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1 11 th -July-2014 식품면역연구회 Focused on food allergy R&D Center Maeil Dairies Co., Ltd Jeong-Min Lee, MD

2 Agenda, Day 1 Allergy on the rise Food immunotherapy - CM, egg Natural history of allergy can be changed Predictor models for food challenge outcome Therapy for food allergy beyond diet Finnish Allergy programme emphasis on prevention of FA

3 Allergy on the rise 1. The global incidence and burden by Beasley Richard : relatively high prevalence of asthma among western countries >10.1% US, Aus, NZ vs low prevalence 2.5% of china, Korea, Japan : HK triple than China due to environmental causes? : Prevalence of asthma 10 years ago, Lancet 9.7% UK, 4.4% Albania. 2% China 7% HK (1994) : Increasing prevalence of asthma worldwide> 1) Finnish- 1990) Finnish young men. increased markedly since ) Tokelanan- northern of NZ, Most immigrated from NZ, dramatically changed incidence of asthma 3) Zibabwean children- rural vs urban, 1991 exercise induced asthma/ high society economy influenced on high prevalence of asthma Summary 1) increasing since 1960s 2) many different countries 3) many different lifestyles 4) influence atopic type

4 Allergy on the rise 2. Blaming the environment by Hanski Ilkka 1) species extinction increasing 2) decreased diversity, mega-trend EMBO reports 3) biodiversity hypothesis influence of decreased microbiota in human immune system is important factor of increasing allergic decreases in worldwide : increasing prevalence of allergic diseases in Finland and global trend : sampling early human microbiota study, skin microbiota RNA 기술이용해서분석 & IgE 감작분석 : usual cut off point 0.35 ku/l 를이용하면 many individuals healthy 들도포함이되어서 isn t it too low? 0.4 ku/l? : study subject 는 land use 3kM 이내반경으로제한 : land use 와 allergic sensitization 함께증가하는경향 -> 이런경향은 12 세정도의어린이에서더크게관찰됨 -> 0.2% (forest) vs. 0.6% (land-use) : farm milk consumption 과 dog ownership 이 allergic sensitization 을낮춘다. (LUKAS cohort) : yard 있는집에서 atopic sensitization 낮다

6 Food immunotherapy- cow s milk 1) Age? 다양한기존연구들 : 한국 7~12 months, 스페인 24~36 개월, 핀란드 6~14 세 2) Eligibility criteria 3) Length of dose escalation phase, maintenance, dose, frequency 4) Tolerance 5) Baked vs non baked 6) Route, OIT is better (JACI 2012) than EPIT 3mo~15 세, 프랑스 19 명 7) First efficacy evaluation, follow up period ~> 다양 8) Combination therapy, herbal, antitslp, omalizumab? 9) Biomarker?: 누구를더오래할것인지, 누구를그만둘것인지에사용할수있을것 10) Mechanism 을알아야 target 을정할수있을것

10 Food immunotherapy- egg 1) Transient vs life-long? 2) Goal a - Desensitization 일단식품알레르기환자에서는 accidental food ingestion 에서안전하게 3) Goal b - Tolerance: life lasting therapeutic, OIT 중단 4-6 주후에도효과지속되어야 4) 얼마나효과가지속되느냐? tolerance 효과지속기간? 아무도모른다. 확실한건치료기간을길게잡았더니 tolerance 획득률이높다는점 5) 따라서재정의, 4-6 주 OIT 끊고 10g OFC 를통과하면 - sustained unresponsiveness 라고함. (OIT-SU), 만약 OIT-T 가획득이안되면다시시작하자. 하기가쉽다. 그리고오래 ( 적어도 1 년이상 ) 끌자. OIT-T 를타겟으로..., tailoring of treatment is needed current paradigm 6) avoidance? 노출시에사망할수도있는점은어떻게할것인가 - Peripheral T cell response, crucial for such benefits 7) development of new treatment, 우연한노출에의한사고를막고, long term immune modulation 을꾀하자

11 Food immunotherapy- egg 8) Heated egg OIT, Nowak-Wegrzyn et al. JACI 2011; muffin and waffle each containing one third of an egg (2.2g of egg protein) were administered 9) Children who incorporated baked egg into the diet were 14.6 times more likely than children in the comparison group to develop regular egg (scrambled egg or French toast) tolerance and they developed tolerance earlier (50 개월 vs 78.7 개월 ) cf. 우유 16 times more likely

