Gender, prick test size and rAra h 2 sIgE level may predict the eliciting dose in patients with peanut allergy: Evidence from the Mirabel survey.

BACKGROUND: Peanut allergy management is based on active avoidance and access to emergency treatment including self-injectable adrenaline. Knowing the dose at which a patient is likely to react is crucial for risk assessment and could significantly improve management by integrating a personalized approach. OBJECTIVE: To develop a threshold dose distribution curve model from routinely collected data. METHODS: The MIRABEL survey is an observational study of 785 patients with peanut allergy/sensitization conducted in France, Belgium and Luxemburg. The current analysis included the 238 participants for whom medical and oral food challenge data were available. Several statistical models (Kaplan-Meier, Cox model, Weibull and Lognormal with predictive factors, basic Weibull and Lognormal) were compared to select the best model and predictive factor combination associated with the threshold doses. Inferences were made with a Bayesian approach. RESULTS: Patients were mainly children (mean age: 9 years [IQR: 6-11]; 87% < 16 years) and males (62%). Median Ara h2 s IgE was of 8kUA/L [IQR: 1-55] and median skin prick test size of 10 mm [IQR: 7-13]. OFC was positive in 204 patients (86%). The median threshold dose was of 67 mg of peanut protein [IQR: 16-244]. The dose at which 1% of the patients are likely to react with objective symptoms was 0.26 [0.03; 2.24] mg of peanut protein. Gender, size of the skin prick test (SPT) and Ara h 2 specific IgE level had a significant impact on the threshold dose distribution curve. The Cox model was the most effective to predict threshold doses with this combination of factors. Girls react to lower doses than boys with a beta coefficient associated to the risk and a 95% credible interval of 0.44 [0.04; 0.77]. The higher the size of the SPT and the Ara h 2 specific IgE level are, the higher the risk of reacting to a small amount of peanut, with beta coefficients associated to the risk and 95% credible intervals of 0.05 [0.02; 0.08] and 0.01 [0.01; 0.02], respectively. CONCLUSION AND CLINICAL RELEVANCE: According to the model, routinely collected data could be used to estimate the threshold dose. The consequences could be the identification of high-risk patients who are susceptible to react to small amounts of peanut and a personalized management of peanut allergy integrating the risk of allergic reaction. Limitations of this study are that assessors of OFC outcome were aware of SPT and Arah2 results, and a further validation study is required to confirm the predictive value of these parameters.

[Genesis of food allergy in infancy]. / Genèse de l'allergie alimentaire du nourrisson: possibilité d'une prophylaxie partielle.

Food allergy originates from physiological fetal Th2 polarization. The normal shift towards Th1 dominance during the first months of life is defective in the atopic infant. Several factors are critical for the development of food allergy. The influence of genetic factors has been shown by familial aggregation studies, and numerous candidate genes have been identified Gene polymorphisms interact with the environment, contributing to fetal programming Heritable epigenetic modifications occur rapidly in response to environmental factors and may explain the recent increase in food allergies and other atopic diseases. Atmospheric agents and the maternal diet during pregnancy may either increase or decrease the risk. Birth conditions, the intestinal microbiota, age at which food diversification begins, and exposure to food allergens and pollutants by inhalation, ingestion and skin contact may all contribute to the onset of food allergy in infancy. Partial prophylaxis is now within reach. Preventive information must be provided to families at high risk of atopy in their offspring.

[Drugs as risk factors of food anaphylaxis in adults]. / Facteurs de risque d'anaphylaxie alimentaire sévère : rôle confirmé de certaines classes de médicaments.

