Allergia alimentare: i dilemmi quotidiani del pediatra Introduzione precoce degli alimenti alla luce dell’allergia alimentare: pro e contro Diego Peroni Le raccomandazioni classiche Tolleranza o Allergia? Le scelte possibili Conclusioni Università di Pisa diego.peroni@unipi.it

Optimal timing for solids introduction – why are the guidelines always changing? Koplin, CEA 2013: 43-826 In the 1960s most infants had been exposed to solids by 4 months of age with the average age of introduction just 8 weeks of age. In the 1970s guidelines recommending delayed introduction of solids until after 4 months, based on the possibly that the rise in celiac disease was due to early introduction of gluten. By the late 1990s expert bodies began to recommend delaying solids until after 6 months of age. È interessante notare come, negli ultimi 50 anni  l’età di inizio del divezzamento sia andata progressivamente ad aumentare in tutti i bambini /// sotto la spinta dell’ IPOTESI /// che l’ introduzione troppo precoce dei cibi solidi potesse favorire la comparsa di malattie allergiche E di altre malattie immuno-mediate come la celiachia

There has been a progressive and dramatic delay in Optimal timing for solids introduction – why are the guidelines always changing? Koplin, CEA 2013: 43-826 In the 1960s most infants had been exposed to solids by 4 months of age with the average age of introduction just 8 weeks of age. In the 1970s guidelines recommending delayed introduction of solids until after 4 months, based on the possibly that the rise in celiac disease was due to early introduction of gluten. By the late 1990s expert bodies began to recommend delaying solids until after 6 months of age. There has been a progressive and dramatic delay in timing of first exposure to solid foods for all children over the last 50 years. Il risultato netto di questo trend  è che negli ultimi 50 anni si è verificato un progressivo e importante ritardo nella prima introduzione degli alimenti solidi, in tutti i bambini

Why late introduction of solid foods? The reasons to delay introduction of solid foods for allergy prevention have centered on the notion that the infant’s gut-mucosal barrier is immature and early exposure to allergens (food proteins) may result in allergic sensitization against food and subseq. to inhalant allergens. Illi S, JACI. 2001;108:709–14 Evidence in humans to support this hypothesis comes from a few studies demonstrating increased risk of eczema and possibly asthma in children first introduced to solids before 3 to 4 months of age. Kajosaari M. Adv Exp Med Biol. 1991;310:453–58 Fergusson DM, Pediatrics. 1990;86:541–46 Le ragioni che hanno favorito tale comportamento sono state principalmente: l’IPOTESI che l’immaturità della barriera GI dei primi mesi di vita potesse favorire la sensibilizzazione ad allergeni alimentari, ed i risultati di alcuni studi di coorte, ormai datati ai primi anni ‘90, in cui era stato osservato un maggior rischio di dermatite atopica nei bambini che introducevano gli alimenti solidi prima del 4° mese di vita

Modifying the infant’s diet to prevent food allergy. Grimshaw K, et al. Arch Dis Child 2017;102:179

AMERICAN ACADEMY OF PEDIATRICS Hypoallergenic Infant Formulas Committee on Nutrition Hypoallergenic Infant Formulas Pediatrics 2000;106:346 the following recommendations seem reasonable at this time: a) No maternal dietary restrictions during pregnancy are necessary with the possible exception of excluding peanuts; b) Breastfeeding mothers should continue breastfeeding for the 1st year of life or longer. During this time, for infants at risk, hypoallergenic formulas can be used to supplement breastfeeding. Mothers should eliminate peanuts and tree nuts (eg, almonds, walnuts, etc) and consider eliminating egg, cow’s milk, fish, and perhaps other foods from their diets while nursing. c) Solid foods should not be introduced into the diet of high-risk infants until 6 months of age, with dairy products delayed until 1 year, egg until 2 years, and peanuts, nuts, and fish until 3 years of age. Alla fine degli anni ‘90 diverse società scientifiche internazionali prendono posizione su questo argomento // Molto rappresentative sono le raccomandazioni dell’ Accademia Americana di Pediatria - che nel 2000 suggeriva come strategie per la prevenzione delle malattie allergiche: L’ eliminazione degli alimenti allergenici dalla dieta materna durante gravidanza e allattamento E l’introduzione dei cibi solidi dopo il 6 mese, con particolare attenzione ai bambini ad alto richio di allergie per familiarità in cui i prodotti derivati del LV dovevano essere introdotti dopo l’anno, l’uovo dopo I 2 anni e arachide, frutta secca e pesce dopo I 3 anni

X X X Recommended Approaches to Prevent Allergies Maternal dietary restriction during pregnancy Breastfeeding Dietary restrictions while breastfeeding The use of hypoallergenic formulas Delaying the introduction of certain foods into the infant’s diet Andando a fare un confronto tra le principali raccomandazioni delle diverse società scientifiche internazionali su questo argomento  si può notare come  X X X

Allergia alimentare: i dilemmi quotidiani del pediatra Introduzione precoce degli alimenti alla luce dell’allergia alimentare: pro e contro Diego Peroni Le raccomandazioni classiche Tolleranza o Allergia? Le scelte possibili Conclusioni Università di Pisa diego.peroni@unipi.it

effector sites inductive sites Schematic representation of the lymphoid elements of the intestinal immune system. Mowatt, Nat Rev Immun. 2003;3:331 effector sites inductive sites Peyer’s patches È noto, che il sistema immunitario associato alla mucosa GI rappresenta il più vasto e complesso organo immunitario del corpo

Oral Tolerance The immune system has the difficult task of maintaining gastrointestinal homeostasis by keeping up a state of non-responsiveness towards dietary antigens and a symbiotic relationship with commensal bacteria, while initiating proper protection against potential pathogenic intruders to prevent the host’s infection. Perrier, Clin Exp Allerg. 2011; 41:20. Quotidianamente questo sistema immunitario mucosale è esposto ad una miriade di proteine alimentari innocue, ma non-self. Nonostante però l’ampia varietà e le dosi relativamente elevate di tali potenziali allergeni, solo pochi pazienti sviluppano reazioni allergiche 

