Allergia al Grano. Roma 27 Maggio Cristiano Caruso UOSA Allergologia

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1 Allergia al Grano Roma 27 Maggio 2017 Cristiano Caruso UOSA Allergologia Fondazione policlinico Gemelli- Roma

2 Sintomi comuni e non

3 Principali cause di allergie alimentari in Italia

4 Reazioni a GRANO Sapone A, et al: BMC Medicine. 2012

5 Interesse nelle patologie correlate al glutine Catassi et al: Nutrients 2013

6 Wheat Allergy (WA) WA is defined as an adverse immunologic reaction to wheat proteins. It depends on the route of allergen exposure and the underlying immunologic mechanisms WA is classified into: classic food allergy affecting the skin, gastrointestinal tract, or respiratory tract; wheat-dependent exercise-induced anaphylaxis (WDEIA); occupational asthma (baker s asthma) and rhinitis; and contact urticaria Sapone A, et al: BMC Medicine. 2012

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8 Allergia a Grano Gliadin is the principal allergen of wheat-dependent exercise-induced anaphylaxis (WDEIA). The primary structure of IgE-binding epitopes in wheat gliadin includes tandem sequencing sites of glutamine residues. Therefore, deamidation would be an effective approach to reduce the allergenicity of wheat proteins. In this study, they are examined the allergenicity of deamidated gliadin in a mouse model of wheat-gliadin allergy. Oral administration of deamidated gliadin to gliadin-sensitized mice suppressed enhancement in intestinal permeability, serum allergen level, serum allergen-specific IgE level, mast-cell-surface expression of FcεRI, and serum and intestinal histamine levels. Results: They indicate that gliadin deamidated with no peptide-bond hydrolysis by cation-exchange resins has low allergenicity even under in vivo conditions. Abe R, et al: Journal Chem 2014

9 Esofagite eosinofila e allergia ad alimenti Eosinophilic esophagitis (EoE) is a chronic T helper 2-type inflammatory disorder. Concurrent allergic diseases have been observed in EoE cases at a high prevalence. In immediate-type food allergy, diagnosis is based on a careful case history followed by a search for food-specific IgE either by skin prick test (SPT) or in vitro (e.g. ImmunoCAP). In children with atopic dermatitis and a food allergy to milk, eggs, peanuts, fish or wheat, the SPT and in vitro determination of specific IgE show excellent sensitivity and negative predictive values, whereas the positive predictive values are low. Consequently, oral food provocation is the gold standard for the diagnosis of food allergy. Similarly, in EoE patients, SPT, atopy patch test and in vitro determination of IgE to foods do not reliably predict food allergy, and the average positive predictive values of these allergy tests are below 50%

10 Algoritmo diagnostico per diagnosi di Allergia Anamnesi positiva per reazione immediata (da 1 a 4 ore dopo l assunzione dell alimento). Skin prick test per alimento/i responsabile/i Prick by prick con alimento fresco. Dosaggio IgE specifiche per alimento (phadia immunocap). Dosaggio IgE per LTP e profilline per alimenti Test di attivazione dei basofili Test di provocazione orale (GOLD Standard)

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12 Feldweg A.M.. et al: JACI in practice April 2017

13 World Allergy Organization Attenzione!! OFCs were performed by starting with a dose of 125 mg, 250 mg, 1gm, 2 gm, 4 gm, 8 gm, and ad lib (minimum of 8 gm). In select cases a lower starting dose (20 60 mg) was chosen for very high risk kids. Each dose was administered with an interval of 15 to 20 minutes until ad lib, doses were reached or the patient experienced a reaction within 2 hours of the last dose.

14 Attenzione Patients who underwent the challenge for wheat tended to be younger, had smaller skin tests but higher levels of sige, had asthma less often, and had a history of prior ingestion or prior reaction to the food tested compared to those children who presented for food challenges to all the other foods

15 Two cases have been published concerning wheat allergy in children with tolerance to a foodstuff of whole-grain wheat cereal biscuit (Weetabix; Weetabix Ltd, Burton Latimer, UK Allergia a LTP del Grano This study present 4 patients with the lipid transfer protein (LTP) syndrome, showing confirmed Tri a 14 mediated cereal allergy by wheat oral food challenge (OFC). These patients present multiple food allergies (tree nuts, rosaceous fruits, lettuce, and cereals). All patients had positive skin test results to wheat, npru p 3, and ntri a 14. Sensitization to other cereal proteins (such as v -5-gliadin and gluten proteins) was not found. Gamboa P.M. et al: JACI 2013

16 Allergia a LTP del Grano Primo paziente con orticaria/angioedema e dolore addominale dopo assunzione di grano; secondo paziente con anafilassi dopo ingestione di pane; terzo anafilassi e asma dopo ingestione e inalazione di farine; quarto paziente con anafilassi post esercizio fisico post prandiale (FDEIA) per tre volte. Oral challenge with Weetabix foodstuff was performed in the patients (53.8 g) who tolerated it without suffering from any symptoms During manufacturing of the Weetabix, proteins might suffer proteolytic processing and/or aggregation and this could prevent their solubility in salt buffers. As observed in our results, the disappearance of the albumin/globulin band (that includes LTPs) after manufacturing cereal has been recently reported. During the elaboration process of Weetabix, pressure and temperature treatment should suffice to inhibit the allergenic activity of LTPs, even their disappearance as soluble form, demonstrated both by SDS-PAGE and the tolerance of wheat-allergic patients.

17 Allergia al Grano nei Bambini The prospective analysis covered 50 children with positive food challenge results (DBPCFC) and positive wheat IgE test result. Resolution of wheat allergy was determined on the basis of food challenge results (open challenge).

