Altered immune cell profiles and impaired CD4 T-cell activation in single and multi-food allergic adolescents.

BACKGROUND: Approximately 5% of adolescents have a food allergy, with peanut and tree nut allergies the most common. Having two or more food allergies in adolescence also doubles the risk of any adverse food reaction, and is associated with increased dietary and social burden. Investigations of immune function in persistently food allergic children are rare. OBJECTIVE: In the present study, we aimed to investigate the immune mechanisms that underlie food allergy in adolescence. METHODS: We used high-dimensional flow cytometry, unsupervised computational analysis and functional studies to comprehensively phenotype a range of non-antigen-specific immune parameters in a group of well-characterized adolescents with clinically defined single peanut allergy, multi-food allergy and aged-matched non-food allergic controls. RESULTS: We show that food allergic adolescents have higher circulating proportions of dendritic cells (p = .0084, FDR-adjusted p = .087, median in no FA: 0.63% live cells, in FA: 0.93%), and higher frequency of activated, memory-like Tregs relative to non-food allergic adolescents (p = .011, FDR-adjusted p = .087, median in no FA: 0.49% live cells, in FA: 0.65%). Cytokine profiling revealed that CD3/CD28 stimulated naïve CD4 T cells from food allergic adolescents produced less IL-6 (p = .0020, FDR-adjusted p = .018, median log2 fold change [stimulated/unstimulated] in no FA: 3.03, in FA: 1.92) and TNFα (p = .0044, FDR-adjusted p = .020, median in no FA: 9.16, in FA: 8.64) and may secrete less IFNγ (p = .035, FDR-adjusted p = .11, median in no FA: 6.29, in FA: 5.67) than naïve CD4 T cells from non-food allergic controls. No differences between clinical groups were observed for LPS-stimulated monocyte secretion of cytokines. CONCLUSIONS: These results have important implications for understanding the evolution of the immune response in food allergy throughout childhood, revealing that dendritic cell and T-cell signatures previously identified in early life may persist through to adolescence.

Hypersensitivity to Vitamins with a Focus on Immediate-Type Reactions: Food or Drug Allergy?

Vitamins are essential substances for normal cell functions, growth, and development. However, they cannot be produced by the human organism, so intake must be through the diet. Vitamin deficiency causes the onset of different diseases, ranging from pellagra to pernicious anemia, which can be corrected by reintroducing the missing vitamin form. To supply the right amount of vitamins to the body, every vitamin naturally occurring in foodstuff has been identified, extracted and synthetically produced, thus allowing either food fortification with these compounds or their pharmaceutical production. Furthermore, the increased importance attributed nowadays to body wellness and the pursuit of a permanent status of health at all costs has greatly encouraged a high consumption of vitamin supplements in modern society, since vitamin megadoses may be responsible for adverse or toxic effects. However, excessive vitamins can induce hypervitaminosis. In the USA, a national survey confirmed that 52% of adult Americans take at least one or more supplement products, vitamins and minerals being the most popular supplements in that country. Although vitamins are widespread natural substances, they may induce immediate or delayed type hypersensitivity reactions. Such adverse events are still underestimated and poorly recognized because only single cases have been reported in the literature, and no general review has yet investigated the mechanisms underlying sensitization to each vitamin, the diagnosis, and the management strategies adopted for vitamin hypersensitivity. Although delayed-type reactions to different vitamins are described in the literature, in our review, attention has been focused mainly on immediate- type reactions. Due to the importance of vitamins, further information regarding the above aspects (pathomechanisms, diagnosis and management) would be highly desirable to focus the state of the art on this particular, underestimated form of allergy, thus increasing allergists' awareness on these elusive hypersensitivity reactions.

Diverse age-incidence patterns of atopic sensitization in an unselected Finnish population up to 12 years.

