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1 (Sicherer SH & Sampson HA, J Allergy Clin Immunol 2014; 133: ) * 본문중 [No.][Fig][Table] 은각각원문내참고문헌번호, 그림및테이블임. Food allergy Epidemiology, pathogenesis, diagnosis & treatment

2 정의 Food Allergy An adverse health effect arising from a specific immune response that occurs reproducibly on exposure to a given food Food Intolerance Non-immunologic adverse reaction to toxic contaminants or pharmacologic properties of the food; it may be due to characteristics of the host, including metabolic disorders (i.e., lactase deficiency) or idiosyncratic responses. Food Any substance that is intended for human consumption, and includes drinks, chewing gum, food additives, and dietary supplements Food Allergen Specific components of food or ingredients within food (typically proteins, but sometimes also chemical haptens) that are recognized by allergen-specific immune cells and elicit specific immunologic reactions, resulting in characteristic symptoms (J Allergy Clin Immunol 2010;126:S1-S58)

3 정의 면역매개성식품부작용의분류 (J Allergy Clin Immunol 2010;126:S1-S58)

4 Epidemiology and Natural history - Prevalence Reference Subject Methods Prevalence Gupta et al., 2011 Soller et al., 2012 Liu et al., 2010 (data from NHANES*) US ( ) (n=38,480) Canada (n=9,667) US ( ) NHANES* US ( ) (n=20,686) Osborne et al., 2011 Nicolaou et al., 2010 Katz et al., 2011 Australia, 1-year-old infants (n=2,848) Electronic household survey Self-reported Food allergen-specific serum IgE result Self-reported Population-based cohort, Include oral food challenges (OFCs) Children 8%, 2.4% have multiple food allergies 3% severe reactions Overall rate of 8% (adjusted) 6.7% in the overall population (children 7.1%, adults 6.6%) Children: cow s milk(2.2%), peanut(1.8%), tree nuts(1.7%) Adults: shellfish(1.9%), fruits(1.6%), vegetables(1.3%) cow s milk(1.8%), egg(1.8%), peanut(1.8%) in 1-5 year old children 8.96% reported food allergy, with 6.53% among children Peanut(3.0%), raw egg(8.9%), sesame(0.8%) UK OFCs included Peanut allergy: 2% at age 8 years Israel (n=13,019) Population-based study * NHANES: National Health & Nutrition Examination Survey Cow s milk protein-induced enterocolitis syndrome: cumulative incidence of 0.34% (44/13,019)

5 Epidemiology and Natural history - Prevalence 정확한유병률은추정하기어려움 - 식품알레르기 ( 성인의 5%, 어린이의 8%), 땅콩알레르기 (2%) 식품알레르기증가추세 - 어린이 (0-17세) 식품알레르기 : 3.4%( ) 5.1%( )[23] - 어린이땅콩알레르기 : % ( , US) ( 한계 : 자가보고, 참여율감소 )[24] - 땅콩알레르기진단 2배 (UK)[25], 3배 (US) 증가 [26] - 중국유아식품알레르기 10년새 (1999 vs. 2009, Chongqing) % 로증가 [27] (OFC 포함, 진단, 하지만단일연구기관결과 )