12 Early dietary intervention EAACI food allergy prevention guideline~> part of food allergy anaphylaxis guidelines: high risk? having one or two parents and/or older siblings with a history of allergic disease (food allergy, atopic eczema/dermatitis, asthma or allergic rhinitis) 1) Effect of breastfeeding, randomized 할수없는이야기, controversial 2) No evidence of specific dietary modulation in pregnant women 3) There's an evidence that HF may reduce the risk of FA in the high risk infants 4) Probiotics, prebiotics, synbiotics~> under investigation 5) 이유식늦추지말것, 반대의견이있기때문에 4 개월이전엔고형식주지말것... 특히 4 개월이전에주면숟가락안좋아함 6) Denmark 에서는 0-4 개월사이에 prevention programme 을 1985 년에가동시켜서효과를보고있단데이터 : FA 7.4(1988)~>3.4%(1999), CMA 2.2~>0.9%

13 Box 4. Recommendation for primary prevention of food allergy Recommendation Exclusive breast feeding is recommended for all infants for the first 4-6 months Dietary restrictions are not recommended for all pregnant or lactating mothers If breast feeding is insufficient or not possible: - High risk infants should receive a hypoallergenic formula with documented preventive effect for the first 5 months. Other infants may receive a standard formula - After the age of 4 months a standard cow s milk based formula is recommended according to standard nutrition recommendation, irrespective of atopic heredity Introduction of complementary foods after the age of 4 months according to normal standard weaning practices and nutrition recommendations, for all children irrespective of atopic heredity No special dietary restrictions after the age of 4 months for infants with high risk for development of allergic disease No with holding or encouraging exposure to highly allergenic foods such as cow s milk, hens egg and peanuts irrespective of atopic heredity, once weaning has recommended Evidence level I-II I-II I II-III II-III Grade C B A-B C C

14 Predictor models for food challenge outcome 1) Scoring system, Cianferoni ) A score of 1 point was assigned for the following criteria for the food challenge score i) age >5 years old ii) prior reaction GI, Resp, multi-organ, or anaphylaxis iii) SPT >9mm iv) sige >5kU/L A score of 4 carries >95% probability to develop anaphylaxis from low dose allergen A score of 3-4 had PPV for anaphylaxis of 62% for milk OFC, 92% for egg A score of 0-1 had a negative predictive value for multisystem reaction of 95% for milk OFC, 91% for egg

15 Predictor models for food challenge outcome 3) Cork-Southampton calculator; accuracy 91% 4) Component test is evolving, Gal d 1 to predict OFC, Ara h 2 level >0.35 accuracy 97.5% 5) No predictor of severity of OFC positive 6) Role of sige/tige Gupta 2014, more persistent FA (PN, TN..) has higher ratio, cf. milk, egg, soya 7) SPT 한계가.. standardization 하기어렵고, 연령, 지역별기준힘들다. 8) 제대로하려면표준화된 and repeatable 한 food protein 이요구된다 # challenge outcome can be predicted, using existing data, test, history remains the key

16 Therapy for food allergy beyond diet 1) TLR-9 agonist 2) Therapy, what do you aim for? desensitization, partial tolerance or total tolerance? 3) SLIT, prefer to pediatrics, in area of pollen, SLIT to hazelnut, JACI 2005;116:1073, 10 명갖고한 pilot study 지만비교적명확한효과를보여줌 4) OIT 가 2000 년대초반에있다가 avoidance dogma 에밀려서막힌느낌있다 5) SOTI, 효과입증 on desensitization, 그런데 long term follow up 에대해서는아직... 게다가증상이심해지기도? JACI 2013 letter 6) Auto injector 주면서 risk 를감당할것인가, 면역치료시들어가는비용은어떻게할것? 7) EPIT, might be interesting in the future 8) 검사항목이많다면 history 를정확히함으로써환자를치료해달라, cross reacting 에대해서도무작정금식할게아니라정확히감별해주는노력을해달라. 그게환자를위한 cure 이다

