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2 Nutricia Paediatric Food Allergy Expert Meeting The speaker had sole editorial control over the content in this slide deck. Any views, opinions or recommendations expressed in the slides are solely those of the speaker and do not necessarily represent those of Nutricia.

3 Future directions in food allergy Paediatric Food Allergy Expert Meeting Royal College of Physicians, London UK December 5, 2016 Anna Nowak-Węgrzyn, MD PhD Associate Professor of Pediatrics Icahn School of Medicine at Mount Sinai New York, NY, USA

4 Learning objective To describe emerging diagnostic tests, treatments and prevention strategies for IgE-mediated food allergy Allergy (immune-mediated) IgE-Mediated Anaphylaxis Urticaria IgE? Atopic Dermatitis Eosinophilic gastroenteritis Non-IgE mediated Isolated gastrointestinal reactions: FPIES Skin rashes

5 DIAGNOSIS

6 Expert panel recommendations Food Allergy diagnostic tests recommended History/physical Skin prick test Allergen specific serum IgE Elimination diet Oral food challenge Not recommended Atopy patch tests Intradermal tests Unproven tests (IgG, kinesiology, VEGA, etc.) Boyce et al Guidelines J Allergy Clin Immunol 2010;126:S19 Sampson et al Practice Parameter JACI 2014;134:

7 Probability of a reaction (%) Food-specific IgE antibody concentrations (or skin test size) correlate with risk of clinical reactivity Curve varies by: Food Disease Age Assay (brand) 20 0 Food-specific IgE Antibody Concentration (or Skin Test Wheal Size) Negative test is not zero risk At certain high IgE values, the chance of a clinical reaction approaches certainty

8 Molecular allergy diagnosis: from allergen source to allergen component Allergen source

9 Molecular allergy diagnosis: from allergen source to allergen component Allergen source Allergen extract

10 Molecular allergy diagnosis: from allergen source to allergen component Allergen source Allergen extract Specific allergen components Cross-reactive allergen components

11 Nomenclature of allergen components Ara h 2 Arahis hypogea, allergen 2 Prefix r for recombinant or n for natural rara h 2 1 nara h 2 established by: WHO/IUIS Allergen Nomenclature Subcommittee

12 Molecular allergology: relationships between pollen and food allergens PR-10 protein family Birch Peanut Birch Peanut Bet v 1 Ara h 8 Gly m 4 Soybean Soybean

13 Plant food allergens Pollen crossreactive components* LTP Pollen non-cross-reactive components** Peanut Ara h 8 Ara h 9 Ara h 1; Ara h 2; Ara h 3 Ara h 5 Arah 4; Ara h 6; Ara h 7 Hazelnut Cor a 1 Cor a 8 Cor a 9, Cor a 14 Cor a 2 Cashew?? Ana o 1, Ana o 2, Ana o 3 Walnut Jug r 5 Jug r 3 Jug r 1, Jug r 2, Jug r 4 Soybean Gly m 4 Gly m 1 Gly m 5 Gly m 3 Gly m 6 Wheat Tri a 12 Tri a 14 baker s asthma PRP-10 Profilin Tri a 19 (ω-5 gliadin) Tri a 21 - alfa gliadin Tri a 26 - HMW glutenin Tri a 28 - AAI dimer 0.19 *Birch tree pollen, Timothy grass pollen for wheat ** Storage seed proteins, albumins and globulins

14 Allergen components biomarkers for predicting clinical reactivity Labile proteins - low amounts - Stable proteins - high amounts - Profilin PR-10 Lipid transfer proteins Storage proteins

15 Future diagnostic tests Basophil Activation Ratios (IgE, IgG) Epitopes More components to other foods Calculators DNA methylation patterns