Oral Tolerance Oral tolerance involves the specific suppression of cellular and humoral immune responses to ingested antigens. Chehade M, J ACI 2005,115:3–12. Oral tolerance is achieved by a unique gut immune system made up of complex regulatory networks among immunocompetent cells (e.g., dendritic cells and T cells) Faria AM, Immunol Rev 2005,206:232–259 The default immune response in the gut is oral tolerance, a state of active inhibition of immune responses to antigens first given orally Ciò si deve al fatto che nella maggior parte dei soggetti si instaura uno stato di TOLLERANZA ORALE = uno stato cioè di «attiva e continua» INIBIZIONE della risposta immunitaria (locale e sistemica) nei confronti di tali antigeni innocui introdotti per via orale  in cui giocano un ruolo fondamentale : cellule epiteliali intestinali, cellule dendritiche sottoepiteliali,linfociti T regolatori

MECHANISMS OF ORAL TOLERANCE Burks JACI 2008;121:1344 Deletion or Anergy or Active Suppression by «Regulatory T-cells» There are 2 primary effector mechanisms for inducing oral tolerance: f 1) High-dose tolerance is mediated by lymphocyte anergy or clonal deletion. Anergy can occur through T-cell receptor ligation in the absence of costimulatory signals. Clonal deletion occurs by means of FAS-mediated apoptosis (CD95). Cioè che però è interessante ai fini della nostra discussione  è che sembrerebbero esserci 2 principali meccanismi in grado di indurre l’inibizione della risposta immunitaria/ e quindi la tolleranza – ed entrambi sarebbero strettamente dipendenti dalla presenza ed in particolare dalla dose di antigene ingerito: - Alte dosi di antigene  indurrebbero la delezione o l’anergia di cloni di Linfociti T effettori X

MECHANISMS OF ORAL TOLERANCE Burks JACI 2008;121:1344 Deletion or Anergy or Active Suppression by «Regulatory T-cells» There are 2 primary effector mechanisms for inducing oral tolerance: f 2) Low doses of antigen favor tolerance driven by regulatory cells, which suppress immune responses through soluble or cell surface–associated downregulatory cytokines, such as IL-10, and TGF-β (active suppression). - Basse dosi di antigene  indurrebbero invece la tolleranza mediante l’attivazione di Linfociti T regolatori con funzioni immunosoppressive attraverso la produzione di citochine downregolatorie (IL-10 e TGF-B), garantendo un’attiva soppressione.

The mucosal immune system has generated two anti-inflammatory strategies: (1) immune exclusion—performed by SIgA to control the epithelial colonization of microorganisms and inhibit the penetration of potentially dangerous agents; and (2) hyporesponsiveness—to avoid local and peripheral hypersensitivity against innocuous antigens. (1) I motivi però per i quali la > parte di bambini va incontro alla tolleranza, mentre solo una piccola % sviluppa allergia sono molto complessi e ancora oggi poco chiari. I meccanismi di difesa e l’integrità della mucosa GI potrebbero avere un ruolo importante  (2) Anti‑inflammatory mucosal adaptive immune defense mechanisms. Brandtzaeg, P. Nat. Rev. Gastroenterol. Hepatol. 2010;7:380–400

Maintenance of mucosal homeostasis in the gut and the abrogation of oral tolerance. Brandtzaeg, P. Nat. Rev. Gastroenterol. Hepatol. 2010;7:380–400 Maintenance of mucosal homeostasis in the gut and the abrogation of oral tolerance. Brandtzaeg, P. Nat. Rev. Gastroenterol. Hepatol. 2010;7:380–400 (3) If an innate or regulatory defect exists, a vicious circle develops that acts reciprocally on the homeostatic network. The epithelium is activated and Ag and microbe‑associated molecular pattern (MAMP) uptake is enhanced both by increased permeability and apical receptor expression.

Biological variables that influence the developing immunophenotype of an infant Brandtzaeg, P. Nat. Rev. Gastroenterol. Hepatol. 2010;7:380–400 Tuttavia però, è bene sempre considerare che molteplici fattori possono influenzare lo sviluppo della tolleranza orale  tra questi, la predisposizione genetica e l’esposizione/il contatto con l’antigene sembrerebbero avere un ruolo predominante. Green boxes represent components that may be subjected to intervention modalities

Allergia alimentare: i dilemmi quotidiani del pediatra Introduzione precoce degli alimenti alla luce dell’allergia alimentare: pro e contro Diego Peroni Le raccomandazioni classiche Tolleranza o Allergia? Le scelte possibili Conclusioni Università di Pisa diego.peroni@unipi.it

Solid Food Introduction in Relation to Eczema; Results from a Four-Year Prospective Birth Cohort Study. Filipiak B, J Pediatr. 2007;151:352-8 In this large population-based prospective birth cohort study, there was no evidence for a protective effect in relation to eczema from delayed introduction of solids beyond the fourth month and of most potentially allergenic solids beyond the sixth month of life. Introduction of solid foods in the first 12 months (birth cohort) Occurrence of eczema during the first 4 yrs of life an intervention group (n=2252) (allergenic food such as cow’s milk and dairy products, eggs, fish, tomatoes, nuts, soy products, and citrus fruits were to be avoided entirely during the 1st year) nonintervention group (n=3739). In controtendenza rispetto allo studio storico sulla coorte Neozelandese di Ferguson che vi ho mostrato all’inizio in cui l’eczema era > prevalente nei bambini che avevano iniziato il divezzamento prima dei 4 mesi  in questo studio tedesco l’introduzione dei cibi solidi dopo il 4° mese e in particolare degli alimenti più allergenici dopo il 6° mese NON sembra avere un effetto protettivo sulla comparsa di eczema (non riduce il rischio di eczema) nei primi 4 anni di vita