BACKGROUND: The temporal sequence in which allergic sensitization to different allergens emerges is not well characterized at the level of general population. OBJECTIVE: We describe the incidence patterns of atopic sensitization to different allergens from birth up to 12 years of age in an unselected Finnish population. METHODS: The study population comprised all children born between 2001 and 2006 identified from the nationwide population register as residents of the province of South Karelia, Finland (n = 5564). The results of allergy tests (22,380 results from skin prick tests, immunoglobulin E [IgE] antibodies, and open food challenges [OFCs], performed in 1827 children) were collected from patient records of all the health care units in the area. RESULTS: The incidence rates of positive results for food and animal allergens as well as positive OFCs for cow's milk showed prominent peaks at 5 months of age. Positive results for pollen allergens started to emerge after 1.5 years of age. The 12-year cumulative incidence of sensitization to food, animal, pollen, and any allergens was 12%, 8%, 10%, and 18%, respectively. The cumulative incidence of sensitization to house dust mites was 1% and to molds or latex less than 1%. Firstborn boys had the highest, and those who were not firstborn girls and children born in rural municipalities had the lowest early incidence of sensitization to inhalation allergens. CONCLUSION: In the unselected population, the atopic sensitization against food and animal allergens began before 6 months of age and was followed by sensitization to pollen allergens before 2 years of age. Primary prevention of sensitization to food and inhalation allergens should therefore occur in early infancy.

[Non-celiac wheat sensitivity - growing evidence for a wheat-dependent immune-mediated disease]. / Allergologie-immunologie Clinique. Sensibilité au blé non cœliaque ­ la fin d'un mythe ?

These past years, double-blinded placebo controlled food challenges in subjects with irritable bowel syndrome (IBS) reporting sensitivity to gluten have identified a group of individuals without celiac disease (CD) in whom symptoms were clearly aggravated by wheat. Not only did the exposure to wheat trigger intestinal symptoms, but also frequently fatigue and a sensation of foggy mind. Recent studies in mice and sensitive subjects suggest an immune activation by various wheat proteins, with a rapid increase of intestinal mucosal permeability and recruitment of intraepithelial lymphocytes. Moreover, markers of epithelial damage and immune activation are increased in the peripheral blood of wheat-sensitive subjects upon challenge, and decrease under gluten-free diet. Larger studies are needed to better characterize this entity and to distinguish it from food-aggravated IBS and a « forme fruste ¼ of CD.

La provocation alimentaire en double aveugle chez des sujets atteints d'un syndrome de l'intestin irritable (IBS) et indiquant une sensibilité au gluten a objectivé des individus sans maladie cœliaque (MC) clairement aggravés par le blé. Les symptômes déclenchés n'étaient pas seulement digestifs, mais aussi de la fatigue et des troubles de la concentration. De nouvelles études chez ces sujets démontrent une activation du système immunitaire par les protéines de blé, avec augmentation de la perméabilité intestinale et recrutement de cellules inflammatoires dans la muqueuse. Des marqueurs d'altération de la barrière intestinale et d'activation immunitaire sont retrouvés dans le sang de sujets sensibles exposés au blé. D'autres études sont nécessaires pour mieux caractériser ce syndrome et le différencier de l'IBS et de formes frustes de MC.

Incidència de la hipersensibilitat a llet de vaca en el primer any de vida a la Catalunya Centra / Incidencia de la hipersensibilidad a leche de vaca en el primer año de vida en la Cataluña Central / Incidence of cow's milk allergy in the first year of life in central Catalonia

Fonament: l'al•lèrgia a proteïnes de llet de vaca és l'al•lèrgia alimentària més freqüent en lactants. La prevalença real és difícil d'establir, donada la gran variabilitat metodològica dels estudis publicats. Objectiu: conèixer la incidència durant el primer any de vida de reaccions d'hipersensibilitat, en concret les mediades per IgE, a proteïnes de llet de vaca en una població de lactants que van fer seguiment en àrees bàsiques d'atenció primària de la Catalunya Central. Valorar si existien diferències de reaccions en lactants segons el trimestre de naixement. Mètode: estudi multicèntric, observacional i prospectiu. Àmbit: àrees bàsiques d'atenció primària del Bages i el Solsonès. Es van incloure els nascuts durant el primer i l'últim trimestre del 2012, i se'n va fer el seguiment durant un any. En cas de sospita de reacció d'hipersensibilitat (RHS) al•lèrgica, es van remetre a l'al•lergòleg. Resultats: durant el primer trimestre van néixer 153 infants, i 125 el darrer trimestre. Van completar el seguiment 139 i 119 lactants, respectivament. En el primer grup es va sospitar RHS en 3/124 (2,4%) alimentats amb fórmula artificial (FA). No es va confirmar cap cas mediat per IgE. En el segon grup, van rebre FA 111 lactants. En cinc es va sospitar una RHS (4,5%) i en quatre es va confirmar RHS al•lèrgica: 2/111 mediada per IgE (1,8%) i 2/111 no me-diada per IgE (1,8%). Els dos pacients amb al•lèrgia mediada per IgE van patir reacció en iniciar l'FA. Conclusions: de 235 infants que van rebre FA, es va sospitar RHS en cinc (2,1%), i es va confirmar mecanisme IgE en dos (0,9 %), tots dos nascuts el darrer trimestre