16 Basophil activation test Blood cell that becomes activated and releases histamine when mixed with the allergen Can measure degree of reactivity to different doses of the allergen Study found that the ratio of cells activated by peanut versus total activation was predictive of severity; and dose of peanut triggering response was related to threshold. Limitations: Not standardized, 10-15% nonreactive, very labor intensive, fresh blood sample Santos AF et al J Allergy Clin Immunol 2015; 135: Song Y et al Ann Allergy Asthma Immunol 2015 Apr;114(4):319-26

17 Epitopes and informatics Lin J et al J Allergy Clin Immunol 2012; 129:1321-9

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19 Cork-Southampton Calculator 6 independent indicators sex, age, history of reaction, sige, total IgE minus sige, SPT DunnGalvin A. et al J Allergy Clin Immunol 2011

20 Conclusions: Diagnosis More accurate diagnostic test are desirable Prediction of severity of the reaction Prediction of natural history

21 Novel immunotherapies for food allergy

22 Food allergy therapy: clinical trials Allergen-specific Allergen non-specific Native food proteins Efficacy and Safety Data Available Milk, egg, peanut, and wheat OIT Modified food proteins Milk, peanut, and hazelnut SLIT Safety Data Available Milk and peanut EPIT Safety Data Available Milk OIT with anti-ige Peanut OIT with anti-ige Multiple food OIT Efficacy and Safety Data Available Extensively heated milk and egg diet E. coli expressing recombinant modified Ara h 1, 2, 3 rectal vaccine Safety Data Available Chinese herbs (FAHF-2) Pilot Data Available Trichuris suis ova therapy Efficacy and Safety Data Available Anti-IgE (in peanut allergy) Anti-IL-5 Probiotics Nowak-Wegrzyn & Albin CEA 2014

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24 We are only 10% human! American Museum of Natural History, 2016

25 Functions of intestinal microbiota Functions Digestive and metabolic Neuronal development Protection against pathogenic bacteria Immune development Mechanism Vitamin production Fermentation of non-digestible CHO SCFA Dietary carcinogens metabolism Modulation of brain gut axis during neuronal development Motor control and anxiety behavior Pathogen displacement Nutrient competition Production of antimicrobial factors Activation of local immune response Contribute to the intestinal barrier function IgA production Control of local and general inflammation Tightening of junctions Induction of tolerance to foods Buccigrossi et al., Curr Opin Gastroenterol 2013, 29:31 38

26 Dysbiosis in early life microbiota and FA Ling et al., Appl Environ Microbiol 2014;80:

27 PRObiotics Oral probiotics are living microorganisms that upon ingestion in specific numbers, exert health benefits beyond those of inherent basic nutrition (sometimes also referred to as good bacteria ). Mostly Bifidobacteria and Lactobacilli Effects are immune stimulation, anti-pathogenic, gut barrier, removal of toxic substances, providing metabolites to gut cells (Gorbach 2002; Marteu & Shanahan 2003; Mercenier 2003) Added value of probiotics particularly in allergic subjects (Majamaa & Isolauri 1997; Kirjavainen & Gibson, 1999; Isolauri 2001; Viljanen 2005, Weston 2005; Sitek 2006; Canani 2012)

28 PREbiotics A prebiotic is a non-digestible food ingredient that beneficially affects the host by selectively stimulating the growth and/or activity of one of a limited number of bacteria in the colon, and thus improves host health. (Gibson and Roberfroid,1995; Gibson et al., 2004) Stimulate growth of beneficial bacteria (Bifidobacteria, Lactobacilli), but not the harmful ones (Gibson, 1999) Prebiotic ingredients stimulate gut microbiota to be more like that of breast fed infants (Boehm 2002, 2003; Schmelze 2003; Moro 2003; Haarman & Knol 2005) Produced bacterial metabolites positively influence immune system (Boehm 2004; Vos 2007) Reduce the incidence of allergy in the infants at risk (Arslanoglu 2008; Van Hoffen 2009)