Anaphylaxis is the most severe type of food allergy. Factors of risk are advanced age, cardiopathy, asthma, mastocytosis. Age may be linked to an increased consumption of drugs: aspirin, nonsteroidal anti-inflammatory drugs, beta-blockers, inhibitors of angiotensin converting enzyme (ACE). A case-control study comparing anaphylaxis and mild food allergies has shown a sharp increase of consumption of these drugs in patients with anaphylaxis, with odds ratio respectively of 10.8 [CI 95%: 3.10-41.3], 8.2 [CI 95%: 1.37-62.51], 6.8 [CI 95%: 1.78-27.78] and 13 [CI 95%: 1.34-310.38]. Besides, exercise potentiates the relative risk of drug consumption. Predominant mechanisms could be an increase of gut permeability enhancing the passage of food allergens in the mucosa and in blood, and the inhibition of ACE, so that the angiotensin homeostatic mechanism deteriorates. Main sites of interference may be endothelium and gut epithelium. Preventive measures excluding the intake of aspirin and nonsteroidal anti-inflammatory drugs before the meals can be recommended for food allergic and food sensitized adults. Treatment of hypertension can address to other families of drugs than ACE inhibitors (ACEI) and beta blockers. The benefit-risk ratio of beta blockers and ACEI has to be carefully considered in the case of cardiopathy. double dagger.

[Eosinophilic inflammation in allergic diseases]. / L'eosinophile: implication dans l'inflammation des maladies allergiques.

Tissular eosinophilia is a common feature of IgE-dependent allergic diseases. The classical concept links activated Th2 lymphocytes to eosinophil attraction and activation. However, comparisons of allergic diseases with non atopic "mirror "diseases reveal more complex underlying pathophysiological mechanisms. This article explores the links between allergic asthma and intrinsic asthma or asthma of the Churg-Strauss syndrome, nasal polyposis, vernal conjunctivitis, eosinophilic esophagitis (food allergy-induced or non allergic), DRESS, Ofuji disease, and eosinophilic cystitis. The results of recent mechanistic studies show that Th2 activation coupled with tissular eosinophilia can no longer be considered a hallmark of atopy. Allergic inflammation may depend on Th1 activation (vernal conjunctivitis, DRESS, eosinophilic esophagitis, etc) and simultaneous viral infection, eliciting drug hypersensitivity (DRESS). A predominant role of the epithelium in eosinophil attraction is an alternative concept with a sound basis in eosinophilic esophagitis. This concept could lead to new therapeutics aimed at controlling epithelial eotaxin 3 expression.

Metallopeptidase activities in hereditary angioedema: effect of androgen prophylaxis on plasma aminopeptidase P.

BACKGROUND: Aminopeptidase P (APP) plays an important role in the catabolism of kinins in human plasma, mostly for des-Arg(9)-bradykinin. Impaired degradation of this active bradykinin metabolite was found to be associated with a decreased APP activity in hypertensive patients who experienced angioedema while being treated with angiotensin I-converting enzyme inhibitors. The pathophysiology of hereditary angioedema is presently attributed only to a quantitative/qualitative C1 inhibitor (CI-INH) defect with increased bradykinin release. OBJECTIVES: In the context of androgen prophylaxis, increased CI-INH function cannot fully explain protection from angioedema attacks alone because of the limited reversion of the CI-INH defects. Therefore we hypothesized that androgen prophylaxis could enhance plasma APP activity. METHODS: Patients with hereditary angioedema were investigated for plasma metallopeptidase activities responsible for kinin catabolism (APP, angiotensin I-converting enzyme, and carboxypeptidase N) and for CI-INH function in treated and untreated patients. RESULTS: APP activity was asymmetrically distributed in untreated patients (n = 147): the mean value was significantly lower than the value in a reference healthy and unmedicated population (n = 116; P < or = .001). Prophylaxis with androgen induced a significant increase in APP activity (P < or = .001), whereas it did not affect the other metallopeptidase activities. In both patient groups, APP activity showed a significant inverse relationship to disease severity (P < or = .001). CONCLUSION: In addition to the effect on circulating CI-INH levels, the increase in APP levels brought on by androgens could contribute to a more effective control of the kinin accumulation considered to be responsible for the symptoms of angioedema.

[Drugs as risk factors of food anaphylaxis in adults: a case-control study]. / Médicaments facteurs de risque de sévérité de l'anaphylaxie alimentaire de l'adulte. Etude cas-contrôle.