Fundamento. La alergia a proteínas de leche de vaca es la alergia alimentaria más frecuente en lactantes. La prevalencia real es difícil de establecer, dada la gran variabilidad metodológica de los estudios publicados. Objetivo. Conocer la incidencia durante el primer año de vida de reacciones de hipersensibilidad, en concreto las mediadas por IgE, a proteínas de leche de vaca en una población de lactantes que hacen seguimiento en áreas básicas de atención primaria de Cataluña Central. Valorar si existen diferencias según el trimestre de nacimiento. Método. Estudio multicéntrico, observacional y prospectivo. Ámbito: áreas básicas de atención primaria del Bages y el Solsonès. Se incluyeron los recién nacidos durante el primer y el último trimestre de 2012, y se hizo seguimiento durante un año. En caso de sospecha de reacción de hipersensibilidad (RHS) alérgica, se remitieron al alergólogo. Resultados. Durante el primer trimestre nacieron 153 niños, y 125 en el último trimestre. Completaron el seguimiento 139 y 119 lactantes, respectivamente. En el primer grupo se sospechó RHS en 3/124 (2,4%) alimentados con fórmula artificial (FA). No se confirmó ningún caso mediado por IgE. En el segundo grupo, 111 lactantes recibieron FA. En cinco se sospechó una RHS (4,5%) y en cuatro se confirmó RHS alérgica: 2/111 mediada por IgE (1,8%) y 2/111 no mediada por IgE (1,8%). Los dos niños con alergia mediada por IgE sufrieron reacción al iniciar la FA. Conclusiones. De 235 niños que recibieron FA, se sospechó RHS en cinco (2,1%), y se confirmó mecanismo IgE en dos (0,9%), ambos nacidos en el último trimestre (AU)

Background. Cow's milk allergy is the most frequent food allergy in infants; however, given the methodological variability in published studies, its real prevalence is difficult to ascertain. Objective. To determine the incidence of hypersensitivity reactions, specifically those IgE mediated, to cow’s milk proteins in a population of infants seen in primary health care centers in Central Catalonia, and to assess differences in reactions according to the trimester of birth. Method. Multicenter, observational, prospective study conducted in primary healthcare centers of the Bages and Solsones. Infants born during the first and last trimesters of 2012 were included. In case of suspected allergic hypersensitivity reaction (AHR), they were referred to an allergologist for confirmation. Results. 153 infants were born during the first trimester and 125 during the last trimester; full one-year follow-up was completed in 139 and 119 infants, respectively. In the first group, an AHR was suspected in three of 124 (2.4%) children fed with artificial formula (AF). In the second group, 111 infants received AF, and an AHR was suspected in five of them (4.5%). AHR was confirmed in four, with two of them being IgE mediated. Both children with IgE-mediated allergy developed an allergic reaction upon initiation of AF. Conclusions. Of 235 children receiving AF, five (2.1%) had an AHR, which was confirmed to be IgE-mediated in two (0.9%), both born in the last trimester of the year (AU)

Gastrointestinal food allergy in Ghanaian children: a case series.

