<마더세이프라운드> 소아알레르기 예방
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  • I Pregnancy: physiological T helper type 2 priming; intrauterine allergen exposure. II Neonatal period: neonatal T helper type 2 responses are lower in infants who develop atopic disease compared with those who remain healthy; mode of delivery, the establishment of gut microbiota and neonatal antigen exposure. III Critical window: healthy infants exhibit a decline in T helper type 2 responses during the early postnatal period, whereas a converse pattern is characteristic in infants developing atopic disease; counterregulatory mechanisms. IV Early symptoms of allergic disease: atopic eczema, food allergy; induction of tolerance, control of allergic inflammation. V Fully established allergic disease:

<마더세이프라운드> 소아알레르기 예방 <마더세이프라운드> 소아알레르기 예방 Presentation Transcript

  • 소아 알레르기 질환의 예방적 접근 관동대학교 의과대학 제일병원 소아청소년과 이 희철
  •  
  • 20 세기 후반부터 질병의 형태가 변하고 있다
    • 세균성질환의 감소
    • 바이러스 질환의 증가 :
    • SARS, H1N1 Flu.
    • 성인병의 증가
    • 종양환자의 증가
    • 알레르기 질환의 급증
    - 공 해 ? 산업화 - 환경의 변화 ?, 서구화된 생활 - 세균감염의 감소 : 환경위생학설 (Hygiene Hypothesis ) ?
  • Regulatory T cell
  • 알레르기란 ?
    • 역사 : 성경인물인 욥이 피부 가려움으로 피가 나도록 긁었다
    • 중요성 : 호흡 – 인간 (Host) – 음식 상호관계에서 발생
    • 사랑이 없으면 안된다 .
    • Atopy 어원 : 그리스어 ‘ Atopia ’ ; different, out of place
    • 알레르겐에 대한 IgE 항체를 생성하는 유전적 소인
    • 환자의 대다수에서 혈청내 IgE 상승 ,
    • 피부반응 검사에서 특정 알레르겐에 양성 반응
  •  
  • Epicutaneous sensitization leads to systemic immune response Spergel JM et al. J Clin Invest 1998; 101:1614–22 - 땅콩 단백질함유 피부연화제 국소도포 : 땅콩 감작이 증가 - 천식 (+) AD(-) vs 천식 (-) AD(+) : 두군 모두 집먼지진드기에 기도 과민성 , 아세틸콜린에 AD 환아에서 천식범위의 반응 > 피부감작이 기도 감작으로 발전 .
  • 아토피피부염
    • 알레르기 질환 , 소양증 , 연령대별 특징적 병변의 부위와 모양
    • 만성 혹은 재발성 경과 , 본인 또는 가족의 아토피 병력
  • 아토피피부염
    • 알레르기 가족력 (+) : 부모 한쪽 30 %, 부모 모두 (+) : 50% 이상
    • 부모 모두 AR : 자녀가 같은 질환 2/3
    • 중등도 와 중증 아토피피부염 : 약 40% 에서 식품 알레르기 연관성 .
    • 유병률 : 15-20 % worldwide. 다양한 원인 , 확고한 치료 방법이 없는 상태
    • 유전적 소인을 가진 사람이 환경의 영향을 받아서
    • 30 -40% 천식 , 50-70% 비염으로 진행
    • 중요성 : 복잡한 병태생리와 다양한 위험요인 파악과 이를 기초로 한
    • 조기관리는 아토피피부염의 예방뿐 아니라 천식 및 비염 등의
    • 알레르기 진행을 차단
    • 피부장벽 / 외피 분화 gene 과 면역반응 / 숙주 방어 gene
    • : AD 의 발현에 중요한 역할 담당
  • 아토피피부염
    • 지루성 피부염
    • 가려움이 적고 호전되는 자연경과
  • 아토피피부염
    • 이차적 바이러스 . 세균감염
    • 곰팡이 감염
  • 아토피피부염
    • 만성화 , 태선화 , 심한 소양증
  • 아토피피부염 발생기전 아토피피부염 유 전 환 경 환경에 대한 비정상적인 Th2 면역반응 염증자극에 대한 피부의 과잉반응 피부 장벽의 기능장애
  • 아토피피부염 위험요소 아토피피부염 유 전 환 경
    • Candidate gene
    • Family History
    • Allergen
    • - Food
    • - Aeroallergen
    • Gem free-like state
    • - Vaccinations, anti-microbial
    • Food consumption pattern
    • Stress
    • Irritants
  • Genetics Inflammation & desquamation Immune Response (host depense genes) Skin Barrier (epidermal differenciation genes) TEWL(impaired barrier formation) Filaggrin (Loss-of–function mutation) Protein SPINK5 gene (uppermost epidermist) LEKT1 inhition 2 serine protease Imbalance of protease vs protease inhibitor impaired barrier function
  • Family history
    • Adult with AD , 60%  children with AD
      • Both parents with AD  81%,
      • One parents with AD and the other with respiratory allergy  59%
    • A stronger correlation between siblings than between siblings and parents
    Candidate genes for atopy and AD
  • Immunopathology IgE and IgE receptors
    • 80% : increased serum IgE levels, sensitization against aeroallergens and food allergens, and/or concomitant AR and BA
    • High-affinity receptor for IgE (FceRI) can be found in the epidermal skin lesions of patients with AD
    Allergen Extrinsic or Intrinsic
    • Two types of AD have been identified