1.43 1.0 0.65 0.64 OR for atopic dermatitis at age 2 yrs 0-3 4-6 7-9 AGE AT FIRST INTRODUCTION OF COW MILK PRODUCTS AND OTHER FOOD PRODUCTS IN RELATION TO INFANT ATOPIC MANIFESTATIONS IN THE FIRST 2 YEARS OF LIFE: THE KOALA BIRTH COHORT STUDY Snijders B, Pediatrics. 2008;122:e115 OR for atopic dermatitis at age 2 yrs 1.5 – 1 – 0.5 – 2558 infants in a Dutch prospective birth cohort 1.43 1.0 In questo altro recente studio prospettico Olandese  in una coorte di 2558 infanti è stata studiata l’associazione tra l’età di introduzione dei prodotti derivati del LV e dei cibi solidi in genere con le manifestazioni di atopia a 2 anni di vita  Quello che si è osservato è che il rischio (OR) di dermatite atopica a 2 anni d’età è maggiore se i prodotti derivati del LV venivano introdotti nella dieta dopo il 9 mese, mentre l’assunzione tra il 4° ed il 9° mese sembra essere protettivo 0.65 0.64 0-3 4-6 7-9 >9 AGE OF INTRODUCTION OF MILK PRODUCTS (mo)

4.31 3.69 1.0 OR for any sensitization 3 4-6 >7 5 - 4 - 3 – 2 – 1 – AGE AT FIRST INTRODUCTION OF COW MILK PRODUCTS AND OTHER FOOD PRODUCTS IN RELATION TO INFANT ATOPIC MANIFESTATIONS IN THE FIRST 2 YEARS OF LIFE: THE KOALA BIRTH COHORT STUDY Snijders B, Pediatrics. 2008;122:e115 OR for any sensitization 5 - 4 - 3 – 2 – 1 – 2558 infants in a Dutch prospective birth cohort 4.31 3.69  E una relazione simile si ha anche per il rischio di sensibilizzazione allergica (valutata mediante il dosaggio delle IgE specifiche su sangue) per allergeni inalanti ed alimenti a 2 anni di vita. 1.0 3 4-6 >7 AGE OF INTRODUCTION OF OTHER FOOD PRODUCTS (mo)

Can early introduction of egg prevent egg allergy in infants Can early introduction of egg prevent egg allergy in infants? A population-based study Koplin JJ, JACI 2010;126:807 OR for development of egg allergy in total population 3.5 – 3.0 – 2.5 – 2.0 – 1.5 – 1.0 – 0.5 – 0.0 3.4 Population-based cross-sectional study. 2589 infants. 1.6 B  Dati emergenti suggeriscono inoltre che l’introduzione ritardata oltre il 6° mese, non solo NON ha effetto preventivo sulle allergie, ma potrebbe addirittura favorire l’insorgenza di allergie, in particolare per gli alimenti allergenici, mentre sarebbe l’introduzione precoce e rogolare a fovorire la tolleranza We have shown that delaying introduction of egg until 10 to 12 months of age or after 12 months of age was associated with significantly higher risk of egg allergy compared with earlier introduction at 4 to 6 months of age. (We have shown that introduction of cooked egg between 4 and 6 months of age decreased the risk of development of egg allergy at age 12 months by fivefold) 1.0 4-6 10-12 >12 Age (mo) of introduction

Can early introduction of egg prevent egg allergy in infants Can early introduction of egg prevent egg allergy in infants? A population-based study Koplin JJ, JACI 2010;126:807 OR for development of egg allergy in total population 3.5 – 3.0 – 2.5 – 2.0 – 1.5 – 1.0 – 0.5 – 0.0 3.4 These findings persisted even in children without risk factors (OR = 3.3; 10-12 mo.) Population-based cross-sectional study. 2589 infants. 1.6 and that this risk was strongest for those from NON-allergic families, providing supportive evidence that this effect was not confounded by una “causalità inversa” (= cioè il maggior rischio di allergia in chi introduce tardivamente l’alimento non può essere spiegato con un “rapporto inverso” cioè che nei bambini a > rischio per familiarità viene volontariamente ritardata introduzione dell’alimento) 1.0 4-6 10-12 >12 Age (mo) of introduction

Early consumption of peanuts in infancy is associated with a low prevalence of peanut allergy. Du Toit, JACI 2008;122:984 % CHILDREN WITH PEANUT ALLERGY 2.0 – 1.5 – 1.0 – 0.5 – Questionnaire Schoolchildren (5171 in the UK and 5615 in Israel). Peanut consumption and weaning in Jewish infants (77 in the UK and 99 in Israel). 1.85% p<0.001 In 2008 in uno studio trasversale condotto su bimbi ebrei che abitavano in Israele (n=5615) e nel Regno Unito (n=5171), the prevalence of PA was 10-fold higher in the UK (1.85%) than in Israel (0.17%, P <.001).  La cosa interessante che questo studio ha evidenziato è che peanut is introduced earlier and is eaten more frequently and in larger quantities in Israel than in the UK, 0.17% UK ISRAEL

Early consumption of peanuts in infancy is associated with a low prevalence of peanut allergy. Du Toit, JACI 2008;122:984 MEDIAN MONTHLY CONSUMPTION OF PEANUTS IN INFANTS AGED 8 TO 14 MONTHS (G PEANUT PROTEIN) 10 – 9 – 8 – 7 – 6 – 5 – 4 – 3 – 2 – 1 – Questionnaire Schoolchildren (5171 in the UK and 5615 in Israel). Peanut consumption and weaning in Jewish infants (77 in the UK and 99 in Israel). p<0.0001 7.1 In 2008 in uno studio trasversale condotto su bimbi ebrei che abitavano in Israele (n=5615) e nel Regno Unito (n=5171), the prevalence of PA was 10-fold higher in the UK (1.85%) than in Israel (0.17%, P <.001).  La cosa interessante che questo studio ha evidenziato è che peanut is introduced earlier and is eaten more frequently and in larger quantities in Israel than in the UK (The median monthly consumption of peanut in Israeli infants aged 8 to 14 months is 7.1 g of peanut protein as opposed to 0 g in the UK. The median number of times peanut is eaten per month was 8 in Israel and 0 in the UK)  These findings raise the question of whether early regular introduction of peanut during infancy, rather than avoidance, will prevent the development of PA 0% UK ISRAEL