Between 1995 and 2008, a case-control study was conducted to determine the role of drugs as risk factors for severe food anaphylaxis in adults. Data including exercise, alcohol intake, and use of aspirin, non steroidal anti-inflammatory drugs, beta-blockers, and angiotensin-converting-enzyme inhibitors (ACEI) were prospectively recorded. Multivariate analysis was used to compare 76 cases of severe anaphylaxis (SA) with 235 cases of mild to moderate food allergy (mmFA). The M/F sex ratio was 54.6% in SA and 36% in mmFA (p < .003). SA represented 17.3% of all food allergies below 45 years and 54.6% over this age. Drug intake did not differ between the two age categories. Drug use was noted in 40.8% of SA and 14.9% of mmFA (p < .0005). Aspirin, NSAIDs, betablockers and ACEI were associated with respectively 15.8%, 6.6%, 10.5% and 5.3% of SA, and with 1.7%, 0.9%, 1.7% and 0.4% of mmFA (p < .003). The respective odds ratios were 10.8, 8.2, 6.8 and 13.0. No other drugs were associated with FA. Exercise and alcohol intake were associated to drugs with respectively 10.5% and 27.6% of SA and 0.4% and 8.1% of mmFA (p < .0005). Exercise drastically increased the risk of drugs. We conclude that aspirin, NSAIDs, betablockers and ACEI are significant risk factors for severe IgE-dependent food allergy. The underlying mechanisms are discussed. Adults with food allergy or sensitization should avoid taking aspirin and NSAIDs before meals and should receive drug families other than ACEI and betablockers for hypertension. In case of pre-existing heart disease, the benefit-risk ratio of ACEI and beta-blockers has to be carefully considered.

Influence of the allelic variants encoded at the Gli-B1 locus, responsible for a major allergen of wheat, on IgE reactivity for patients suffering from food allergy to wheat.

Wheat presents an important genetic diversity that could be useful to look for cultivars with reduced allergencity. omega5-Gliadins have been described as major allergens for wheat allergic patients suffering from wheat-dependent exercise-induced anaphylaxis (WDEIA) and some cases of chronic urticaria (U). Our objective was to study the influence of genetic variability at the Gli-B1 locus encoding for omega5-gliadins on the reactivity of IgE antibodies from these patients. We selected cultivars expressing 13 alleles at Gli-B1 including a wheat/rye translocation and studied the reactivity to gliadins of a rabbit antiserum specific for omega5-gliadins and of IgE from 10 patients. The antiserum and IgE from nine patients with WDEIA and U strongly detected omega5-gliadins expressed by most of the Gli-B1 alleles but showed no or faint responses to the gliadins and secalins extracted from the translocated wheat. The selection of genotypes lacking the Gli-B1 locus may reduce wheat allergenicity.

[Allergic risk and role of the Allergy Vigilance Network]. / Risque allergique et sécurité alimentaire: le rôle du réseau allergo-vigilance.

The recent increase in the incidence of severe anaphylaxis calls for continual assessment of risk factor and dangers associated with food allergy, keeping abreast of changes in the food industry. Allergologists, regulatory bodies and the food industry are all responsible for food safety. The Allergy Vigilance Network, founded by a university research team and comprising 398 French and Belgian allergologists, has developed a three-point strategy. First, reporting cases of severe anaphylaxis of document allergic origin makes it possible to monitor the prevalence of food allergens and to evaluate the quality of management of allergy-related emergencies, thus providing data suitable for estimating the economic burden of anaphylaxis. The second objective of the network is to set up multicenter trials to determine the prevalence of sensitization to risk allergens, such as peanut, lupin and plant pollen, of which transgenic varieties will soon emerge. The third objective is screening and long-term monitoring of dangers related to new foods, ingredients and adjuvant sensitizing factors. Post-marketing monitoring of potential allergic risks arising from genetically modified food is another aim of the network, together with the establishment of a serum bank, following WHO/FAO recommendations. The Allergy Vigilance Network, together with the French National Institute for Food Safety (AFSSA), the Ministry of Consumer Affairs (DGCCRF) and various patient associations, is striving to analyse and deal with dangers related to the allergenicity of natural and modified food proteins.