BACKGROUND: Food allergy is an adverse health effect arising from a specific immune response that occurs reproducibly on exposure to a given food. Food allergies are classified into three types: Ig(immunoglobulin)E mediated, mixed IgE and cell mediated and cell-mediated non IgE mediated. Gastrointestinal (GIT) food allergy has classically encompassed a number of different clinical entities: food protein-induced enterocolitis syndrome (FPIES), food protein-induced proctocolitis (FPIP), food protein-induced enteropathy and eosinophilic gastrointestinal disorders (EGID). CASE PRESENTATIONS: These are 5 cases of infants and toddlers who presented with various features of gastrointestinal food allergies, the commonest of which is lower gastrointestinal bleed. Two infants on exclusive breast feeding, presented with lower gastrointestinal bleeding and these resolved with maternal dietary milk and all dairy elimination. The third infant had rectal bleeding at age 6 months after the introduction of infant formula. The bleeding and eczema resolved with the introduction of hydrolyzed formula. One of the toddlers presented with severe eczema and malnutrition which improved with 6 food elimination. The last case had massive lower gastrointestinal bleed which resulted in hemicolectomy with no improvement until dietary elimination was instituted. CONCLUSION: Gastrointestinal food allergy is not uncommon in children in Ghana. A high index of suspicion is required to make the right diagnosis, to minimize morbidity and unnecessary therapy. SOURCE OF FUNDING: None.

[Non-allergic gluten sensitivity. A controversial disease - or not yet sufficiently explored?]. / Nichtallergische Glutensensitivität. Ein umstrittenes Krankheitsbild - oder noch nicht ausreichend erforscht?

The avoidance of wheat, gluten and other cereal products is a growing phenomenon in industrialized countries. The diagnostic criteria of celiac disease and of food allergy to wheat flour and/or other cereals are clearly defined. Only about 0.5-25 % of the population are affected from both of these immunological diseases.Nevertheless, there exists a significantly greater proportion of people reporting at least subjectively significant complaints and quality of life improvements after switching to a wheat- or gluten-free diet. Celiac disease or wheat allergy cannot be detected in these individuals on the basis of established criteria. The absence of clear diagnostic autoimmune or allergic criteria in these wheat sensitive patients has resulted in the description of non-celiac gluten sensitivity.It is clinically detectable in only very few individuals and may manifest with either intestinal, extra-intestinal or neurovegetative and psychosomatic symptoms, respectively. However, non-celiac disease gluten sensitivity has to be differentiated critically from irritable bowel syndrome, carbohydrate malassimilation, postinfectious conditions and psychosomatic diseases.Pathophysiologically, non-celiac disease gluten sensitivity is still poorly characterized; several non-immunological mechanisms are discussed to contribute to non-celiac gluten sensitivity. These include the effects of fructo- and galacto-oligosaccharides, of trypsin inhibitors of amylase, and wheat lectin agglutinins, which may influence or modulate intestinal permeability and/or a non-specific immune or effector cell degranulation within the gastrointestinal tract. In addition, further metabolic effects with direct or indirect influence on the intestinal flora are currently discussed.In addition to subjectively reported changes in symptoms that may affect variably intestinal, as well as extra-intestinal and/or neuropsychiatric symptoms, some studies suggest that there is little reproducibility of complaints from gluten exposure. For a definitive diagnosis of non-celiac gluten sensitivity, structured (blinded) challenge tests with wheat or gluten are mandatory as well as re-challenge after a defined time of gluten avoidance to establish non-celiac disease gluten sensitivity as a persistent disease entity.

[Phenotypes of food allergy in children].

Questions of food allergy heterogeneity, approaches to allocation of various phenotypes on the basis of clinical signs and immunological markers taking into account an etiology and immune mechanisms of the disease are considered in the article. Allocation of phenotypes contributes the best understanding of essence and it expedient for development of individual approach to diet and therapy.

[Food Allergy and Intolerance : Distinction, Definitions and Delimitation]. / Nahrungsmittelallergien und andere -unverträglichkeiten : Bedeutung, Begriffe und Begrenzung.