Household peanut consumption as a risk factor for the development of peanut allergy Fox JACI 2009; 123:417 g. peanut protein / week Peanut allergy among children with food allergy (n= 293) as a function of environmental exposure depending on whether child first ate peanuts by 12 months. In a recent cross-sectional study the relevant route of peanut exposure in the development of allergy was evaluated. - (non nella slide) C’è una relazione diretta tra il grado di esposizione ambientale (non-orale) alle arachidi (valutato come dose di arachidi consumata dai familiari del bambino) e lo sviluppo di PA : The median weekly household peanut consumption in the patients with PA was significantly increased compared with that seen in control subjects without allergy and high-risk control subjects - (slide) Early oral exposure to peanut (prima dei 12 mesi di vita) in infants with high environmental peanut exposure might have had a protective effect against the development of PA These findings suggest that Questo studio dimostra che: complete allergen avoidance is an unattainable therapeutic goal and it might even be harmful in quanto High levels of “environmental” exposure to peanut during infancy can promote sensitization (per la possibile sensibilizzazione per via cutanea), whereas low levels and early regular oral exposure may actually be important for promoting tolerance (vedi anche Du Troit_PEANUT; Koplin_EGG; Alm_FISH).

THE IMPORTANCE OF EARLY COMPLEMENTARY FEEDING IN THE DEVELOPMENT OF ORAL TOLERANCE: CONCERNS AND CONTROVERSIES. Prescott S, Pediatr All Immunol 2008;19:375 Pertanto, alla luce delle più recenti evidenze presentate, e in controtendenza con le raccomandazioni degli anni ‘90 di ritardare l’introduzione degli alimenti  la comparsa di un efficace tolleranza orale agli alimenti sembrerebbe dipendere dall’ESPOSIZIONE REGOLARE e PRECOCE agli alimenti (e non dall’evitamento) durante un intervallo di tempo compreso tra il 4° al 6° mese di vita (17-26 settimane), che viene indicato come FINESTRA DI OPPORTUNITA’ PER LA TOLLERANZA (in cui gli alimenti possono cioè essere introdotti con un rischio minore di sviluppare allergie) ////// Al contrario, si è osservato che l’introduzione ritardata OLTRE questo periodo aumenta il rischio non solo di malattie allergiche ma anche di malattia celiaca e di autoimmunità Possible 'window of tolerance' for introduction of complementary foods.

THE IMPORTANCE OF EARLY COMPLEMENTARY FEEDING IN THE DEVELOPMENT OF ORAL TOLERANCE: CONCERNS AND CONTROVERSIES. Prescott Pediatr Allergy Immunol 2008;19:375 The normal development of oral tolerance is an antigen-driven process and may logically depend on regular exposure to foods and other antigens during a critical early window. La «tolleranza orale» è infatti un processo strettamente dipendente dalla presenza/dall’esposizione all’antigene (=antigen driven process)  ed è pertanto verosimile che delays in allergen exposure can lead to failure of oral tolerance Possible 'window of tolerance' for introduction of complementary foods.

THE IMPORTANCE OF EARLY COMPLEMENTARY FEEDING IN THE DEVELOPMENT OF ORAL TOLERANCE: CONCERNS AND CONTROVERSIES. Prescott Pediatr Allergy Immunol 2008;19:375 Oral tolerance is also likely to depend on other conducive exposures such as favourable gut colonization, breast milk and/or other nutritional immunomodulatory factors Tuttavia... There is also evidence that other factors such as favourable gut colonization and continued breastfeeding can promote tolerance and have protective effects during this period when complementary feeding is initiated. Possible 'window of tolerance' for introduction of complementary foods.

È ormai noto che il latte materno favorisce la maturazione della barriera GI e del sistema immunitario ad essa associato Continued breastfeeding when complementary feeding is initiated can promote tolerance and have protective effects

Allergia alimentare: i dilemmi quotidiani del pediatra Introduzione precoce degli alimenti alla luce dell’allergia alimentare: pro e contro Diego Peroni Le raccomandazioni classiche Tolleranza o Allergia? E gli studi della letteratura? Conclusioni Università di Pisa diego.peroni@unipi.it

Modifying the infant’s diet to prevent food allergy. Grimshaw K, et al. Arch Dis Child 2017;102:179

Randomized placebo-controlled trial of hen’s egg consumption for primary prevention in infants. Bellach J, JACI 2017;139:1591 Hen’s Egg Allergy Prevention (HEAP) study included 4-6-month-old infants who were not sensitized against hen’s egg, (IgE). Infants were received either verum (184, egg white powder) or placebo (199, rice powder) added to the first weaning food 3 times a week under a concurrent egg-free diet from age 4 to 6 until 12 months. The primary outcome was sensitization to hen’s egg

Randomized placebo-controlled trial of hen’s egg consumption for primary prevention in infants. Bellach J, JACI 2017;139:1591 HEAP study included 4-6-month-old infants who were not sensitized against hen’s egg, (IgE). Infants were received either verum (184, egg white powder) or placebo (199, rice powder) added to the first weaning food 3 times a week under a concurrent egg-free diet from age 4 to 6 until 12 months. The primary outcome was sensitization to hen’s egg

Infants with IgE-mediated egg allergy Randomized controlled trial of early regular egg intake to prevent egg allergy. D Palmer JACI 2017 Infants with IgE-mediated egg allergy The Starting Time of Egg Protein (STEP) trial. Infants aged 4 to 6 months were randomly allocated to receive daily pasteurized raw whole egg powder (n 407) or a color-matched rice powder (n 513) to age 10 months The primary outcome was IgE-mediated egg allergy defined by a positive pasteurized raw egg challenge and egg sensitization at age 12 months p<NS 10,3% 7,0% Early Introduction Placebo