18 Allergia al Grano nei bambini All the patients at initial diagnosis had positive food challenge results (with symptoms occurring within 2 hours after wheat consumption) and positive SPT as well as the levels of sige for wheat (wsige) higher than 0.7 ku/l. The OFC (open food challenge) began with the application of a drop of wheat groats - semolina (10% wheat cooked in water) on the upper lip. Thereafter wheat was given orally in increasing amounts in 15-minute intervals starting from a dose of 50 mg to reach the total of g ( g of wheat protein). If there was no reaction to the food challenge, wheat was administered daily (>20 g of wheat) at home for 7 days by the open method to ensure that there were no other adverse symptoms.

19 Allergia al grano nei bambini The risk of continued WA was high in those diagnosed children who, despite the elimination diet, had been demonstrating rising wsige for several years. The median of age in which those children reached maximum concentration of wsige was 5.5 years. An important factor that modified the Wheat Tolerance age was the level of wsige max.

20 Combining analyses of basophil allergen threshold sensitivity, CD-sens, and IgE antibodies to hydrolyzed wheat, ω-5 gliadin and timothy grass enhances the prediction of wheat challenge outcome Method: 24 children (aged 1-15 years) with a wheat allergy diagnosis underwent an open wheat challenge CD-sens and IgE-Ab to wheat, hydrolyzed wheat protein (HWP), ω-5 gliadin and timothy grass were analyzed and related to the challenge outcome N Nilsson et al, Int Arch Allergy Immunol 2013

21 Documento marzo 2017

22 Quadro del problema

23 Allergeni Occulti Il fenomeno degli allergeni occulti è legato alla presenza in modo non esplicito di un allergene in un alimento, apparentemente non correlato al cibo verso cui è presente allergia; un esempio classico è rappresentato dalle guarnizioni di un dolce con gelatina di pesce (che a sua volta, potrebbe contenere tracce di proteine di altri animali). Il miglior modo di affrontare il problema degli allergeni occulti è il rispetto della legislazione armonizzata sulle procedure di etichettatura che mira a consentire l esatta conoscenza degli ingredienti, compresi quelli minori.

24 Allergeni Occulti La confezione industriale dei cibi ha enormemente amplificato la possibilità di reperire, in modo del tutto inaspettato, allergeni occulti (es: latte o soia nei salumi, caseina nel vino...) con lo scatenamento di reazioni verso cibi totalmente estranei ed apparentemente innocui rispetto alle sensibilizzazioni note. Inoltre, alcune pratiche tecnologiche tradizionali ammesse, come l utilizzo di chiarificanti di origine animale per la preparazione di bevande alcoliche (vino e birra), hanno recentemente stimolato ricerche ed investigazioni scientifiche funzionali a definire se le proteine allergizzanti possano o meno residuare nel prodotto finito, e risultare o meno - pericolose per gli individui allergici. Anche in questo caso, si parla di allergeni occulti o nascosti.

25 Allergeni Occulti L accuratezza di quanto dichiarato in etichetta è essenziale per il successo delle diete di eliminazione. Da indagini svolte su soggetti con allergia alimentare, emerge che la lettura delle etichette è considerata un problema serio, o molto serio, da una larga quota degli intervistati, che segnalano la frequente necessità di contattare direttamente le ditte produttrici per avere chiarimenti.

26 Take Home Messages 1. Quando vedete un esofagite eosinofila o una gastroenterite eosinofila, pensare a una comorbidità di allergia IgE mediata (sensibilità a PR-10) ad alimenti non è così raro. (dunque inviare a centro allergologico). 2. La sensibilità dei test in vivo e in vitro nell allergia a Grano supera di poco il 50% e il Gold Standard rimane il Oral provocation test da effettuare in ambiente protetto e con linee guida.

27 Prevalence of allergy to wheat in patients who report a history of reactions after ingesting food which contains gluten. The association between food allergy and celiac disease (CD) and Non celiac Gluten sensitivity (NCGS) is still to be clarified. Gluten-related disorders have gradually emerged as an epidemiologically relevant phenomenon with a global prevalence that is estimated around 5%, drawing the attention of the scientific community.. According to a study performed by the National Health and Nutrition Examination Survey in the United States, the prevalence of self-prescribed GFD in an unselected population of subjects aged 6 years or older was 0.5%. Epidemiological studies report a prevalence of WA in american population of around 0.4% untill 0.6%. Molecular-based allergy (MA) diagnostics could overcome some limitations of sige in vitro assays using wheat flour extracts. We have used omega-5 gliadin (Tri a 19) and nsltp (Tri a 14), gliadin, wheat, gluten that are available in the ImmunoCAP assay, whereas the alpha-amylase/trypsin inhibitor (Tri a aa/ TI) is available only in the microarray ISAC assay. The sige to omega-5 gliadin assay is highly reliable and now widely used to identify the patients with WDEIA. Of a total of 104 patients with a history of immediate reactions and not immediate after ingesting gluten, we found wheat protein sensitization in 14 patients (13%). In addition of 300 celiac patients we also found 5 patients with allergy to wheat or wheat protein (1.5%) different percentage than that Caruso C*., De Vitis I. et al: Official journal of EAACI Clinical and molecular allergy APRIL 2017

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29 Microbiota and allergy disease PRACTALL CONSENSUS AAAI JACI APRIL2017

30 Take Home Messages 3. Attenzione ai test di provocazione con Grano e alla reintroduzione in soggetti con IgE positive a varie molecole (r tri a 14, 19, Grano, Gliadina) perché c è rischio di anafilassi.

31 Grazie infinite per l attenzione Cristiano.caruso@policlinicogemelli.it EAACI MEMBER and ERS MEMBER Member of Task force of Food Allergy and Anaphilaxys