Immunologically mediated hypersensitivity to foods is defined as food allergy, mainly due to immunglobulins of class E (IgE) triggering immediate reactions (type I hypersensitivity) with possible involvement of mucosa, skin, airways, intestinal tract, and the vascular system. Primary food allergy is based on (early) IgE sensitization against animal (e. g., cow's milk, hen's eggs) or plant proteins (e. g. peanut, hazelnut or wheat). In the case of secondary food allergies, IgE against pollen proteins (e. g., birch) reacts to structurally related food proteins (with cross-reactions to stone and pit fruits). Non-immunological food intolerance reactions are mostly based on carbohydrate malassimilation (e. g., lactose intolerance, fructose malabsorption) and are rarely due to pseudo-allergies (e. g., flavors, dyes, preservatives) primarily in patients with chronic urticaria. Common intestinal symptoms are mainly due to functional disorders (e. g., irritable bowel disease), rarely because of inflammatory intestinal diseases (e. g., celiac disease). Histamine intolerance, gluten hypersensitivity, and so-called food type III hypersensitivities are controversial diagnoses. The aforementioned disease entities/models are of variable importance for the affected individuals, the public health system, and society in general.

Diversity of Food Allergy.

Food allergy is defined as an immune system-mediated adverse reaction to food components. Food allergic reactions are mostly IgE mediated and also known as immediate type hypersensitivity (type I reaction). There are several characteristic clinical types of food allergy, such as Anaphylaxis, Food-dependent exercise-induced anaphylaxis (FDEIA), and Oral allergy syndrome (OAS). In addition, food allergy is also classified into two types (class 1 and class 2) based on the pathophysiological mechanism. In the class 2 food allergy, pollen allergy causes plant food allergy; therefore this type of allergy is sometimes called Pollen-food allergy syndrome (PFAS). The risk of food allergy (allergenicity) may vary with the treatment of the food allergens. The formation or status of the causative food affects its allergenicity. Class 1 food allergens are generally heat-, enzyme-, and low pH-resistant glycoproteins ranging in size from 10 to 70 kD. Class 1 food allergens induce allergic sensitization via the gastrointestinal tract and are responsible for systemic reactions. Class 2 food allergens are generally heat-labile, susceptible to digestion, and highly homologous with pollen allergens. Taken together, it may be important to consider the diversity of food allergy in order to fight against food allergy.

Nonceliac Gluten Sensitivity.

Nonceliac gluten sensitivity (NCGS) is the clinical term used to describe gastrointestinal (GI) and/or extraintestinal symptoms associated with gluten ingestion. The prevalence of NCGS is unknown. The condition has clinical features that overlap with those of celiac disease (CD) and wheat allergy (WA). The pathophysiologic process in NCGS is thought to be through an innate immune mechanism, whereas CD and WA are autoimmune- and allergen-mediated, respectively. However, dietary triggers other than gluten, such as the fermentable oligosaccharides, disaccharides, monosaccharides, and polyols, have been implicated. Currently, no clinical biomarker is available to diagnose NCGS. Exclusion of CD and WA is necessary in the evaluation of a patient suspected to have NCGS. The onset of symptoms in patients with NCGS can occur within hours or days of gluten ingestion. Patients with NCGS have GI and extraintestinal symptoms that typically disappear when gluten-containing grains are eliminated from their diets. However, most patients suspected to have NCGS have already initiated a gluten-free diet at the time of an evaluation. A gluten elimination diet followed by a monitored open challenge of gluten intake to document recurrence of GI and/or extraintestinal symptoms can sometimes be helpful. If NCGS is strongly suggested, then a skilled dietitian with experience in counseling on gluten-free diets can provide proper patient education. Additional research studies are warranted to further our understanding of NCGS, including its pathogenesis and epidemiology, and to identify a biomarker to facilitate diagnosis and patient selection for proper management.

Understanding administrative coding of emergency department visits for unspecified acute allergic reactions.