29 Prebiotic Commensal bacteria Fiber Probiotic Bacteriocins Defensins Acetate SCFA Propionate Butyrate GPR109A Pathogen Mesenteric lymph node T regs Th17 IL-10 Tolerogenic DC TGF-b IL-10 Allergy Tolerance Inflammation Autoimmunity

30 Human milk = the ultimate SYNbiotic! = prebiotic + probiotic Hunt KM, et PLOS ONE 6(6): e Fernández L, et al. Pharmacological Research, Volume 69, Issue 1, 2013, 1 10 Petherick Nature 2010;65:S5-S7

31 Can nutritional formulas be modified - using a SYNbiotic approach - to alter the intestinal microbiota and improve clinical outcomes in children?

32 Evidence for benefits of synbiotics in allergic disease Synbiotics prevent atopic eczema and increase resistance to infections in infants at risk of allergy (Kukkonen 2007; 2008) Synbiotics, including B. breve, support clinical improvement in infants with IgE-associated atopic dermatitis (AD) (Van der Aa 2010) and reduction of asthma-like symptoms in infants with AD (Van der Aa 2011) Synbiotics, including B. breve, reduced allergen-specific immune response and improve respiratory parameters in allergic asthmatic adults (Van de Pol 2011)

33 AAF + specific synbiotics promotes Bifidobacteria growth and reduces Eubacterium/Clostridia, similar to breast fed infants Bifidobacterium species in fecal microbiota E.rectale IC coccoides cluster in fecal microbiota Michaelis et al., Allergy. 2016; 71 (S102): 58

34 Conclusion Nutritional strategies employing PRObiotics AND PREbiotic fiber - hence SYNbiotics are important for addressing dysbiosis of the developing intestinal microbiota and stimulating critical development of the immune system in early life. An ongoing international multicenter clinical trial of AAF with synbiotic for treatment of IgE-CMA [PRESTO]

35 PREVENTION OF FOOD ALLERGY An ounce of prevention is worth a pound of cure. Benjamin Franklin

36 Past prevention rationale Strict avoidance of food allergens until infant s immune system matures will prevent development of food allergy - contamination & environmental exposure make strict food allergen avoidance virtually impossible - high levels of environmental exposure to peanut during infancy promote sensitization (Fox AT et al. JACI 2009;123:417-23) - early oral exposure may actually promote tolerance - peanut allergy in Israel 1/10 th prevalence compared to UK (du Toit JACI 2008; 122:984) - milk allergy in Israel - followed ~13,000 infants; 381 (2.9%) developed CMA (Katz Y et al. JACI 2010; 126:77-82)

37 Infants introducing cooked egg 4-6 months were 5 times less likely to develop egg allergy than if introduced after 10 months Unadjusted Adjusted * N % allergic OR OR P (95% CI) (95% CI) P Cooked egg given first 4-6 months months months ( ) 6.0 ( ) 4.4 ( ) 5.4 ( ) Baked egg given first 4-6 months 7-9 months months ( ) 1.3 ( ) ( ) 1.0 ( ) 0.99 Koplin J et al JACI 2010

38 Dual antigen exposure: Lack hypothesis 39

39 Dietary intervention trials Learning Early About Peanut Allergy: early introduction of peanut prevention of PN allergy DuToit G et al. NEJM 2015 LEAP-ON: tolerance to PN maintained DuToit G et al. NEJM 2016 Enquiring About Tolerance: early introduction of 6 foods: milk, egg, peanut, fish, sesame & wheat Perkin MR et al. NEJM 2016 Prevention of Egg Allergy in Infants with AD (PETIT) - egg Natsume O et al. JACI 2016 (Abstr) Solids Timing for Allergy Research: egg Palmer DJ et al. JACI 2016 Hen s Egg Allergy Prevention: egg Bellach J et al. JACI 2016 Beating Egg Allergy Trial: egg Wei-Liang Tan et al. JACI 2016 (Abstr) Starting Time for Egg Protein: egg Univ. Western Australia Grimshaw K et al. Arch Dis Child 2016 (epub)

