allergy to flaxseed in 1317 subjects.

BACKGROUND: Foods containing flaxseed proteins rich inpolyunsaturatedfatty acids are new on the market. OBJECTIVES: In a population of patients attending the allergology department, we evaluated the frequency of sensitization to flaxseed, characterized allergens and looked for modifications related to industrial processing. METHODS: Natural, heated and extruded flaxseeds were tested using prick-in-prick tests (PIP using the fresh seed), SDS PAGE, immunoblots, immunoblot inhibition and Fourier Transform Infrared (FTIR) spectroscopy. RESULTS: PIP tests to natural flaxseed were positive in 5.8% of the 1317 patients. 73 of 77 PIP-positive patients were atopic. There was cross-reactivity with five seeds. peanut, soybean, rapeseed, lupine and wheat, and with rape pollen. Immunoblot inhibition by bromelain confirmed the presence of specific IgE to cross-reactive carbohydrate determinants (CCD). 0.15% of this population presented with food allergy to flaxseed and positive PIP to heated and extruded flaxseed. Two sera showed that clinically relevant allergens in industrial products had MW between 25 and 38 kDa. Sensitization to processed flaxseed characterized only the allergic subjects. FTIR spectroscopy showed major modifications in 3 and alpha structures following industrial processing. CONCLUSION: Positive prick tests to natural flaxseed were mainly due to cross-reactions. Flaxseed allergy is rare and could be detected by PIP to heated extruded flaxseed. Increasing consumption callsfor monitoring of clinical risk.

Peanut allergy diagnosis in the context of grass pollen sensitization for 125 patients: roles of peanut and cross-reactive carbohydrate determinants specific IgE.

BACKGROUND: In vitro testing for food allergy may yield clinically irrelevant results due to cross-reactive carbohydrate determinants (CCD) specific immunoglobulin E (sIgE) induced by pollen exposure. The performances of 2 in vitro methods were evaluated for peanut sIgE measurement in patients allergic to grass pollen with or without subsequent allergy to peanuts. The correlation between clinically irrelevant peanut sIgE and the presence of CCD sIgE was investigated. METHODS: In vitro measurement of peanut sIgE was performed using the Pharmacia ImmunoCap system Radio Immuno Assay (RIA) and the Immulite 2000 3gAllergy system. Discrepancies between in vitro results and peanut allergy diagnosis were evaluated by measurement of CCD sIgE using bromelain and ascorbic acid oxydase (AAO). RESULTS: The sensitivity was 100% with both systems for the diagnosis of allergy to peanut (58 patients), nevertheless the specificity obtained with Immulite (73%) was better than that obtained using ImmunoCap (46%) in patients who were not allergic to peanuts, but who had a grass pollen allergy (n = 41). In 22 out of 41 patients who presented clinically irrelevant peanut sIgE results using ImmunoCAP, CCD sIgE was detected in 72% of the cases by bromelain and in 86% by AAO. In 11 patients out of 41 who presented irrelevant peanut sIgE results using Immulite, CCD sIgE was detected in 81% of the cases by bromelain and in 100% by AAO. CONCLUSION: The Immulite 2000 system had better specificity than the ImmunoCap system for accurate diagnosis of peanut allergy in patients allergic to grass pollen. CCD sIgE was identified in most of the false-positive peanut sIgE results.

Pre-lethal anaphylaxis to carboxymethylcellulose confirmed by identification of specific IgE--review of the literature.

BACKGROUND: Carboxymethylcellulose (CMC) is used extensively in the pharmaceutical and food industries on account of its various properties. Anaphylactic reactions are rare. It has been reported principally after intra-articular infiltration of sustained-release corticosteroids containing CMC and, very rarely, after barium enema. METHODS: A case of pre-lethal anaphylactic shock after barium enema was studied by prick-test, intra-dermal reaction (IDR), leukocyte histamine release test (LHRT), basophil activation test (BAT), cystein-leukotriene release test (CAST) and dot-blot analysis. RESULTS: IDR to CMC was positive at a concentration of 10 microg/ml. BAT and CAST were positive. Specific IgE were identified using dot-blot analysis. DISCUSSION: This is the third report of CMC-specific IgE and the second of anaphylaxis to CMC associated with a barium suspension in contact with GI tract mucosa. CMC as an excipient in medicinal products may therefore be a risk factor for severe anaphylaxis after injection or following contact with GI tract mucosa. Sensitization and allergic reactions by CMC in food additives have to be considered.

Interest of ImmunoCAP system to recombinant omega-5 gliadin for the diagnosis of exercise-induced wheat allergy.