6 Epidemiology and Natural history - Risk factors Factors Examples 비타민 D 비타민 D < 15 ng/ml 인경우는비타민 D> 30ng/mL 인경우보다땅콩감작위험이높음 ( 어린이및청소년 3,136 명조사, )[31] 적도에서먼지역 (UV 조사적음 ) 일수록 IgE- 매개성달걀, 땅콩알레르기높음 ( 호주 )[32] 출생계절이위험인자임 [33] 어린이의식품유발성아나필락시스가 US 북부지역에서더많음 [34] 비타민 D 의충분한섭취가식품알레르기를예방 [35] 임신중산모의비타민 D 섭취는식품감작의위험을낮춤 [36] 산모의높은비타민 D 수준이아이들의식품알레르기진단과관련있음 (378 쌍조사, 독일 )[37] 노출시기 유아가식품알레르겐에빨리노출되는것이위험 지속적인알레르겐회피가위험 ( 경구관용기회를잃음 ) 유전, 내분비적영향 부 ( 富 ), 생활방식 남자아이가여자아이보다위험도가더높음 [14] 여성이남성보다위험도가높음 [42] 부유해질수록위험도가높음 [25] 인종 갑각류알레르기가백인보다는흑인 / 아프리칸아메리칸에서높음 [42] 히스패닉계가아닌흑인이식품알레르기를가질가능성이높음 ( 혈청학적결과 )[14] 환경, 환경 + 유전 도시에사는아토피를가진아이들에서갑각류감작율이매우높음 : 바퀴벌레에있는교차반응성이있는단백질에노출된것과관련있을것임 [43, 44] 미국에서태어난아이들이위험도가크고, 미국밖에서태어난아이들중에서 2 세이전에들어온아이들은위험도가큼, 그러나미국에서태어난아이들중이민자들의아이들은위험도가큼 [45] 미생물에노출 food allergy decreased with increasing birth order, possibly reflecting exposure to more infection from siblings 소변중내분비장애물질수준과식품감작율의관계 : 항균효과가있는 triclosan 만이식품감작위험증가 ( 남성중에서 )[47] Combinations 위험요소 : 부모, 형제자매의알레르기이력, 호주보다는동아시아에서태어난부모 vs. 방어요소 :older sibling, 집에개를키움 (453 Australian infants with confirmed egg allergy by OFC/5276) [50] 달걀알레르기와심각한천식은땅콩감작을예측하는강한지표 [51] Comorbidities 천식과식품알레르기는상호연관성이있음 [14,52,53]

7 Epidemiology and Natural history - Natural course 일반적으로, 어린시절식품알레르기중우유, 달걀, 밀, 콩에대한것은어린시절에완화하지만, 땅콩, 견과류, 갑각류에대한알레르기는지속됨. 예후는장애에따라서차이가있음 (i.e., 식품알레르기와연관된호산성식도염 (EoE) 는완화되는경우가상대적으로적음 [54]) 우유, 달걀, 밀, 콩에서와같이흔히 자라면서사라지는 (outgrown)" 알레르기에대해서는완화율이더딤. (i.e., 콩알레르기는 4세까지 25%, 6세까지 45%, 10세까지 69% 에서완화됨 [55]) 향후완화여부를조기에예측할수있는지표 ( 마커 ) 를찾기위한연구가활발히진행되고있음 - 10mL 이내우유 OFC(+), 피부반응시험 (SPT) wheal size 큼, 첫반응시기가생후 30일이내 [57], 우유 sige 수치, 아토피성피부염 (AD) 강도 [58] 이러한수치를이용하여완화가능성을추정하는계산기가고안됨. 식품에서 IgE가결합하는특정단백질, IgE에의해인식되는단백질내에피톱, 결합친화성을평가하는심화된시험들에대한연구진행중임.

8 Pathogenesis Pathogenesis 를이해하는데있어유전 - 환경상호작용을설명하는것은매우중요 - 모유수유가식품감작의증가와관련있음. 하지만, 이영향은 IL-12 receptor β 1, Toll-like receptor 9, 및 thymic stromal lymphopoietin genes 의 functional genetic variants 에의존적임 (prospective study of 970 children)[68]. - Cord blood vitamin D level 은유아기식품알레르겐에대한감작과연관성이없음 (Boston birth cohort, n=649). 하지만, candidate gene single nucleotide polymorphism 으로시험했을때, IL4 gene polymorphism 과다른 3 개 gene 이감작의위험요인일수있음 [69]. Microbiome 이중요한환경노출내부인자 ( internal environment exposure) 로뜨고있으며, prebiotics 및 probiotics 처방이치료의한방법임. - Probiotic supplementation decreased allergen-induced production of IL-5 & IL-10; higher levels of ovalbumin-induced CXCL 10 at birth and CCL 17 at 24 month [71] 알레르기결과에영향을주는주요면역요인들에대한연구가활발히진행되고있음. - Mononuclear cell allergen stimulation screening was performed with PCR analysis to 7 key markers of immune regulation and T H 1/T H 2 bias. Allergen-induced IL4 expression 만이우유에대한임상적알레르기, 우유와땅콩에대한감작과관련이있음 [72].