AIM: Emergency department (ED) visits for food-related acute allergic reactions enable estimation of temporal trends in food allergy prevalence. To use this approach in New Zealand requires an understanding of the proportion of ED visits coded as 'anaphylaxis, unspecified' or 'allergy, unspecified' that are food-related allergic reactions. METHOD: We reviewed all ED presentations of children, coded as 'anaphylaxis, unspecified' or 'allergy, unspecified', from 1988-2011 to the Auckland City Hospital ED. Charts were reviewed independently by two investigators to determine agreement on categorisation of presentations as being food-related acute allergic reactions. We compared ED presentation rates in different time intervals using rate ratios (RR) and 95% confidence intervals (CI). RESULTS: Sixty-five (29%) of the 221 ED presentations given a discharge code of 'anaphylaxis, unspecified' or 'allergy, unspecified', were a food-related allergic reaction. Inter-observer agreement was very good (kappa >0.80). The ED presentation rate with food-related allergic reactions in 2004-2011 was 98% higher than in 1988-1995 (RR=1.98, 95%CI 1.10-3.72). By contrast, ED presentation rates for non-food-related allergic reactions did not change over these years. CONCLUSION: ED presentations for food-related allergic reactions are identifiable from within ED presentations coded as 'anaphylaxis, unspecified' or 'allergy, unspecified'. ED presentations for food-related allergic reactions have increased over time in Auckland.

Non-celiac gluten sensitivity: Time for sifting the grain.

In the last few years, a new nomenclature has been proposed for the disease induced by the ingestion of gluten, a protein present in wheat, rice, barley and oats. Besides celiac disease and wheat allergy, the most studied forms of gluten-related disorders characterized by an evident immune mechanism (autoimmune in celiac disease and IgE-mediated in wheat allergy), a new entity has been included, apparently not driven by an aberrant immune response: the non-celiac gluten sensitivity (NCGS). NCGS is characterized by a heterogeneous clinical picture with intestinal and extraintestinal symptoms arising after gluten ingestion and rapidly improving after its withdrawal from the diet. The pathogenesis of NCGS is largely unknown, but a mixture of factors such as the stimulation of the innate immune system, the direct cytotoxic effects of gluten, and probably the synergy with other wheat molecules, are clues for the complicated puzzle. In addition, the diagnostic procedures still remain problematic due to the absence of efficient diagnostic markers; thus, diagnosis is based upon the symptomatic response to a gluten-free diet and the recurrence of symptoms after gluten reintroduction with the possibility of an important involvement of a placebo effect. The temporary withdrawal of gluten seems a reasonable therapy, but the timing of gluten reintroduction and the correct patient management approach are have not yet been determined.

Diagnosis of gluten related disorders: Celiac disease, wheat allergy and non-celiac gluten sensitivity.

Cereal crops and cereal consumption have had a vital role in Mankind's history. In the recent years gluten ingestion has been linked with a range of clinical disorders. Gluten-related disorders have gradually emerged as an epidemiologically relevant phenomenon with an estimated global prevalence around 5%. Celiac disease, wheat allergy and non-celiac gluten sensitivity represent different gluten-related disorders. Similar clinical manifestations can be observed in these disorders, yet there are peculiar pathogenetic pathways involved in their development. Celiac disease and wheat allergy have been extensively studied, while non-celiac gluten sensitivity is a relatively novel clinical entity, believed to be closely related to other gastrointestinal functional syndromes. The diagnosis of celiac disease and wheat allergy is based on a combination of findings from the patient's clinical history and specific tests, including serology and duodenal biopsies in case of celiac disease, or laboratory and functional assays for wheat allergy. On the other hand, non-celiac gluten sensitivity is still mainly a diagnosis of exclusion, in the absence of clear-cut diagnostic criteria. A multimodal pragmatic approach combining findings from the clinical history, symptoms, serological and histological tests is required in order to reach an accurate diagnosis. A thorough knowledge of the differences and overlap in clinical presentation among gluten-related disorders, and between them and other gastrointestinal disorders, will help clinicians in the process of differential diagnosis.

[Neonatal food allergy].

Food allergy is defined as abnormal immune response elicited by food intake, in which a variety of clinical symptoms will appear as a result of physiological dysfunction and/or tissue damage. Possible mechanisms for food allergy include gastrointestinal tract barrier damage, failure to induce oral immune tolerance, intrauterine sensitization, and allergen transmission during pregnancy and breastfeeding. Hereditary and environmental factors can also contribute to the disease. Gastrointestinal disorders are the main clinical manifestations of the disease. However, hypoalbuminemia, growth retardation, and even acute circulatory failure or shock may occur in severe cases. Oral food challenges are the "gold standard" for the diagnosis of food allergy. Avoidance and replacement of the responsible food are the only effective treatment options for neonatal food allergy. The use of probiotics can offer protection against the disease.