E corretto parlare ancora di allergia a noce

E’ corretto parlare ancora di allergia a noce e semi? Eleonora Savi

Ha senso parlare ancora di allergia alla frutta a guscio? Gli allergici alla nocciola sono tutti uguali?

Allergici 1 Sensibilizzati Sintomi lievi al cavo orale o sistemici 2 ingerendo nocciola fresca o una torta(nutella) 3 SENSIBILIZZAZIONE a molecole diverse

Allergia alle Arachidi : molecole con stabilità diversa alla cottura e alla digestione Ara h 1 Ara h 9 Ara h 2 Ara h 8 Ara h 3 Nome Latino: Ara h = Arachis hypogaea

4 Molecole omologhe di fonti diverse non crociano sempre tra loro

Risk assessment

Stabilità delle proteine Proteine Labili Reazioni locali Proteine Stabili Reazioni sistemiche

Risk assessment per famiglia di proteine Diagnostica Molecolare - Risk assessment Luengo O Clin and Transitional Allergy 2014; 4: 28

There are whole-allergen tests with poor predictive values for clinical reactivity, such as soy, wheat and hazelnut. C. R. D. may outperform whole allergen testing providing more detailed information on the sensitization profile.

LOLIUM 18 KUL Ig. E ARACHIDE 4 KUL Ig. E PROFILINA 3. 9 KUL Ig. E

Bet v 1 PR 10

Risk assessment

Risk assessment

Tri a 14 Par j 2 , Art v 3 LTP Pru p 3 Lac s 1 CHE RAPPORTO ESISTE ? Cor a 8

Le molecole nell’allergia alimentare Alimenti origine vegetale Proteine termo e gastro stabili Pesca Mela Pru p 3 Mal d 3 Nocciola Cor a 9 Cor a 14 Ara h 1 Ara h 2 Ara h 3 Jug r 1 Frutta fresca Arachide Frutta secca Nocciola Arachide Noce Soia Grano LTP Proteine di deposito Cor a 8 Ara h 9 Jug r 3 LTP Gly m 5 Gly m 6 Proteine di deposito Tri a 14 LTP Tri a 19 Gliadina ω 5 gliadina α, β, γ, ω Proteine termo e gastro labili Pru p 1 Pr 10 Pru p 4 Profilina MUXF 3 CCD Alimenti origine Animale Latte Bos d 4 Bos d 5 Bos d 6 Bos d 8 α lattoalbumina β lattoglobulina Albumina Caseina Termo e gastro labile Termo e gastro stabile Uovo Gal d 1 Gal d 2 Gal d 4 Ovomucoide Ovoalbumina Lisozima Termo e gastro stabile Termo e gastro labile Pesce Gad c 1 Parvalbumina Termo e gastro stabile Crostacei Pen a 1 Tropomiosina Termo e gastro stabile CCD MUXF 3

568 pz LTP-positivi dopo Immuno. CAP-ISAC 82% positivi a Pru p 3, pesca 71% positivi a Jug r 3, noce 55% positivi Ara h 9, arachide 60% positivi a Pla a 3, platano 50% positivi a Art v 3, assenzio pz monosensibilizzati pz sensibilizzati a 7 LTP

Risk assessment

Seed Storage Proteins Bassa cross-reattività: la positività Ig. E nei confronti di una seedstorage protein non sempre correla con la positività di altre seedstorage proteins

Superfamiglia delle CUPINE Superfamiglia delle PROLAMINE Proteine del sistema difensivo Proteine metaboliche e strutturali PR 3 2 S SEEDViciline STORAGEAlbumine PROTEINS Ara h 1 Ara h 2 -6 -7 Chitinasi Mal d 4 Ara h 5 Cor a 11 Legumine LTP Ara h 3 -4 Pu p 3 Cora 9 Cor a 8 PR 5 Proteine taumatino simili Mal d 3 Oleosine Profiline Inibitori dell’a amilasi PR 10 Proteine Riso, Grano Ara h 8 omologhe di Bet v 1 Mal d 1 Pru p 1 Le famiglie allergeniche vegetali Pru p 4

Albumine 2 S

Nonostante la struttura delle seed-storage proteins sia molto conservata, vi è una scarsa cross-reattività tra le varie fonti alimentari.

IDENTITA’ SEQUENZA AMINOACIDICA Ara h 2 E ALTRE 2 S Ara h 2 vs 2 S negli alimenti ALIMENTI % IDENTITA’ Lupino 38% Soia Gly m 8 * 31% Nocciola Cor a 14 * 25% Sesamo Ses i 1 * 27% Noce brasiliana Ber e 1 * 23% Noce Jug r 1 * 22% Pistacchio Pis v 1 * 22% Anacardo Ana o 3 * 21% Sesamo Ses i 2 * 20% Girasole * Allergome 14% § solo Uni. Prot

2 S Albumine Ara h 2 29% 24% Cor a 14 (solo unicap) 66% 47% 28% 41% Jug r 1 Ana o 3 Pis v 1 (solo unicap)

CUPINE VICILINE 7 S GLOBULINE LEGUMINE 11 S GLOBULINE

CUPINE (superfamiglia) Caratterizzate da una struttura a β-botte (dal latino cupa=botte) in base al coefficiente di sedimentazione vengono divise in VICILINO simili (7 s) Non contengono cisteina non hanno ponti disolfuro LEGUMINO simili (11 s)