9 Pathogenesis 식품알레르기에서감작의경로를밝히는것 ( 특히, 비경구경로 ) 의중요성이최근부각됨. - Respiratory sensitization: pollen-food-related allergy, cat-pork-related allergy[74], wheat allergy induced by wheat protein-based soap[75] - Skin exposure to environmental food allergens: filaggrin(flg) loss-function mutations are associated with peanut allergy[76] - Intracutaneous routes: tick bites sensitization to carbohydrate galactose-α-1,3- galactose(α-gal) in the gut of the tick Ixodes ricinus delayed allergic responses and anaphylaxis hours after ingestion of mammalian meat 식품을준비 / 가공하는방법, 식품의비단백질구성물또한 pathogenesis 에영향줌. - 가열은단백질의 3 차구조를변형시켜식품알레르겐을파괴하기도하고, maillard 반응등을통해더많은알레르겐을생성할수있음 [83] - Dietary isoflavone 이땅콩에대한알레르기성감작을억제함 [85].

10 The effects of food processing on the allergenicity of food Food processing Moist heat (i.e., boiling, extrusion, autoclaving, retorting, frying) Dry heat (i.e., roasting, baking, air drying, microwave) High Pressure Pulsed Ultraviolet light (PUV) Ohmic heating Power Ultrasound Pulsed Electric Field (PEF) Change of allergenicity Peanut Ara h1, Ara h2, Ara h3 ; Almonds (-) Shrimp whole shrimp ; tropomyosin ; Fish parvalbumin (-)(90 C) or (retorting) Milk caseine (-); whey ; β-lactalbumin ; Egg ovomucoid & ovalbumin ; (-) Soybean 7S & 11S, 2S ; Gly m Bd 30K(P34) (retorting); (extrusion) Peanut ; Egg decreased; Almond (-); Hazelnut Wheat gliadin ; wheat bread ; wheat pasta (-) Milk β-lactoglobulin ; Rice ; Soybean Gly m 1 Peanut Ara h1 ; Soybean glycinin & β-conglycinin ; Shrimp tropomyosin Egg ; Milk whey & casein ; Wheat gluten Milk Shrimp Egg ovalbumin Gamma irradiation Egg ovalbumin ; Shrimp ; Tree nuts almond, cashew, walnut (-) Genetic modification Chemical modification Physical modification Enzymatic hydrolysis Egg ovomucoid ; Peanut Ara h2, Ara h6 Soybean Gly m Bd30K ; SKTI ; Gly m Bd 28K & β-conglycinin(α & α subunit) Buckwheat ; Soybean Gly m Bd 30K ; Wheat ; Peanut Ara h1, 2, 3 ; Cherries Buckwheat ; Wheat Buckwheat ; Soybean 7S, 11S, 2S ; Peanut ; Lentil ; Milk ; Egg ; Rice Table was modified from Food Engineering Reviews. 2011;3(1):26-43

11 Diagnosis - Clinical Disorders 식품알레르기는아니지만이와비슷한증상을나타내는많은장애들이존재 - Toxic reactions (i.e., scombroid fish poisoning) - Neurologic responses (i.e., auriculotemporal syndrome) - Gustatory rhinitis 만성천식, 만성비염, 아토피성피부염등의질환의 trigger 는식품이외에도다양 호산성식도염 (eosinophilic esophagitis, EoE) 진단시 food trigger 에대한의심을높 여야하고, 식이를통한치료시도해야함. - EoE 가있는환자들의식단에서알레르기유발가능성이있는식품을제거시 EoE 가호전되는것을확인 [90-93]

12 Diagnosis - Diagnostic approaches Recommended - medical history & physical examination - elimination diets - SPTs - sige measurements - OFCs Non-recommended - intradermal tests - total serum IgE measurements - APTs - the use of APTs, sige measurements, and SPTs in combination - a number of nonstandardized and unproved tests (measurement of basophil histamine release, applied kinesiology, allergen-specific IgG4 measurement, electrodermal testing, and several others)