[Diagnosis of allergic rhinitis: from clues to evidence]. / Comment s'orienter vers une rhinite allergique.

The high prevalence of allergic rhinitis in westernized countries, and the impact of allergic rhinitis on asthma require a well established diagnosis. Clues of increasing value can be obtained by any practitioner, relying on information about familial and personal atopic background, a precise record of symptoms of nasal hyperreactivity rhinorrhea, sneezing and pruritus, and of the evaluation of symptoms over the year. A precise questionnaire may be completed by a biologic screening for atopy, in order to refer the patient to the allergist to add evidence of the etiology by skin tests, search for specific IgE, and nasal challenges for specific cases.

[Cross reactivity of food allergens and its clinical relevance]. / Allergies alimentaires croisées: quelles nouveautés ?

Cross-reactions between food allergens and other allergens are a major focus of interest. They include cross-allergies between Betulaceae and Compositae pollen, and also between fruits and vegetables (Prunoideae and Apiaceae). Cross-allergies between animal allergens include mites, cockroaches and crustaceans, milk and meat, animal epithelia, meat and egg. Cross-reactivity results from homology between protein sequences, and is highly likely when this homology reaches about 70%. Phylogenetically similar proteins occur in all species and are known as pan allergens. Profilins, Bet v1 homologues, and lipid transfer proteins have varying degrees of clinical relevance. The involvement of cross-reactivity in the persistence of sensitization and in allergic disorders is unclear. The consequences of cross-reactivity during specific immunotherapy with total allergenic extracts are random. Interpretation of biological tests of IgE binding is also biased by cross-reactivity. The use of panels of major recombinant allergens should help to identify specific sensitization profiles as well as clinically relevant sensitization. Cross-reactivity between epitopes of inhalants and of food allergens may perpetuate and intensify allergic disorders. The consequences of cross-reactivity between allergens and autologous proteins are unknown.

Structural Basis of IgE Binding to α- and γ-Gliadins: Contribution of Disulfide Bonds and Repetitive and Nonrepetitive Domains.

Wheat products cause IgE-mediated allergies. The present study aimed to decipher the molecular basis of α- and γ-gliadin allergenicity. Gliadins and their domains, the repetitive N-terminal and the nonrepetitive C-terminal domains, were cloned and expressed in Escherichia coli. Their secondary structures and their IgE binding capacity were compared with those of natural proteins before and after reduction/alkylation. Allergenicity was evaluated with sera from patients who had a wheat food allergy or baker's asthma. The secondary structures of natural and recombinant proteins were slightly different. Compared with natural gliadins, recombinant proteins retained IgE binding but with reduced reactivity. Reduction/alkylation decreased IgE binding for both natural and recombinant gliadins. Although more continuous epitopes were identified in the N-terminal domains of α- and γ-gliadins, both the N-terminal and C-terminal domains contributed to IgE binding. As for other members of the prolamin superfamily, disulfide bonds appear to be of high importance for IgE binding.

Update on threshold doses of food allergens: implications for patients and the food industry.