17 Finnish Allergy programme emphasis on prevention of FA 1) 전문가 -NGO- 학교 - 정부연합체계, 2011 년이후로 population campaign 을진행하고있음 2) Population 대상으로 allergen tolerance 증가시키는노력을해서 avoidance 50% 까지감소시켰고 3) 심각한반응을집중적으로컨트롤함으로써증상재현을 40% 감소시켰고 4) Avoidance 개입정책은 severe symptom pt 에국한해서, mild 는따로컨트롤, 아이들의성장에더포커싱하는방향임! 5) Clinic, school 의 action plan 정비, FA OIT 를권고하고있음 (6-7 세부터, 3 차대학종합병원, 많은 project 진행중 ) 6) NGO 힘을빌려서 patient education 힘쓰고있고, 학회는 provocation test guideline 제정중임 7) 현재 AD incidence rising 잡은성과 8) 다양한식품 in infancy 를유도하고있다 ; 임신중, high risk 포함. incidence 감소의효과를보고있음 (JACI 2014)

18 Agenda, Day 2 Pro and con early regular egg exposure in infants induces tolerance The Patient Organization Committee Workshop on raising the quality of life of the allergic patient

19 early regular egg exposure in infants induces tolerance Pro by Susan Prescott, Australia 1) Clear evidence in normal, high risk, allergic infants 2) Without exposure tolerance cannot develop 3) Early; solids from 4-6 months, including allergenic foods (ASCIA) early is better than late 4) Regular, not infrequent or not irregular! regularly give and continuously give! regular is better than irregular 5) Early regular exposure through the oral route is required for oral intolerance ' 제한식이가위험을자초할수있다 ' 6) Cutaneous exposure is less tolerogenic! oral exposure 없이피부로만노출되는 AD pt. 야말로 high risk 7) Treg, IgG4 를증가시키는면역학적반응과, clinical food challenge 를통과하는 tolerance 를모두획득할수있는방법 'immunotherapy 개념 ' 8) Primary immune tolerance: STEP(starting egg protein) study, in high risk infants/ STAR (starting effect in eczema) study 결과도뒷받침하는개념 9) 5 개월부터규칙적으로 egg 노출된아이들이 OVA-IgG4 농도가그렇지않은 (8 개월 ) 경우보다놓다, JACI ) mild reaction 을처음에보이는경우에강행하여 tolerance 를유도한경험이많다!

20 early regular egg exposure in infants induces tolerance Con by Susanne Halken, Denmark 1) Development of food allergy depend on a complex interaction, it's complex! 2) Route of exposure is various 3) 모유에약 3ng/ml 씩 EW 가있고, 매트리스먼지에도들어가있는데이노출이면 tolerance 유도로가능하다. 조작없이 natural tolerance 로가자. 4) Pediatrics 2013;132:6: /Koplin JJ et al, JACI 개월에계란을먹은아이들이계란알레르기위험도놓았다는반대근거들 5) Palmer DJ, JACI 2013, eczema 환자 4-8 개월사이에 egg powder 를규칙적으로먹였는데먹이던첫주에약 31% 가 adverse reaction 을경험하고 egg intake 못했다는보고

21 Food allergy thresholds: a clinician's perspective Sponsored by Dutch food safety authority by Andre Knulst, Netherlands 1) Threshold, strongly needed/ without this, unable to advice patient adequately, eliciting dose, severe reaction dose 찾아내야함 2) UK, Netherland 많은환자들이 fatal reaction 을겪고있는데.. 네덜란드시작을보면, 32% 의상품이 PN 이나 casein 이들었단걸이야기하지않고시장에나와있다 3) 유럽 2007 년상황보면 25-50% 가라벨에포함된걸정확히알리지않고있고, 이로인한예상치못한반응들이보고되고있음 4) 심한증상도피부, 입에만문제가있는것이아니라 25% 정도에서복부, 호흡기, 순환계증상유발 5) May contain labeling 붙은것보다, 표기안된것이농도가더높은경우도발생 6) 100% avoidance 는현실적으로불가능, 얼마까지는허용할지를 set 하는것이더중요한이유! 7) Threshold 계산할때고려할것이많다. 대표적으로증상이주관적인가, 객관적인가 8) 라벨을아이콘화하는작업이필요할것이다