11 S Globuline Ara h 3 Cor a 9 47% 44% 76% 60% 47% 63% Jug r 4 (manca) Ana o 2 Pis v 2 (solo ISAC)

IDENTITA’ SEQUENZA AMINOACIDICA Ara h 3 E ALTRE 11 S Ara h 3 vs 11 S negli alimenti ALIMENTI % IDENTITA’ Soia Gly m 6 * 54% Pisello 49% Lupino 48% Nocciola Cor a 9 * 41% Noce Jug r 4 * 41% Pistacchio Pis v 5 * 39% Anacardo Ana o 2 * 39% Mandorla Pru d 6 * 37% Pistacchio Pis v 2 * 34% Noce brasiliana Ber e 2 * 33% Zucca 33% Sesamo Ses i 7 * 31% Sesamo Ses i 6 * 30% * Allergome § solo Uni. Prot

EBM nella Diagnostica Molecolare Verweij M. M. Ped Allergy Immunol 2011; 22: 196 -201

ALLERGY 2018 • r. Cor a 1 (Bet v 1 homologue) • r. Cor a 2 (profilin) • r. Cor a 8 (LTP) • n. Cor a 9 (11 S globulin) • r. Cor a 11 (7 S vicilin) • n. Cor a 12 (oleosin) • r. Cor a 14 (2 S albumin) • 729 patients • 120 children • Sera of 423 patients were available for CRD

Allergy. 2018; 73: 549– 559 There is evidence that the seed storage proteins Cor a 9 (11 S globulin) and Cor a 14 (2 S albumin) are associated with more severe reactions similar to lipid transfer protein ( LTP) Cor a 8 in the Mediterranean area. In Northern and Central Europe , sensitization to Bet v 1 – homologue Cor a 1 is typically seen in adolescents and adults with sensitization to birch pollen and oral symptoms

• Sensitization to Cor a 1 and to Cor a 2 was negatively associated with severe symptoms. • In sera of patients sensitized to Cor a 9 s. Ig. E levels were significantly higher in those with severe symptoms (11. 3 k. UA/L) than in patients with moderate and mild symptoms (1. 68 and 0. 73 k. UA/L). • No significant differences in Ig. E levels against hazelnut extract were observed between patients of different severity.

IDENTITA’ SEQUENZA AMINOACIDICA Ara h 1 E ALTRE 7 S Ara h 1 vs 7 S negli alimenti ALIMENTI % IDENTITA’ Lupino Lup an 1 * 41% Soia Gly m 5 * 38% Lenticchia Len c 1 * 36% Pisello Pis s 1 * 35% Fava Noce 34% Jug r 2 * Fagiolino Sesamo 28% Ses i 3 * Zucca Nocciola 30% 27% 25% Cor a 11 * Cece 25% Pistacchio Pis v 3 * 24% Anacardo Ana o 1 * 23% * Allergome § solo Uni. Prot

7 S Globuline Ara h 1 34% 27% Cor a 11 (manca) 49% 55% 35% Jug r 2 (solo ISAC) Ana o 1 Pis v 3 (manca)

Retrospective definition of reaction risk in Italian children with peanut, hazelnut and walnut allergy through component-resolved diagnosis M. Giovannini March 2018 • Ara h 2 is the component with greatest discrimination capability between severe and mild reactions to peanut, as already reported by several studies in literature. • Ara h 8 sensitization is considered a marker of primary sensitization to pollen and of tolerance in moderate or local reactions to peanut. • Ara h 9 belongs to the LTP family and is considered a marker of severe systemic reactions as well as of oral allergy syndrome.

Ara h 2 is a more specific marker for identifying challenge-proven peanut allergy, and s. Ig. E level to Ara h 2 can be an indicator to reduce the need for OFC • Defensins occuring in the lipophilic peanut fraction, termed Ara h 12 and Ara h 13, were associated with more severe reactions (Petersen et al. , 2015).

Walnut: Walnut the presence of positive s-Ig. E against Jug r 1, Jug r 2 and Jug r 3 is associated with a history of severe anaphylaxis to such food.

High frequency of Ig. E sensitization towards kiwi seed storage proteins among peanut allergic individuals also reporting allergy to kiwi Jenny van Odijk clin mol allergy 2017 11 S globulins were demonstrated to be the protein which mediated the highest degree of Ig. E crossreactivity between proteins from several legumes and peanut. Ig. E antibodies towards 2 S albumins from hazelnut (Cor a 14) was demonstrated to not cause crossreactive allergic reactions to the homologous protein from peanut (Ara h 2).