PURPOSE OF REVIEW: The purpose of this review is to bring the reader up to date on the importance of assessing a food's lowest observed adverse-effect level (LOAEL) with two aims. Firstly, to help industry choose tests with a level of sensitivity capable of detecting food allergens hidden in industrial products. Secondly, to specify protective measures for highly allergic individuals in order to prevent recurrent severe anaphylaxis. The review also seeks to highlight the present issues and unsolved questions. RECENT FINDINGS: Thanks to standardized oral-provocation tests (double-blind placebo-controlled food challenges), LOAELs have been identified for many IgE-dependent food allergies. Most studies concern the pediatric population. Data is available for milk, egg, peanut, wheat flour, and sesame. The LOAELs are commonly in the range of 1-2 mg of natural foods, representing a few hundred micrograms of protein. These minimal reactive doses characterize about 1% of people allergic to milk, egg, or peanut. The level at which no observed adverse effect is seen might be a few tens of micrograms of protein for peanut. At the present time, allergy to oil seems to be restricted to unrefined cold-pressed oils. SUMMARY: Concerning IgE-dependent food allergies, the threshold dose inducing symptoms is now known to vary a great deal according to the individual. A reactive dose of less than 65 mg characterizes 16 and 18% of patients allergic to egg or peanut. Less than 30 mg of milk proteins characterizes 5% of those allergic to milk. For milk, egg, and peanut, 1% of patients have a very low threshold, about 1 mg. Such data emphasize the necessity of using detection tests with a sensitivity better than 10 parts per million. The modifications of allergenicity undergone by protein ingredients that are now commonly introduced into industrially made products are not yet sufficiently known. A better knowledge of the reactive doses of these proteins is needed.

[Allergic risk of transgenic food: prevention strategies]. / Risque allergique des aliments transgéniques: stratégies de prévention.

Numerous allergens proceed from foods. The allergic risk of transgenic foods needs to be evaluated according recommendations from the Joint Expert Committee FAO/WHO. Potential issues are the risk of cross reactivity with existing allergens, the modification of allergenicity of the transgenic protein induced by a modified metabolism in the host, the modified allergenicity of the proteins of the transgenic plant, a potential neo-allergenicity of the transgenic protein, and the risk of dissemination through pollens, inducing a respiratory sensitization then a cross food allergy. The algorithm includes three steps for evaluation: first the search for significant homology of the protein with allergens listed in allergen databanks, or the identity of a sequence of six aminoacids with known allergens, then a cross reactivity explored through the binding to IgEs from patients allergic to the source of the gene, or allergic to organisms of the same group or botanical family, and finally the extent of the pepsine resistance. The risk of immunogenicity has to be studied with appropriate animal models. A post-marketing surveillance is recommended for monitoring of adverse effects. The structure of an Allergo-Vigilance Network, the tools for efficiency and the groups at higher risk will be discussed.

[The use of adrenaline for the treatment of anaphylaxis: the use by first-aid personnel is recommended]. / Utilisation de l'adrénaline dans le traitement de l'anaphylaxie : nécessité d'autorisation d'emploi par les secouristes.

UNLABELLED: Anaphylaxis is the most serious form of the IgE-dependent food allergy, with lethal risk. The incidence is sharply rising. OBJECTIVE: Analysis of the actual management of anaphylaxis, searching for the appropriateness with the International Guidelines highlighting the absolute need of epinephrine, and further suggestions for the improvement of treatment. METHOD: A general review of international studies stemming from Emergency Departments (ED), Paediatric, Resuscitation, Cardiologic or Allergy Departments over 1999-2012, as well of International Guidelines about the management of anaphylaxis. RESULTS: The self-injectable epinephrine by the patients is under-used. Treatment by epinephrine in ED has a low concordance with recommended guidelines. The discharge prescriptions of self-injectable epinephrine and referral to allergy testing are quite insufficient. CONCLUSION: The actual management of anaphylaxis does not fit with the International Guidelines. Anaphylaxis treatment protocols according to the international criteria should be applied in ED. Risk reduction strategies cannot rely only on the self-administration of epinephrine by the patient and should put forward a better efficiency of all first-aid care providers. A targeted educational intervention should be developed to improve the care of emergency medical services providers. They should have self-injectable-epinephrine available and should be coached to use it properly.

Molecular and immunological characterization of wheat Serpin (Tri a 33).