22 Food allergy thresholds: a clinician's perspective 9) Co-factor 영향을받는것도문제, 예 ) 천식, 감기, 운동, 약물, 술, 항히스타민제등의복용, 연령? 10) Threshold distribution curve 는세월지나도크게바뀌지않는다. 11) Children 이 adult 보다낮은 threshold 12) Low fat recipe 에서 threshold 높다. 13) Company has to calculate action level (max concentration allergen in product, ppm concentration of allergen) 14) The action level = reference dose (mg protein)/ reference amount (kg)

23 + Nature of the challenge material did not have any influence on ED05 and ED10 of PN Reference dose / Egg 0.03mg / Cow s milk 0.1mg / Wheat 1.0mg / Soy 1.0mg

24 J Allergy Clin Immunol 2014;133: Similar situation exists for hypoallergenic infant formula, in which oral challenge trials of a much smaller number (typically 28-30) of infants with milk allergy establish that the particular formula is safe for 90% of such infants at a 95% confidence level

25 Food allergy thresholds and labelling: a consumer (patient) perspective 1) 소비자의관점에서식품라벨에대해캐나다에서설문조사를시행함 2) FARE consumer survey 명이응답함 3) 20 국가응답 4) 많은응답자가 threshold dose 에대한이해가없는상황, 가이드는하지않고설문진행함 5) 반수이상의응답자가심한반응을경험하였다고이야기함 6) Allergen threshold 에대해서반수이상이조금혹은거의지식이없다고응답 7) 만약당신이금식하고있는식품이안전한농도로들어있다고이야기해주면구매의사가있는가 No 57%, Yes 19% ~> 공포감 8) Clinician 들이 strongly counseling of avoidance 한영향이크다고봄 9) 전체적으로 threshold 이하농도면사겠다고하는국가적빈도는약 20% 10) Scientific threshold 가존재한단걸믿을수있냔질문에도대다수가 no 11) 라벨을읽고어떻게행동하느냐? may contain 안산다 81%/ 같은설비를이용한다면안산다 75%/ 항원다루는설비에서만든다고하면안산다 55% 12) 일반소비자에게 threshold 를이해시키는것이어렵고, allergist 들이 avoid allergen 을 advice 하고있는상황에서혼란이있는상황, threshold 를이해시키려면 campaign 을크게넓혀가는노력이필요한상황 13) 라벨에대해서는 may contain 이너무많은것에대해절망감느낀다고응답함

26 Agenda, Day 3 The EAACI anaphylaxis program Year in Review 6 : Food allergy Food processing and food allergy Mills Immunotherapy in food allergy Beyer Non IgE mediated food allergy in infants Nowak- Wegrzyn

27 The EAACI anaphylaxis program 1. Introduction 1) cost 100 billion/yr in Europe 2) 30 min for food/ mean time to respiratory or cardiac arrest 2. Remaining barriers in anaphylaxis by Margitta Worm, Germany 1) NORA, network for online registration of anaphylaxis- collects data from countries throughout Europe in a standardized manner to gain a better understanding of the disease, triggers, cofactors and medications use 2) NORA participating centers are informed about latest anaphylaxis findings from registry 3) Adrenalin is underused! results from NORA 다수에서 antihistamines 나 corticosteroid 를약 50% adrenalin 대신 ( 약 20% 사용률 ) 4) Severe reaction 시 use of anaphylaxis 가증가하긴하지만, 의사들이 severe anaphylaxis event 를예상하기어려운점을이해하지못하고있는부분이있다. 5) Anaphylaxis severity can progress rapidly! So, adrenaline should be administrated rapidly ( 심각성과상관없이 )

28 The EAACI anaphylaxis program 6) Adrenaline use for anaphylaxis remains <20% till 2011, but in recent years, use of adrenaline first line for anaphylaxis going up to 30% 7) Use of adrenaline auto-injectors varies among different countries among EU, UK 가가장잘하고있고. 100% 로쳤을때, 다수의국가가 50% 도안되는사용률