Randomized controlled trial of early regular egg intake to prevent egg allergy. D Palmer JACI 2017 Infants with IgE-mediated egg allergy The Starting Time of Egg Protein (STEP) trial. Infants aged 4 to 6 months were randomly allocated to receive daily pasteurized raw whole egg powder (n 407) or a color-matched rice powder (n 513) to age 10 months The primary outcome was IgE-mediated egg allergy defined by a positive pasteurized raw egg challenge and egg sensitization at age 12 months ..but all infants followed an egg-free diet and cooked egg was introduced to both groups at age 10 months! p<NS 10,3% 7,0% Early Introduction Placebo

Randomized controlled trial of early regular egg intake to prevent egg allergy. D Palmer, JACI, 2017;139:1600 The Starting Time of Egg Protein (STEP) trial:4-6 mo. infants were randomly allocated to receive daily pasteurized raw whole egg powder (407) or a color-matched rice powder (413) to age 10 months. All infants followed an egg-free diet and cooked egg was introduced to both groups at age 10 months. The primary outcome was IgE-mediated egg allergy defined by a positive pasteurized raw egg challenge and egg sensitization at age 12 months

Randomized controlled trial of early regular egg intake to prevent egg allergy. D Palmer JACI 2017 The Starting Time of Egg Protein (STEP) trial. Infants aged 4 to 6 months were randomly allocated to receive daily pasteurized raw whole egg powder (n 407) or a color-matched rice powder (n 513) to age 10 months The primary outcome was IgE-mediated egg allergy defined by a positive pasteurized raw egg challenge and egg sensitization at age 12 months ..but infants who stopped taking the study powder because of a confirmed allergic reaction were 6,1% 1,5% Early Introduction Placebo

A randomized trial of egg introduction from 4 months of age in infants at risk for egg allergy. J. Tan , JACI, 2017;139:1621 Beating Egg Allergy Trial (BEAT) Study: infants with at least 1 first-degree relative with allergic disease. Infants with a skin prick test (SPT) response to egg white (EW) of less than 2 mm were randomized at age 4 months to receive whole egg powder or placebo (rice powder) until 8 months of age, with all other dietary egg excluded. Diets were liberalized at 8 months in both groups. The primary outcome was an EW SPT response of 3 mm or greater at age 12 months

Proportion of participants in the placebo and egg treatment groups A randomized trial of egg introduction from 4 months of age in infants at risk for egg allergy. J. Tan , JACI, 2017;139:1621 Beating Egg Allergy Trial (BEAT) Study: infants with at least 1 first-degree relative with allergic disease. Infants with a skin prick test (SPT) response to egg white (EW) of less than 2 mm were randomized at age 4 months to receive whole egg powder or placebo (rice powder) until 8 months of age, with all other dietary egg excluded. Diets were liberalized at 8 months in both groups. The primary outcome was an EW SPT response of 3 mm or greater at age 12 months Proportion of participants in the placebo and egg treatment groups who had EW-SPT responses of 3mm or greater at 12 months of age

A randomized trial of egg introduction from 4 months of age in infants at risk for egg allergy. J. Tan , JACI, 2017;139:1621 Beating Egg Allergy Trial (BEAT) Study: infants with at least 1 first-degree relative with allergic disease. Infants with a skin prick test (SPT) response to egg white (EW) of less than 2 mm were randomized at age 4 months to receive whole egg powder or placebo (rice powder) until 8 months of age, with all other dietary egg excluded. Diets were liberalized at 8 months in both groups. The primary outcome was an EW SPT response of 3 mm or greater at age 12 months data suggest that, for infants at risk of egg allergy and who are able to tolerate it, introduction of regular egg immediately after successful first weaning solids at a low dose might be beneficial and with no evidence of harm

A randomized trial of egg introduction from 4 months of age in infants at risk for egg allergy. J. Tan , JACI, 2017;139:1621 Beating Egg Allergy Trial (BEAT) Study: infants with at least 1 first-degree relative with allergic disease. Infants with a skin prick test (SPT) response to egg white (EW) of less than 2 mm were randomized at age 4 months to receive whole egg powder or placebo (rice powder) until 8 months of age, with all other dietary egg excluded. Diets were liberalized at 8 months in both groups. The primary outcome was an EW SPT response of 3 mm or greater at age 12 months Ebbene, nessuno dei tre ha fornito risultati clinicamente rilevanti a favore della introduzione precoce, davvero significativo direi! SMS data suggest that, for infants at risk of egg allergy and who are able to tolerate it, introduction of regular egg immediately after successful first weaning solids at a low dose might be beneficial and with no evidence of harm

Modifying the infant’s diet to prevent food allergy. Grimshaw K, et al. Arch Dis Child 2017;102:179

Modifying the infant’s diet to prevent food allergy. Grimshaw K, et al. Arch Dis Child 2017;102:179 The question Is there a causal relationship between early consumption and reduced risk of food allergy? 3 RCTs have reported fully: Solids Timing for Allergy Research (STAR), Learning Early About Peanut (LEAP) Enquiring About Tolerance (EAT).

At 12 mo. diagnosis of IgE food allergy The Solids Timing for Allergy Research STAR Study enrolled 86 high risk infants aged 4-6 months with moderate/severe eczema. Infants received egg powder 50– – 40– 30– 20– 51% p<0.11 33% Egg ingestion group Controls

At 12 mo. diagnosis of IgE food allergy But in the active group 31% had an allergic reaction leading to the study being stopped.. 50– – 40– 30– 20– 51% p<0.11 33% Egg ingestion group Controls

These theory, that early regular introduction of foods, such as peanut, can lead to tolerance and protect against the development of FA is currently being tested in this RCT  The LEAP study - involves 640 high-risk children (egg allergy and/or severe eczema) who were enrolled at age 4 to 10 months. - Each child was randomly assigned to one of the 2 approaches: avoidance or consumption. Children in the avoidance group completely avoid eating peanut-containing foods; the intervention group is fed at least 6 g peanut protein weekly, distributed over at least three meals each week. - The primary outcome of this study assesses the effects of this intervention on the proportion of children with peanut allergy at 5 yr of age. The proportion of each group with PA by 5 years of age will be used to determine which approach, avoidance or consumption, works best for preventing PA. The study will reach completion in 2013.