SCOPE: Several wheat proteins are responsible for food and respiratory allergies. Due to their large polymorphism, the allergenic potential of a number of them has not yet been precisely established. The aim of this work was to perform a thorough assessment of serpin (Tri a 33) allergenicity. METHODS AND RESULTS: Recombinant wheat Serpin-Z2B isoform (rSerpin-Z2B) was expressed in Escherichia coli. Synchrotron radiation circular dichroism data indicated that the recombinant serpin contains slightly more ß-strands than α-helix structures. IgE reactivity of sera from 103 patients with food allergy and 29 patients with Baker's asthma was evaluated using ELISA, a model of basophil activation and linear epitope mapping (Pepscan). Twenty percent of patients with food allergy to wheat and 31% of those with Baker's asthma displayed rSerpin-Z2B-specific IgE in ELISA. The protein was able to induce IgE-dependent basophil degranulation. The Pepscan experiment identified four regions involved in IgE binding to serpin. Heating the protein induced its irreversible denaturation and impaired IgE binding, revealing the predominance of conformational epitopes. CONCLUSION: This study confirms wheat serpin allergenicity and shows that recombinant serpin may be a marker of a broad spectrum of sensitization to wheat proteins.

Skin reactions to intradermal neuromuscular blocking agent injections: a randomized multicenter trial in healthy volunteers.

BACKGROUND: Numerous reports confirm the performance of intradermal tests for the diagnosis of anaphylaxis during anesthesia; however, there is controversy over their diagnostic value regarding the newer neuromuscular blocking agents (NMBAs). METHODS: One hundred eleven healthy volunteers were randomly assigned to receive intradermal injections of two NMBAs, at five increasing concentrations. A concentration was considered as a reactive concentration when it led to a positive reaction in more than 5% of the subjects. These concentrations were compared with the maximal concentration recommended for the diagnosis of sensitization to NMBAs. RESULTS: The maximal nonreactive concentrations were 10 m for suxamethonium; 10 m for pancuronium, vecuronium, rocuronium, and cisatracurium; and 10 m for atracurium and mivacurium. Except for mivacurium, these nonreactive concentrations were close to the maximal concentrations used for the diagnosis of sensitization against NMBAs. For mivacurium, the nonreactive concentrations were higher than the maximal concentration currently recommended in clinical practice. CONCLUSION: The aminosteroidal NMBAs pancuronium, vecuronium, and rocuronium and the benzylisoquinoline cisatracurium have a similar potency to induce a nonspecific skin reactivity. If the criteria for positivity and the maximal concentrations of the commercially available compounds recommended by French practice guidelines are used, the risk of false-positive results is limited, and only minor modifications of these recommendations could be suggested. A slight reduction in the maximal concentration used for rocuronium from 1:100 to 1:200 and an increase from 1:1,000 to 1:200 for mivacurium can be proposed.

Predictive value of skin prick tests using recombinant allergens for diagnosis of peanut allergy.

BACKGROUND: Current diagnosis of peanut allergy relies on natural extracts that lack standardization. Recombinant DNA technology allows production of pure biochemically characterized proteins. Their usefulness for peanut allergy diagnosis is not established. OBJECTIVE: This study aimed to evaluate the diagnostic value of the 3 major recombinant peanut allergens. METHODS: Recombinant (r) Ara h 1, rAra h 2, and rAra h 3 were produced according to the recommendations of good manufacturing practice for recombinant allergens. Skin prick tests (SPTs) and IgE ELISA assays were performed in 30 patients with peanut allergy and 30 control subjects without food allergy: 15 nonatopic and 15 sensitized to birch pollen. Disease severity was graded by clinical scoring. RESULTS: All patients with peanut allergy showed positive SPT results to rAra h 2; 40% reacted with rAra h 1 and 27% with rAra h 3. No control subjects reacted with any of the recombinant allergens. Monosensitization to rAra h 2 was observed in 53% of patients. Neither SPT size nor levels of specific IgE were correlated with the disease severity. However, patients with monosensitization to rAra h 2 had a significantly lower severity score than polysensitized subjects and a lower level of specific IgE against peanut extract and rAra h 2. CONCLUSION: Skin prick tests to individual recombinant peanut allergens appear to be a safe and effective diagnostic tool. Cosensitization to rAra h 2 and rArah 1 and/or rAra h 3 is predictive of more severe reactions. CLINICAL IMPLICATIONS: Recombinant peanut allergens can be used by SPTs for diagnosis and evaluation of allergy severity.