13 Diagnosis - Diagnostic approaches 진단을위한기본적인접근법 [Fig. 1] 식품알레르기 ( 면역반응 ) 와일치하는히스토리? Yes No 독소 (scombroid), 대사장애 ( 유당불내증 ), 식품의 pharmacologic components( 카페인 ), 또는정의되지않은메커니즘에의해야기된부작용에대한추가시험과관리에대해논의 IgE- 매개성알레르기에일치하는히스토리? No 아토피성피부염또는호산성식도염의병력? Yes Yes 평가는 IgE Ab 에대한시험을포함할수있음하지만제거식이와 OFC 에더의존 No IgE- 비매개성질환의평가는일반적으로제거식이와 OFC 를요구그러나, 히스토리는추정하는진단을하는데설득력이있음. 질병의경과와 / 또는특정알레르기의완화를평가하기위한주기적인재평가재시험시기는특정질병, trigger, 히스토리, 환자연령에따라다양

14 Diagnosis - Diagnostic approaches 위험성, 비용, 시간등의문제가있을지라도, OFCs 를진단에포함시켜야함. - 식품을제한섭취하는 AD 어린이 125 명의연구에서, OFC 364 건결과중 89% 가음성으로나타남 [96]. 이들은식사제한의범위를줄일수있었음. 즉, 다양한식품을섭취함으로써삶의질을높일수있음. - Double-blind, placebo controlled OFCs 가표준화됨. SPTs? sige? sige/total IgE? 논란이있음. 더많은연구가필요함. Component-Resolved Diagnostics (CRD) - 달걀, 우유, 밀, 과일, 새우, 헤이즐넛, 땅콩등에서입증이되었으나, 일반적인시험방법들이가지는한계를완전히벗어나지는못함. - CRD 연구는땅콩알레르기에서가장연구가많이되어있음. 최근많은연구들에서는땅콩 IgE 수준이반응의심각성과관련이있을것이고, CRD 가이에대한추가적인정보를줄것이라고제시하고있음. - 우유, 달걀에대해 baked form 을이용한연구가많이진행되고있음. 달걀흰자에대해서 SPTs 는결과를예측하는데도움이되지못했으나, sige 수치는결과예측에유용하였음 [144]. Stepped approaches to testing might be most effective - Considering only peanut IgE (95 OFC) or SPT (50 OFC) or Ara h 2 (44 OFC) vs. sige & Ara h 2 (21 OFC) [138] - 6 개변수 (SPT, serum food-specific IgE, total IgE, symptom history, sex, age) 에근거한예측모델을이용해땅콩, 우유, 달걀에대한반응가능성 (97% 정확도 ) 또는관용 (94%) 을계산. 하나의변수만이용할때보다정확 [115].

15 Pearls & pitfalls regarding diagnosis of food allergy [Table Ⅰ] Pearl/observation Additional details Clinical application A positive skin test or serum food-specific IgE test result indicates sensitization but not necessarily clinical allergy Dose, manner of preparation, and ancillary (eliciting) factors might alter reaction outcomes. IgE binding to homologous proteins among food groups and between foods and pollens might have variable clinical relevance. Screening with indiscriminate panels of tests is poorly informative. Screening tests with common allergens that have not been ingested and tolerated but pose increased risk can be considered (eg, tree nuts for a child who reacted to peanut but has not ingested nuts). Alcohol, NSAIDs, and exercise are among eliciting factors that might facilitate a reaction. Heating might alter allergenicity (eg, bakery products with egg/milk might be tolerated when whole forms are not and cooked fruits might be tolerated when raw fruits are not). A low dose might be tolerated while larger amounts are not. Rates of clinical cross-reactivity: Allergy to: Peanut A tree nut A fish Shellfish Grain Milk Related food Most legumes Other tree nut Other fish Another shellfish Another grain Goat/sheep milk Mare milk Beef History and epidemiologic considerations should guide test selection. Tolerated foods generally need not be tested. Differential diagnosis should include alternative allergen triggers (environmental aeroallergens) and nonallergic diseases (eg, intolerance). History should focus on amounts triggering a reaction and ancillary factors. History should explore the types of foods tolerated or not tolerated. Care should be taken in not overtesting. For some categories, food avoidance of Approximate clinical entire group might be prudent, reaction rate especially to avoid cross-contact in 5% preparation, but individualization might 35% be possible. Higher for: walnut-pecan, almond-hazel, cashewpistachio 50% 75% 20% >90% 5% 10% (Continued)