40 Median g of PN protein / wk % PA Prevalence Background to LEAP trial % p < Prevalence of Peanut Allergy in Children 4 18 yrs % United Kingdom Israel p < g/month Peanut Protein Consumption 8-14 months g/week United Kingdom 5171 Israel United Kingdom Israel Du Toit G et al. JACI 2008;122:

41 LEAP trial Purpose: Determine whether early introduction of peanut will prevent development of allergy in high risk infants High risk defined as young infants with - Egg allergy: Children with either - SPT 6 mm to egg white & no known exposure to egg - SPT 3 mm to egg white & history of allergic symptoms related to exposure to hen s egg. - Severe eczema: - based on frequent use of topical steroids or calcineurin inhibitors or - grade 40 using the modified SCORAD evaluation Du Toit G et al. NEJM 2015; 372:

42 Du Toit G et al. NEJM 2015; 372: LEAP trial design 2 g PN protein 3x s/wk to age 5 yrs Intervention grp: SPT-Positive Stratum (n=47) n=319 Intervention grp: PN SPT-Negative Stratum (n=272) Recruitment: n = 640 infants with severe eczema and/or egg allergy 76 excluded - PN SPT > 4 mm Control Grp: SPT-Positive Stratum (n=51) n=321 Age at Control Grp: PN SPT-Negative Stratum (n=270) clinic visits: 4-11 months 12 months 30 months 60 months

43 LEAP outcome: intention-totreat analysis 86% Relative Reduction 70% Relative Reduction 81% Relative Reduction Du Toit G et al. NEJM 2015; 372:

44 LEAP-On study design Enrolled 556 of 628 subjects completing LEAP trial Adherence during 1 yr elimination: Avoidance Grp 90.4%; Consumption Grp 69.3% 3 new cases of peanut allergy in each group, but no significant difference in peanut allergy after 1 yr elimination Du Toit G et al. NEJM 2016

45 Questions raised by LEAP Is it necessary to give 2 g PN protein 3x s/wk? (6g/wk) - Israeli infants ingest about 2 g peanut protein/week Is it necessary to continue dosing until age 5 years? - Would ad lib dosing after 1 or 2 years be sufficient as long as peanut was ingested at least weekly? What is the risk of poor compliance or early termination? Will this early introduction apply to other foods?

46 Perkin MR et al. NEJM 2016 Clinical reactivity EAT trial 1,162 infants enrolled in the trial (median age = 3.4 months) Randomized to early introduction of milk, egg, peanut, fish, wheat & sesame (567) or standard feeding (595) Overall, by ITT analysis, there was no significant difference in food allergy or SPTs between groups Adherence Early feeding: 42.8%; Standard: 92.9%

47 Hen s Egg Allergy Prevention Screened 406 unselected infants 4 6 mos of age - Blinded RCT: egg or placebo to 12 mo of age - Outcome: egg sensitization or allergic reactivity at 1 yr - 11 anaphylactic reactions during screening OFC n = 406 screened 17 underwent OFC n = 383 nonsensitized Conclusion: early introduction not protective Bellach et al. JACI 2016 e-pub

48 Enhancement of skin barrier to prevent atopic dermatitis Protection of the skin barrier from dryness & irritation plus aggressive treatment of inflammation may prevent sensitization Decrease use of bathing, soaps & anti-microbials Apply emollients Limit allergen contact exposure Aggressive use of corticosteroids/calcineurin inhibitors

49 Conclusions: Prevention Prevalence of eczema & food allergy have been increasing over past 2 decades Early introduction of peanut in high risk infants may prevent peanut allergy Prevention of other food allergies may be decreased by earlier introduction Children with eczema are at highest risk for developing food allergy & therefore prevention and aggressive treatment of eczema may decrease food allergy

50 THANK YOU