Peanut allergy at DBPCC at 5 yrs Randomized trial of peanut consumption in infants at risk for peanut allergy. Du Toit G, N Engl J Med 2015;372:803 Peanut allergy at DBPCC at 5 yrs The LEAP Study (Learning early about Peanut) 530 high risk infants moderate/severe eczema and/or egg allergy Aged 4-11 mo. Open label peanut (7gr/day) consumption or placebo At 5 yrs DBPCC p<0.001 15,7% 1,9% Open label Peanut Controls

Peanut allergy in 98 with SPT peanut positivity Randomized trial of peanut consumption in infants at risk for peanut allergy. Du Toit G, N Engl J Med 2015;372:803 Peanut allergy in 98 with SPT peanut positivity The LEAP Study (Learning early about Peanut) 530 high risk infants moderate/severe eczema and/or egg allergy Aged 4-11 mo. Open label peanut consumption or placebo At 5 yrs DBPCC p<0.004 35,3% 10,6% Open label Peanut Controls

35,3% 10,6% Findings led to a consensus Randomized trial of peanut consumption in infants at risk for peanut allergy. Du Toit G, N Engl J Med 2015;372:803 Peanut allergy in 98 with SPT peanut positivity The LEAP Study (Learning early about Peanut) 530 high risk infants moderate/severe eczema and/or egg allergy Aged 4-11 mo. Open label peanut consumption or placebo At 5 yrs DBPCC Findings led to a consensus communication, providing interim guidance on early peanut introduction and the prevention of peanut allergy in high risk p<0.004 35,3% 10,6% Open label Peanut Controls

Peanut allergy at 6 years Effect of avoidance on peanut allergy after early peanut consumption. Du Toit, N Eng J Med 2016;374:1435 Peanut allergy at 6 years The LEAP-ON Study (Learning early about Peanut) 530 high risk infants At 5 yrs DBPCC Peanut avoidance for 1 yr Clinical re-evaluation p<0.001 18,6% 4,8% Open label Peanut Controls

18,6% 4,8% Results suggest that early introduction of Effect of avoidance on peanut allergy after early peanut consumption. Du Toit, N Eng J Med 2016;374:1435 Peanut allergy at 6 years The LEAP-ON Study (Learning early about Peanut) 530 high risk infants At 5 yrs DBPCC Peanut avoidance for 1 yr Clinical re-evaluation Results suggest that early introduction of peanuts into the diet may induce long term tolerance..to peanuts p<0.001 18,6% 4,8% Open label Peanut Controls

Food allergy at 1 of the 6 foods between 1-3 yrs Enquiring about Tolerance (EAT) Study. 1303 exclusively breast-fed infants who were 3 months of age and randomly assigned them to the early introduction of six allergenic foods (peanut, cooked egg, cow’s milk, sesame, whitefish, and wheat; early-introduction group) or to the current practice recommended in the United Kingdom of exclusive breast-feeding to approximately 6 months of age (standard introduction group). Food allergy at 1 of the 6 foods between 1-3 yrs p<NS 7,1% 5,6% Standard introduction Early introduction

Food allergy at 1 of the 6 foods between 1-3 yrs Enquiring about Tolerance (EAT) Study. However, when the analysis was adjusted for adherence to early introduction .. Food allergy at 1 of the 6 foods between 1-3 yrs 6,4% p<0,03 2,4% Standard introduction Early introduction

6,4% 2,4% However, when the analysis was Food allergy at 1 of the 6 foods between 1-3 yrs However, when the analysis was adjusted for adherence to early introduction .. Suggesting introduction of sufficient amounts of allergenic foods into the infant diet at 3– 6 months alongside continued breastfeeding may be effective in the prevention of food allergy. 6,4% p<0,03 2,4% Standard introduction Early introduction

6,4% 2,4% However, when the analysis was Food allergy at 1 of the 6 foods between 1-3 yrs However, when the analysis was adjusted for adherence to early introduction .. However, poor adherence to the study protocol highlights the challenges around introducing solids into the diets of infants less than 6 months of age. 6,4% p<0,03 2,4% Standard introduction Early introduction

Food allergy at 1 of the 6 foods between 1-3 yrs Suggesting introduction of sufficient amounts of allergenic foods into the infant diet at 3– 6 months alongside continued breastfeeding may be effective in the prevention of food allergy. However, poor adherence to the study protocol highlights the challenges around introducing solids into the diets of infants less than 6 months of age. Food allergy at 1 of the 6 foods between 1-3 yrs However, when the analysis was adjusted for adherence to early introduction .. Less than half the participants in the early-introduction group (42.8%) adhered to the trial protocol. 6,4% p<0,03 2,4% Standard introduction Early introduction

Infants 4–5 months of age with eczema Two-step egg introduction for prevention of egg allergy in high-risk infants with eczema (PETIT): a randomised, double-blind, placebo-controlled trial. Natsume O., Lancet 2017; 389: 276 Infants 4–5 months of age with eczema Early introduction of egg or placebo In the egg group consumed orally 50 mg of heated egg powder per day from 6 months to 9 months of age and 250 mg per day thereafter until 12 months of age Aggressively treated participants’ eczema Primary outcome was the proportion of participants with hen’s egg allergy Markers of participants’ skin conditions

Primary analysis population. Per-protocol analysis. Two-step egg introduction for prevention of egg allergy in high-risk infants with eczema (PETIT): a randomised, double-blind, placebo-controlled trial. Natsume O., Lancet 2017; 389: 276 Prevalence of egg allergy Primary analysis population. Per-protocol analysis. Infants 4–5 months of age with eczema Early introduction of egg or placebo In the egg group consumed orally 50 mg of heated egg powder per day from 6 months to 9 months of age and 250 mg per day thereafter until 12 months of age Aggressively treated participants’ eczema Primary outcome was the proportion of participants with hen’s egg allergy