16 Pearls & pitfalls regarding diagnosis of food allergy [Table Ⅰ] Pearl/observation Additional details Clinical application Tests for serum food-specific IgE might not provide comparable results among manufacturers. Component testing might differentiate clinical reactivity (IgE binding to potent stable allergens) from less clinically relevant sensitization (binding to labile proteins). Serum/skin test results might be negative despite clinical reactivity. Increasingly high serum foodspecific IgE levels or increasingly larger skin test wheal size indicate higher chances of clinical allergy. At specific high levels of IgE or large skin tests, clinical reactivity is highly likely; however, studies are limited, and variations in diagnostic cutoff values are reported. In the United States, there are 3 major test manufacturers. Food Peanut Hazelnut Soy Labile Ara h 8 Cor a 1, Cor a 2 Gly m 3, Gly m 4 This could be due to reagent lacking relevant protein. This could be because the reaction is not IgE mediated. Correlation of tests with outcomes vary by center, age, and disease (equivalent results are generally more predictive of allergy in a younger patient). Results are not highly correlated with severity. Food Egg Milk Peanut Mean age, 5 y; 50% react* 2 2 2/5 Care must be taken in evaluating test results over time when different manufacturers are used. Stable Concentration of IgE binding to components Ara h 1, Ara h 2, Ara h 3, Ara h 6 also relates to outcomes, but similar to Cor a 9, Cor a 11, Cor a 14 standard tests, correlations have not been Gly m 5, Gly m 6 established and vary by, for example, center and patient selection. Caution: severe reactions can occur despite Mean age, 5 y; ~95% react Age <2 y; ~95% react 2 5 lack of noted binding to measured allergen. Do not discount a convincing history because of a negative test result. Consider testing with fresh food (prick-prick test); these can be stored frozen. Be cognizant of non IgE-mediated allergic reactions. Test results should not be viewed solely as positive/ negative. Results can be followed over time to monitor allergy persistence/resolution. Specific correlative values might not be applicable over all patient groups. OFCs can be deferred, particularly if there is a clinical history. When evaluating individual studies, predictive values might not apply to populations with different demographic and referral patterns.

17 Diagnosis - Diagnostic approaches 향후진단은 OFC 에덜의존하고예측이개선되는것을목표로, cellular & humoral testing, 그리고시험결과를해석하는좀더정교한알고리즘에근거할것임. 단백질내특정에피톱에의결합, 결합패턴, 정도, 친화력등을평가 Testing humoral responses, diagnosis with T-cell proliferative responses, metabolomics, basophil activation

18 Management/Treatment - Avoidance & emergency management 현재의관리 : 알레르겐회피, 알레르기반응의즉각적치료 Care in this article - circumstances warranting prescription of self-injectable epinephrine - the importance of education about prehospital treatment of reactions - education about avoidance (eg, cross-contact, traveling, restaurants, school issues, and label reading) - legislation regarding labeling, food manufacturing, and increasing access to epinephrine, the availability of advocacy organizations, numerous resources for education developed by a number of constituencies 안전성을증진시키기위해교육이반드시필요 - 식품알레르기센터에서관리를받고있음에도불구하고, 우유또는달걀알레르기환자는연간 0.81번의알레르기반응을보였음. 56% 는 1번이상의반응을보고. (1) 조심성이부족해서 ( 라벨확인의실수, 비의도적섭취 ) (2) 식사준비시 cross-contact이있거나부모가준비해주지않은것을먹은경우 [153] - 반응의 11.4% 는심각했으며, 보호자가심각성을인지하지못했거나에피네프린이이용가능하지못했거나, 보호자가이를투여하기두려워했기때문에 29% 만이에피네프린치료.