BACKGROUND: omega-5 gliadin is a major allergen in exercise-induced wheat allergy (EIWA), but it is also implicated in immediate-type reactions to wheat. An ImmunoCAP assay to measure omega-5 gliadin-specific IgE has become available. This study aimed to evaluate this new biological test in wheat allergy diagnosis and to also determine if it was able to discriminate EIWA from other types of wheat allergy. METHODS: Sixty-one patients with wheat allergy were divided into 3 groups as a function of their symptoms (EIWA, immediate-type reactions and atopic dermatitis). These patients underwent skin prick tests with purified omega gliadins and ImmunoCAP to wheat flour, gluten and recombinant omega-5 gliadin. RESULTS: The experimental data showed that 78% of EIWA patients had a positive skin prick test to natural omega-5 gliadin and the same proportion had detectable specific IgE to recombinant omega-5 gliadin, indicating that omega-5 gliadin is the main allergen, but not the only one, in our population. Additionally, we showed that this detection was not EIWA specific since omega-5 gliadin-specific IgE was detected in 30% of other patients who had a wheat allergy. These results lead to a positive predictive value of 37.5% and to a negative predictive value of 91%. CONCLUSIONS: Although not specific to EIWA, the new ImmunoCAP omega-5 gliadin is an important biological test because of its negative predictive value. In case of food-dependent exercise-induced allergy, the absence of omega-5 gliadin-specific IgE will almost completely exclude the implication of wheat.

Evaluation of an in vitro mast cell degranulation test in the context of food allergy to wheat.

BACKGROUND: Antigenic profiles obtained by ELISA with IgE from patients with wheat food allergy (WFA) established that major allergens are albumins/globulins (AG) for children suffering from atopic eczema/dermatitis syndrome (AEDS), omega5-gliadins for adults suffering from wheat-dependent exercise-induced anaphylaxis (WDEIA), anaphylaxis or urticaria and low-molecular-weight (LMW) glutenin subunits for patients with anaphylaxis. We aimed to characterize a new mast cell transfectant for its ability to degranulate with wheat proteins and patient sera and compare these results to those obtained by ELISA. METHODS: Thirty sera from patients with WFA were tested: 14 with AEDS (group 1) and 16 with WDEIA, anaphylaxis or urticaria (group 2). An IgE Fc receptor (FcepsilonRI) humanized rat RBL-2H3 line was established by transfection with cDNAs encoding alpha-, beta- and gamma-subunits for the human IgE receptor. RESULTS: A humanized RBL clone was selected for its capacity to express mRNA alpha-, beta- and gamma-subunits of FcepsilonRI, to bind allergen-specific human IgE and to degranulate. In group 1, sera induced enhanced degranulation with AG extract, but rarely reacted with gliadins and glutenins. In group 2, half of the sera showed degranulation with LMW glutenins whereas the AG fraction and lipid transfer proteins were rarely positive. omega5-Gliadins did not appear as a major allergen in degranulation assays, although functional allergen-specific IgE was measurable in appreciable amounts. CONCLUSION: Our data demonstrate that in wheat food allergen evaluation, correlation exists between mast cell degranulation and IgE measurements, depending on the type of allergen. Therefore, the biological activity of some allergen types may also be affected by other parameters.

Oral desensitization in children with milk and egg allergies obtains recovery in a significant proportion of cases. A randomized study in 60 children with cow's milk allergy and 90 children with egg allergy.

BACKGROUND: Food allergy is treated by avoidance diets in order to prevent anaphylactic reactions and to cure chronic associated symptoms. However, the natural history is left unchanged. OBJECTIVE: To search for a beneficial effect of an oral desensitization protocol to allergenic foods in IgE-dependent milk or egg allergies in children. METHODS: 60 children with documented cow's milk allergy (13 months-6.5 years), and 90 children with egg allergy (12 months-8 years), were consecutively included after 6-12 months of avoidance diet, if a SBPCFC to 60 ml milk (60 ml) or to 965 mg of raw egg white was negative. They were randomized for uninterrupted avoidance or oral desensitization (group A or OD). Six months later, a new SBPCFC was performed with, up to 200 ml of milk or 7g of raw egg white. Prick tests and specific IgE levels were carried out simultaneously. RESULTS: Data were obtained for 57 children with CMA (30 A and 27 OD), and 84 children with EA (35 A and 49 OD). The two groups (AD or OD group) were similar with regard to means of ages, the size of PT wheals and the level of IgEs at baseline. MILK ALLERGY: A SBPCFC to milk was positive in 11.1% of those following OD vs. 40% after A (p < .025). The size of PT decreased after OD and increased after A (-3.4 mm vs. +0.84 mm; p < .002). EGG ALLERGY: The SBPCFC to egg was positive in 30.6% after OD vs. 48.6% after A (p < .1). After 6 months, in the OD group, the mean size of the PT and the level of specific IgE were significantly reduced compared to the A group. In the A group, the threshold of reactivity was often lower, or more serious symptoms were observed. CONCLUSION: Oral desensitization helps the egg and milk allergic children to overcome their allergies. Since the avoidance of these foods is likely to increase sensitization as well as to lower the threshold of reactivity, an active treatment is required. Further attempts to standardize the procedures of oral desensitization are expected.