Two-step egg introduction for prevention of egg allergy in high-risk infants with eczema (PETIT): a randomised, double-blind, placebo-controlled trial. Natsume O., Lancet 2017; 389: 276 Infants 4–5 months of age with eczema Early introduction of egg or placebo In the egg group consumed orally 50 mg of heated egg powder per day from 6 months to 9 months of age and 250 mg per day thereafter until 12 months of age Aggressively treated participants’ eczema Primary outcome was the proportion of participants with hen’s egg allergy

concentration, or challenge tests before introduction. Two-step egg introduction for prevention of egg allergy in high-risk infants with eczema (PETIT): a randomised, double-blind, placebo-controlled trial. Natsume O., Lancet 2017; 389: 276 A small amount of solid food is safe, even for sensitised infants, and this stepwise approach is practical at a population level because infants do not need to be screened by skin prick, serum-specific IgE concentration, or challenge tests before introduction. Infants 4–5 months of age with eczema Early introduction of egg or placebo In the egg group consumed orally 50 mg of heated egg powder per day from 6 months to 9 months of age and 250 mg per day thereafter until 12 months of age Aggressively treated participants’ eczema Primary outcome was the proportion of participants with hen’s egg allergy

concentration, or challenge tests before introduction. Two-step egg introduction for prevention of egg allergy in high-risk infants with eczema (PETIT): a randomised, double-blind, placebo-controlled trial. Natsume O., Lancet 2017; 389: 276 Infants 4–5 months of age with eczema Early introduction of egg or placebo In the egg group consumed orally 50 mg of heated egg powder per day from 6 months to 9 months of age and 250 mg per day thereafter until 12 months of age Aggressively treated participants’ eczema Primary outcome was the proportion of participants with hen’s egg allergy A small amount of solid food is safe, even for sensitised infants, and this stepwise approach is practical at a population level because infants do not need to be screened by skin prick, serum-specific IgE concentration, or challenge tests before introduction. Additional trials are needed to test this approach for prevention of other types of food allergies. Optimal control of eczema might be an integral part of the preventive programme to minimise the chance of percutaneous sensitisations

Early introduction of food reduces food allergy – Pro. Palmer PAI 2017 Findings from randomised controlled trials investigating the timing of commencement of regular inclusion of peanut and/or egg in infant diets on food allergy outcomes: Enquiring About Tolerance (EAT), Learning Early About Peanut Allergy (LEAP), Beating Egg Allergy Trial (BEAT), Hen’s Egg Allergy Prevention(HEAP), Solids Timing for Allergy Reduction (STAR), and Starting Time of Egg Protein (STEP) trials.

In the EAT trial, the rate of adherence was the highest for dairy products in the form of yogurt, as opposed to textural food such as egg. This difference may well be due to the rather immature oral motor skills of young infants at 3 to 4 months of age and also to concerns of the parents about choking. If feeding these foods is safe, -What is the minimal amount needed for inducing tolerance to these foods? -Will the regimen be as effective if we introduce these foods at a later age but early enough before sensitization may occur? -How can we improve the preparation of foods to make them easier for parents to administer?

children and hope that they will EAT. Evidence is building that early consumption rather than delayed introduction of foods is likely to be more beneficial as a strategy for the primary prevention of food allergy. So feed your children and hope that they will EAT. In the EAT trial, the rate of adherence was the highest for dairy products in the form of yogurt, as opposed to textural food such as egg. This difference may well be due to the rather immature oral motor skills of young infants at 3 to 4 months of age and also to concerns of the parents about choking. If feeding these foods is safe, -What is the minimal amount needed for inducing tolerance to these foods? -Will the regimen be as effective if we introduce these foods at a later age but early enough before sensitization may occur? -How can we improve the preparation of foods to make them easier for parents to administer?

Allergia alimentare: i dilemmi quotidiani del pediatra Introduzione precoce degli alimenti alla luce dell’allergia alimentare: pro e contro Diego Peroni Le raccomandazioni classiche Tolleranza o Allergia? Le scelte possibili Conclusioni Università di Pisa diego.peroni@unipi.it

Timing of Allergenic Food Introduction to the Infant Diet and Risk of Allergic or Autoimmune Disease A Systematic Review and Meta-analysis. Ierodiakonou, JAMA. 2016;316(11):1181

In this systematic review, early introduction of egg or peanut Timing of Allergenic Food Introduction to the Infant Diet and Risk of Allergic or Autoimmune Disease A Systematic Review and Meta-analysis. Ierodiakonou, JAMA. 2016;316(11):1181 In this systematic review, early introduction of egg or peanut to the infant diet was associated with lower risk of developing egg or peanut allergy. These findings must be considered in the context of limitations in the primary studies.

Timing of Allergenic Food Introduction to the Infant Diet and Risk of Allergic or Autoimmune Disease A Systematic Review and Meta-analysis. Ierodiakonou, JAMA. 2016;316(11):1181 Early Allergenic Food Introduction and Risk of Food Allergy or Food Sensitization

Timing of Allergenic Food Introduction to the Infant Diet and Risk of Allergic or Autoimmune Disease A Systematic Review and Meta-analysis. Ierodiakonou, JAMA. 2016;316(11):1181 There was moderate-certainty evidence from 5 trials (1915 participants) that early egg introduction at 4 to 6 months was associated with reduced egg allergy (risk ratio [RR], 0.56; 95%CI, 0.36-0.87; I2 = 36%; P = .009). Early Allergenic Food Introduction and Risk of Food Allergy or Food Sensitization

Timing of Allergenic Food Introduction to the Infant Diet and Risk of Allergic or Autoimmune Disease A Systematic Review and Meta-analysis. Ierodiakonou, JAMA. 2016;316(11):1181 Early Allergenic Food Introduction and Risk of Food Allergy or Food Sensitization There was moderate-certainty evidence from 5 trials (1915 participants) that early egg introduction at 4 to 6 months was associated with reduced egg allergy (risk ratio [RR], 0.56; 95%CI, 0.36-0.87; I2 = 36%; P = .009). There was moderate-certainty evidence from 2 trials (1550 participants) that early peanut introduction at 4 to 11 months was associated with reduced peanut allergy (RR, 0.29; 95%CI, 0.11-0.74; I2 = 66%; P = .009).