19 Management consideration [Table Ⅱ] Area Topics Examples of educational advice, pearls, and resources Avoidance Manufactured products Restaurants Travel School Home By age Vigilance Experimentation Caregivers Anxiety, emotional Nutrition Ingestion vs noningestion Resources (examples) Label reading each purchase, understanding labeling laws, avoidance of products with advisory warnings Discuss allergy with staff, use written chef cards, educate about severity and cross-contact, suggest methods to avoid inclusion of allergens (eg, aluminum foil on grill) Prepare ahead for extra medications, safe meals, nearby medical assistance, consider rooms with kitchenette, carry written materials Written emergency plans in place, avoidance strategies (eg, craft projects), provisions for mealtimes, field trips, substitute teachers, bus travel, delegation of care Avoid cross-contact in meal preparation, organize cupboards Tight supervision for toddlers; young school age taught not to take food or share; older school age transition to read labels, speak to restaurant staff, and discuss allergy and symptoms and therapy; teens carry and know when and how to self-treat and education of peers Education on always having medications ready, plans in place, ensuring safe food, medical identification jewelry Specify that if there is doubt of a true allergy, ingestion should be discussed in context of medically supervised food challenge and not home trials Educate all caregivers on avoidance and emergency management Acknowledge anxiety, potential bullying, need for balance of caution, and maintenance of a normal lifestyle; refer for mental health support Nutritional counseling and growth monitoring for children Emphasize differences in risk from ingestion exposure (higher risk) vs skin contact (low risk unless transfer to mouth) vs inhalation (depends on food and density of exposure) with regard to potential symptom severity and treatment, taking into consideration age, specific allergies, and circumstances of exposure References 2, 152, 157, and 161. Web sites: foodallergy.org; cofargroup.org; aaaai.org, acaai. org, aafa.org; allergyready.com; ww.cdc.gov/healthyyouth (Continued)

20 Management consideration [Table Ⅱ] Area Topics Examples of educational advice, pearls, and resources Emergency management Prevention (primary) Other Carrying medications Using medications Preparedness By age Emergency plans Dosing Resources (examples) Pregnancy Infant Weaning Resources (examples) Encourage education about & participation in research studies Emphasize having medications at all times, even if no planned food ingestion; make provisions to increase ease of carrying or access (packs, holsters, and larger purses) Review specifics on when (symptoms) and how to use medications and alerting emergency teams (call 911, not necessarily linked to administration of epinephrine) and educate about safety of epinephrine and need for early administration, educate not to rely on antihistamines or inhaled bronchodilators Plans tailored to age, ability to self-treat, allergy, locations, wearing medical identification jewelry Transition responsibility of anaphylaxis management gradually through preteen to teen years, carry and know when and how to self-treat Establish written emergency plans, as well as a team approach to manage a reaction Generally transition from a 0.15-mg autoinjector to 0.3 mg around 55 lbs; for infants, weigh options of autoinjector versus ampule/syringe Reference 2 Web sites: foodallergy.org; cofargroup.org; aaaai.org; acaai.org Commercial autoinjector Web sites Identification jewelry: medicalert.org Healthy diet, specific allergen avoidance not recommended Breast-feed (exclusively >4 months) if at risk of allergy (family history of allergy); if unable to do so, consider hydrolyzed infant formula (see text); no maternal diet restrictions Recommended Not to delay solids beyond 4-6 months, includes allowing allergenic foods (not necessarily as weaning foods, however) References 2, 3, 162, 163 Resource: clinicaltrials.gov; foodallergy.org

21 Management/Treatment - Avoidance & emergency management 각국가마다식품알레르겐표시기준을가지고있음. may contain label - 대부분의국가에서자발적으로시행 - 권고라벨을가진제품의 5.3% 는검출가능한단백질을포함, 이러한경고가없는제품의 1.9% 가오염되어있었음 [166]. - 우유에대한권고라벨이있는제품검사결과, 초콜릿제품에서주로오염이있었음 (42%)[167]. - 미량이포함되어있을지라도민감한사람들에게위험할수있음. 반응의역치 (threshold) 에대한연구가진행중에있음.