29 The EAACI anaphylaxis program 8) 심지어 anaphylaxis reaction 으로퇴원하는환자에서도 AAI 처방률은 27%, 였고세계적으로봤을때아직다수의국가에서 AAI 사용이불가능한상태

30 The EAACI anaphylaxis program 3. The EAACI anaphylaxis guidelines and declaration by Antonella Muraro, Italy 1) What is new and different about the EAACI guideline? AAI i_must be given ii_should be given 을 clinical picture 로최초제안 2) Previous anaphylaxis reaction, EIA, Idiopathic anaphylaxis, moderate to severe asthma*, venom anaphylaxis <- must be given! 3) Mild to moderate allergic reaction to PN and/or TN, teenager or young adult with a food allergy, remote from medical help and prev mild-mod allergic reaction, mil-to -moderate allergic reactions to traces of food, 1 개 factor 있으면 AAI 처방고려하고, 2 개이상이면 should 처방하라 4) 80% 의 fatal anaphylaxis 를경험한환자의종전반응은 mild 했다고보고됨 5) IM epi injection 이 grade B 의 evidence 밖에안되는건 RCT 를못해서이지, 중요하지않단뜻이아니다! 6) Anaphylaxis 를예견하는건불가. 유일한예방법은 AAI 처방임 7) 의사, 환자 ( 교육으로 34~>84% 까지이해력높였단결과 ), 학교선생님의 knowledge 가모두아직은많이낮은상태, 지속적인 campaign 특히정확한사용법을알리는노력이요구된다

31 두개이상시 should prescribe~

33 Food processing and food allergy 1. Food processing and food allergy by Clare Mills, United Kingdom 1) Chemical modification and aggregation may alter allergenicity of foods 2) PN, powder 와 roasting allergen distribution 다르다 3) Heating(15 분, 섭씨 110 도 boiling) Ara h1 은 roasted Ara h1 보다 allergenic activity 가낮음 4) 같은 heating 이라도 sugar add 한 boiling 에서 Ara h1 density lower 5) Maillard modification on Ara h 1 seem more extensive than for other peanut allergens -- JACI letter accepted, Ara h 2 에 allergenic individual 한경우 boiling+sugar PN 에 tolerant 할수있단이야기

35 Non IgE mediated food allergy in infants 3. Non IgE mediated food allergy in infants by Anna Nowak-Wegrzyn, United States 1) Still, pathophysiology unknown 2) FPIES, Food Protein-Induced Enterocolitis Syndrome: 2-6 시간지난이후에 vomiting, dramatic! sleepy, diarrhea (Severe, IV fluid, pale, ER visit) 3) CM 67%, soy 41%, rice 19%, oat 18% most common, one grain 에반응있으면다른 grain 에도문제있을가능성 50% 넘음 4) Majority are allergic to single food 66% (Caubet JC, et al JACI 2014) 5) Vomiting 45%, vomiting+diarrhea 54.7%, severe dehydration 5%; vomiting is critical! 6) Age of resolution 3 세경 70%, 5 세경 85% 7) 35% 에서는 IgE mediated allergic symptom 으로진행할수있다... 이데이터들은 Mount Sinai 것. data bias 가있을수있음 8) Ondansetron for FPIES; 0.2mg/kg/dose _ IV bolus ~> rapid resolution 경험있음 (JACI 2013;132: ) oral hasn't helpful, epinephrine doesn t work, steroids acting shortly... 5 세이하에서 IM ondansetron 사용한것도 10 분내 acting, 효과있었다고함. (Sopo SM et al JACI 2014) 9) Allergic proctocolitis, median age 53d, 48% CMF, ebf 33%, reintroduction mean 295 일경, elimination diet 가중요하다. Re-challenge 오래지않아할것. 특히 infection relating 된경우는한달이면끝나는경우가있다. 10) Vague 한 GI symptom 있으면 Non-IgE mediated CM allergy 를고려하기 (Kalach N et al Clin Chem Lab Med 2013) 진단에가장도움이되는건 intestinal permeability 와 fecal EDN (eosinophil derived neurotoxin) 측정

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ÀÇÇÐ°�ÁÂc00Ì»óÀÏ˘ Common Allergic Diseases in Children Sang - Il Lee, M.D. Department of pediatrics Sungkyunkwan University School of Medicine, Samsung Medical Center E - mail : silee@smc.samsung.co.kr Abstract Allergy