Timing of Allergenic Food Introduction to the Infant Diet and Risk of Allergic or Autoimmune Disease A Systematic Review and Meta-analysis. Ierodiakonou, JAMA. 2016;316(11):1181 High-certainty evidence that timing of gluten introduction was not associated with celiac disease risk

Agostoni C, J Pediatr Gastroenterol Nutr 2008;46:99–110. Complementary feeding: a commentary by the ESPGHAN Committee on Nutrition. Agostoni C, J Pediatr Gastroenterol Nutr 2008;46:99–110. The European Society for Pediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) committee recommends that: No convincing scientific evidence that avoidance/delayed introduction of potentially allergenic foods, reduces allergies, both in infants at increased risk for the development of allergy and in those not. Exclusive breast-feeding for at least 4 months and breastfeeding up to 6 months is a desirable goal. Complementary foods can be introduced after 17 weeks (~ 4 months) but no later than 26 weeks (~ 6months). Continued breast-feeding is recommended along with the introduction of complementary feeding. Nel 2008, alla luce delle evidenze scientifiche che vi ho presentato, diverse società scientifiche hanno deciso di RIVEDERE le raccomandazioni fatte alla fine degli anni ‘90 in tema di prevenzione primaria delle malattie allergiche . Uno dei punti più condivisi delle diverse società ed in netta in controtendenza con le raccomandazioni precedenti è che  ad oggi NON ci sono sufficienti evidenze scientifiche per cui  ritardare l’introduzione degli alimenti solidi dopo il 6° mese, anche di quelli allergenici, sia protettivo nei confronti delle malattie allergiche, tanto nei bambini considerati a rischio che in quelli non a rischio. Anzi ritardare l’introduzione degli alimenti potrebbe addirittura favorire l’insorgenza di allergie. Il divezzamento va iniziato tra il 4° ed il 6° mese di vita, e comunque non prima delle 17 settimane e non dopo le 26 settimane di vita. mantenendo se possibile l’allattamento al seno durante il divezzamento During the complementary feeding period, >90% of the iron requirements of a breast-fed infant must be met by complementary foods, which should provide sufficient bioavailable iron. It is prudent to avoid both early (<4 months) and late (≥7 months) introduction of gluten, and to introduce gluten gradually while the infant is still breast-fed, in as much as this may reduce the risk of celiac disease, type 1 diabetes mellitus, and wheat allergy.

Primary Prevention of Allergic Disease through Nutritional Interventions. Fleisher D, JACI:In Practice 2013;1:29-36 TARGET POPULATION: All children, including those with siblings who already have allergies MATERNAL AVOIDANCE: Dietary restriction during pregnancy and lactation not recommended BREAST FEEDING: Exclusive breast-feeding for at least 4 months and up to 6 months is endorsed, and should be encouraged for as long as the mother and infant wish to continue. This for the many nutritional and non-nutritional benefits of breast feeding for both mother and child Continuation of breast feeding at the time foods are first introduced may help prevent development of allergy to those foods. Questi raccomandazioni sono state condivise da diverse società scientifiche internazionali nel mondo e sono state racchiuse in questo recente lavoro dell’Accademia americana di allergologia ed immunologia Tali raccomandazioni nutrizionali sono valide per tutti i bambini, compresi quelli considerati maggiormente a rischio di sviluppare malattie allergiche. Innanzitutto, notare come Le Diete di eliminazione materne degli alimenti allergenici, sia durante la gravidanza che durante l’allattamento, non sono raccomandate per la prevenzione primaria delle allergie. L’allattamento al seno andrebbe consigliato in forma esclusiva per i primi 4 mesi e continuato durante il divezzamento e fin quando la madre o il bambino vogliono continuarlo, per i benefici nutrizionali, immunologici e psicologici dell’allattamento al seno sia per la madre che per il bambino

Primary Prevention of Allergic Disease through Nutritional Interventions. Fleisher D, JACI:In Practice 2013;1:29-36 STARTING COMPLEMENTARY FOODS: From 4-6 months onwards when a child is ready, parents should consider introducing a new food every 3-5 days (regardless of whether the food is thought to be highly allergenic). In this way, reactions can be more clearly identified and the food excluded (or continued) as a part of a varied diet. Infants are unlikely to develop a new allergy to any food that is already tolerated, if it is given regularly. Continuation of breast feeding at the time foods are first introduced may help prevent development of allergy to those foods Quando iniziare il divezzamento: tra i 4 ed i 6 mesi di vita, o comunque non prima delle 17 settimane e non dopo le 26 settimane, quando il bambino è pronto (ovvero quando il bambino è capace di stare seduto ed ha un buon controllo di testa e collo), introducendo un alimento nuovo per volta ogni 3-5 giorni per poter valutare al meglio l’accettazione ed eventuali reazioni allergiche. Mantenendo se possibile l’allattamento al seno (Il latte materno rimane un alimento fondamentale anche in questo periodo e gli alimenti solidi devono essere considerati una sua «integrazione» (=«complementary food») e non una sua sostituzione)

Primary Prevention of Allergic Disease through Nutritional Interventions. Fleisher D, JACI:In Practice 2013;1:29-36 ALLERGENIC FOODS: There are no particular allergenic foods that need to be avoided. Some children will develop allergies, but there is no way of accurately predicting who. Whole cow’s milk, as opposed to CM- formulas and CM dairy products, such as cheese and yogurt, that are safe before age 1 year, should be avoided until age 1 year for reasons unrelated to allergic disease, that is increased renal solute load and low iron content. There is insufficient evidence to support previous advice to specifically delay or avoid potentially allergenic foods (such as egg, peanuts, nuts, wheat, cow’s milk and fish) for the prevention of food allergy or eczema. This also applies to infants with siblings who already have allergies to these foods.