22 Food allergen labeling in countries Korea eggs(only poultry), milk, buckwheat, peanuts, soybean, wheat, mackerel, crab, pork, peach, tomato, sulfite and sulfur dioxide (>10mg/kg or 10mg/L) U.S.A. milk, eggs, fish, crustacean shellfish, tree nut, wheat, peanuts, soybean (Food Allergen Labeling and Consumer Protection Act of 2004) EU cereals containing gluten, crustacean shellfish, eggs, fish, peanuts, soybean, milk and dairy product, nuts, celery, mustard, sesame, sulfite and sulfur dioxide (>10mg/kg or 10mg/L), lupin, molluscs (REGULATION (EU) No 1169/2011) Japan mandatory: wheat, buckwheat, eggs, milk, peanuts, shrimp, crab recommend: abalone, squid, salmon and salmon roe, beef, pork, chicken, mackerel, soybean, walnut, orange, kiwi, peach, yam, apple, gelatin, banana, pine mushroom (JP FOOD SANITARY 11-5) China crustacean shellfish, fish, eggs, peanuts, tree nuts, soybean, milk, cereals containing gluten Hong Kong cereals containing gluten, crustacean shellfish, eggs, fish, peanuts, soybeans, milk(including lactose), tree nuts, sulfite and sulfur dioxide (>10mg/kg or 10mg/L) (Food and Drugs (Composition and Labelling) (Amendment) Regulation 2004) Canada tree nuts, peanuts, sesame seeds, wheat, cereals containing gluten, eggs, milk, soybeans, crustaceans, shellfish, fish, mustard seeds, sulfite and sulfur dioxide (>10mg/kg or 10mg/L) (FOOD AND DRUGS ACT, SOR/ ) Australia & peanuts, tree nuts, milk, eggs, sesame seeds, fish and shellfish, soy and wheat, cereals containing gluten, New Zealand sulfite and sulfur dioxide (>10mg/kg or 10mg/L) warning statements : food containing the bee product royal jelly

23 Management/Treatment - Prevention 최근, 아토피성질환또는식품알레르기를방지하기위한방법으로서지속적으로알레르겐을피하는방법은배제되고있음. 여전히논란이있을지라도, 임신시알레르겐을피하는식단은권장되지않음. - 임신중땅콩을자주섭취한산모의아이는그렇지않은아이에비해 18개월에천식을가질확률낮음, 견과류도유사한결과 [173] vs. 임신중산모의땅콩섭취가유아의땅콩 IgE 수치증가위험있음 (positive-dose response) [174] - 특별히조제된영아식 ( 가수분해 ) 은아토피예방의효과는있을지도모르지만, 식품알레르기예방효과는약함 특정식품또는알레르겐의지속적인회피가오히려아토피또는식품알레르기에대한위험요인일수있음. 건강한아기에게알레르기성음식을지연시킬이유는없지만, 아기가아토피나식품알레르기증상을보일시에는저알레르기성식품으로된이유식으로시작하여점차적으로진행하면서좀더많은평가를하는등어느정도주의가필요함.

24 Management/Treatment - Prevention 예방을위한능동적접근법은 prebiotics, probiotics, synbiotics, bacterial lysates 에초점을둠. - 특정 strain이최소한천식을낮춰줄것이라제안하는연구가있지만, 여전히논란이되고있음 World Allergy Organization 리뷰는 probiotics가알레르기예방과치료에있어서확실한역할을하는것은아니라고결론내림 [185].