EBM nella Diagnostica Molecolare Hasegawa M. Allergology International 2009; 58: 209 -215

Cross reattività Pistacchio – Anacardo • I pazienti che reagiscono all’anacardo reagiscono al pistacchio e vicersa • I pazienti che reagiscono alla noce reagiscono anche al pecan nocciola • I pazienti che reagiscono ai semi di agrumi reagiscono anche all’anacardo - pistacchio

Frutta secca - Nocciola Sintomi: vomito, diarrea, sindrome orale allergica, orticaria, angioedema e anafilassi Allergeni termogastro stabili Oleosine difficile diagnosi non si trovano nei test diagnostici Allergeni termogastro labili Cor a 9 Cor a 14 Cor a 11 Proteine di deposito Cor a 8 LTP Cor a 1 Pru p 4 Rischio di Anafilassi Valutare l’eliminazione dell’alimento Consigli dietetici e comportamentali PR-10 Profilina

Frutta secca - Noci Sintomi: vomito, diarrea, sindrome orale allergica, orticaria, angioedema e anafilassi Allergeni termogastro stabili LTP Noce Jug r 3* Allergeni termogastro labili Proteine di deposito Jug r 1* Noce brasiliana Ber e 1 Anacardo Ana o 3 X-reattività con nocciolo americano Cor a 1 Pru p 4 Profilina x-reattività con pistacchio MUXF 3* Rischio di Anafilassi Valutare l’eliminazione dell’alimento PR-10 Consigli dietetici e comportamentali CCD

Frutta Secca Sintomi: vomito, diarrea, sindrome orale allergica, orticaria, angioedema e anafilassi Allergeni termogastro stabili LTP Arachide Ara h 9 Nocciola Cor a 8 Noce Jug r 3 Allergeni termogastro labili Proteine di deposito Ara h 1 Ara h 2 Ara h 6 Ara h 3 Cor a 9 Cor a 14 Jug r 1 Noce brasiliana Ber e 1 Anacardo Ana o 3 Valutare l’eliminazione dell’alimento X-reattività con nocciolo americano Pru p 1 PR-10 Pru p 4 Profilina MUXF 3 X-reattività con pistacchio Consigli dietetici e comportamentali CCD

High frequency of Ig. E sensitization towards kiwi seed storage proteins among peanut allergic individuals also reporting allergy to kiwi Jenny van Odijk, Clin Mol Allergy 2017 • 39% of the peanut allergic patients in this cohort also reported kiwi fruit allergy, they displayed a higher degree of sensitization to kiwi storage proteins from both kiwi and peanut, and a higher extent of allergy to other nuts and legumes. • There was a correlation between Ig. E levels to 11 S and 7 S storage proteins from kiwi and peanut and a co-sensitization to the 2 S albumin Act d 13.

PR 10 Act d 8 Profilina Act d 9 n. LTP Act d 10 Thaumatina Act d 2 Actinidin Act d 1 Phytocistatin Act d 4 Kiwelin Act d 5 Major latex protein Act d 11 Cor a 9 Cupin 11 s globulin Act d 12 2 s Albumin Act d 13 Cor a 14

• In the group of peanut allergic patients not reporting kiwi allergy, the individuals displayed a higher frequency of peanut storage protein sensitization, especially to Ara h 2, and presented with fewer symptoms to other nuts and legumes. The results implicate the presence of at least two phenotypes of peanut allergic. One group with a broader cross-sensitization profile and having co-existing symptoms to both kiwi and other plant foods and a second group with a strong peanut sensitization to the major allergen Ara h 2 and less symptoms to other plant foods

Debates in allergy medicine: Molecular allergy diagnosis with ISAC will replace screenings by skin prick test in the future. J Jensen-Jarolim E, 2017 World Allergy Organ • Considering the risk of provocation tests and skin prick testing in patients with a previous systemic reaction, Molecular allergy diagnosis with Ig. E testing is an interesting alternative tool allowing orientation on the Ig. E profile and level of sensitization.

How change the prescription? 112 patients were prescribed adrenaline, 111 after CRD: in 19 cases the sensitization had been underestimated and adrenaline was prescribed only after CRD was carried out

Take home message • The physician has to define the clinical relevance of the diagnostic test result, not the test itself.

Rivalutazione Prick test 2017 • • • Noce 2 mm Mandorla negativo Arachide negativo Pinolo negativo Anacardo negativo Castagna negativo Nocciola 8 MM Betulla 6 mm Graminacee 10 mm Parietaria 8 mm Profilina 6 MM LTP pesca negativo

ISAC Test Positivo • PR 10 • Cor a 1 • Jug r 3 LTP • Bet v 1 • Bet v 2

ALIMENTI VEGETALI: omologhi del Bet v 1 I trattamenti termici industriali eliminano l’allergenicità degli allergeni Bet v 1 -omologhi presenti nella frutta fresca (TERMOLABILI). NOCCIOLA Pastorello EA, 2002 MELA Asero R, 2006

Conclusioni • Debole positività noce Jug r 1 Jug r 3 • Positività alla nocciola Cor a 1 PR 10 labile • Cor a 9 Cor a 8 negativi • Non darei adrenalina raccomanderei solo dolci con nocciola processata. Evitare noce • Su insistenza della madre non convinta a dare dolci con nocciola • Pb. P Nutella 8 mm

Cosa mi manca? • Cor a 14 1. 8 kul 2 s Albumina