25 Future therapies [Table E2] Therapy Immune rationale Benefits Observations to date Standard subcutaneous immunotherapy (native allergens) Sublingual/oral immunotherapy Epicutaneous immunotherapy Modified protein vaccine Peptide vaccine (overlapping peptides) Conjugation of immune stimulatory sequences to allergen and additional adjuvant methods Antigen presentation in nonmucosal sites results in TH1 skewing Antigen presentation to mucosal site provides desensitization and might induce tolerance Proved for venom and respiratory allergy, possible benefit (pollen) for oral allergy syndrome Natural foods, reduced risk of systemic anaphylaxis compared with injections Primarily avoided for risk of anaphylaxis (eg, peanut) Mounting evidence for desensitization and relative safety; unclear effect on tolerance Antigen presentation through skin Low risk, natural food Pilot studies show promise for safety and efficacy, trials underway Reduced IgE activation by mutation of IgE-binding epitopes Peptides are less likely to crosslink IgE, avoiding mast cell activation Enhance TH2 response by activating innate immune receptors (using specific sequences or whole bacteria) A safer form of immunotherapy compared with injection of native protein No requirement for IgE epitope mapping/mutation Increased efficacy, possibly improved safety Murine models show promise, human study of peanut showed reactions Limited Preclinical studies (Continued)

26 Future therapies [Table E2] Therapy Immune rationale Benefits Observations to date Plasmid DNA-encoded vaccines Anti-IgE antibodies Anti-IgE plus oral immunotherapy Traditional Chinese medicine Cytokine/anticytokine/an tireceptor/antimediator Fusion proteins Probiotics, Trichuris suis ova Endogenous production of allergen might result in tolerance Targeted toward Fc portion of antibody, can inactivate IgE with reduced risk for activating mast cells Might reduce side effects of oral immunotherapy, speed desensitization, improve tolerance Mechanism appears to include altered T-cell responses with increased IFN-g and IL-10 To interrupt inflammatory signals To inhibit degranulation, enhance effectiveness of immunotherapy Possible 1-dose treatment Not food-specific Food specific but might not require long periods of anti- IgE Not food specific Might allow directed interruption of inflammatory processes without need for food restriction Targeted reduction of effector Responses, possible directed immunotherapy Murine models reveal strainspecific response Preliminary studies showed improved threshold overall but did not show uniform protection Pilot studies show promise, clinical trials underway Murine models show efficacy; human safety studies completed; clinical trials underway Primarily preclinical Preclinical Alter immune response Not food specific Mixed results in trials thus far or too preliminary

27 What do we know? 식품알레르기유병률은높고 ( 인구의 10% 정도까지 ), 지난수십년간증가되어왔음. 수많은유전적, 환경적위험요인들이밝혀져왔음. 감작경로, 알레르겐특성, 면역반응에대한이해는진단과치료에대한이해를제공할것임. 식품알레르기에의한질환은범주가넓음. 진단은발병과역학을환자의히스토리와시험결과에결합시키는데의존함. CRD의사용이임상시험에적용되고있음. 현재의관리방법은알레르겐회피와응급처치에대한주의를요구함. 안전성과삶의질을증진시키기위해환자와의사들이이용가능한교육과상담을개선할많은자료들이존재함. 더욱확실한치료를위해많은임상시험들이수행되고있음.

28 What is still unknown? 식품알레르기증가의원인 환경적, 유전적위험요인을예방대책의개선으로전환하는것 가장좋은진단법 관리시안전성과삶의질을어떻게극대화하는지 가장새로운치료옵션 식품알레르기의진단및치료에의 각개인에게맞는 접근법이요구될것이지만찾기힘듦.

29 Key concepts & therapeutic implications 시험중식품특이 IgE의존재는감작을의미하는것이지만, 진단과는별개임. 진단및관리를위해서는식품알레르기및다른식품에대한부작용의역학, 자연경과, pathogenesis, 임상적징후에대한지식이요구됨. Medical history가열쇠임, 비침습성시험은 supportive and possibly diagnostic, OFC는가장확실한시험임. 관리를위해서는알레르겐을피하는법과아나필락시스를즉각적으로, 적절하게치료하는것에관한교육과주의가요구됨. 치료에대한다양한접근법이연구하에있고, 환자들은임상실험을의식해야함.