      • - Allergic, or extrinsic, form, 70% to 80% of the adult patients with AD , sensitization toward environmental allergens, increased serum IgE levels
      • - Nonallergic or intrinsic form, 20% to 30% of adult patients with AD, low IgE serum levels and the absence of any detectable allergen sensitization
  • Allergen Sensitization to food allergens
    • Associated with infantile AD and related to disease severity
    • Predictive for persistence of symptoms throughout childhood
    • Clinically relevant food allergies are estimated in about 35 - 40% of children with AD (Clin Exp Allergy 1999; 29:91-6)
    • The overall prevalence of food allergy in infants with AD ranged from 20 to 80% in various studies, and may be estimated at 30%.
  • Allergen Aeroallerens (pets, mites and pollens)
    • Increase the risk factors for AD and AD severity (Allergy 2004;59(suppl 78):53-60)
    • Trigger for exacerbations in adult AD
        • Many AD patients have IgE Ab to inhalant allergens in keeping with their skin tests . ( J Allergy Clin Immunol 1983;72:27-33 )
        • Inhalant allergens applied to skin of AD patients by patch test induce acute eczematous lesions . (J Invest Dermatol 1984;83:290-5)
        • Severity of AD is correlated with the degree of sensitization to aeroallergens. ( J Allergy Clin Immunol 1999;104:1280-4. )
        • These studies suggest that inhalation or contact with aeroallergens may be involved in the pathogenesis of AD .
    • Homes of patients with eczema have higher numbers of HDM than homes of healthy people. (Br J Dermatol 1992;127:322–7.)
    • HDM might cause an exacerbation of the eczematous skin lesions in a high number of AD patients. (J Allergy Clin Immunol 1996;97:1064–70.)
    • Eczematous skin lesion and ear swelling caused by repeated application of Der p crude extract in NC/Nga mice has a Th2-dominant background. ( International Immunopharmacology 2006;6:1616–22. )
    • Der p 1 exposure resulted in a significant rise of dermal blood flow after 48 h in patients with AD. (Clin Exp Allergy 2006;36:338-45.)
    • Der p 1 content in mattresses is not associated with disease activity in patients with AD. (Clin Exp Allergy 1999;29:920–5.)
    • No effect was observed in patients with atopic eczema after undertaking HDM avoidance measures. (Lancet 2001;358:188–93.)
    House dust mite (HDM) Allergen
    • Hypothesis
      • decreasing antioxidant (fruit and vegetables), increased n-6 polyunsaturated fatty acid (PUFA;(margarine, vegetable oil), decreased n-3 PUFA (oily fish) intakes have contributed to the recent increases in asthma and atopic disease. (UK)
    • Epidemiologic studies
      • Dietary changes between dietary antioxidants and lipids : allergic disease.
      • n-6 vs n-3 PUFA metabolism
      • 4-series LT : proinflammatory activity
      • 2- series PGE2: immunomodulatory promotion Th2 phenotype
      • EPA & DHA : inhibition linoleic acid metabolism , COX-2 gene expression and activity
      • Intake during pregnancy and early childhood : area of active investigation.
    Nutrients Diet as a risk factor for atopy and asthma
  •  
  • Stress
    • Increased levels of nerve growth factor and substance P
    Microorganisms
    • S. aureus - secreting toxins called superantigens
    • Disseminated infections with herpes simplex or vaccinia virus
    • Smallpox vaccination is contraindicated in patients with AD unless there
    • is imminent danger of exposure to smallpox
    • Fungal infections
    Irritant factors Skin barrier dysfunction
    • Dry skin and increased transepidermal water loss
    • Reduced ceramides, changes in stratum corneum pH levels, overexpression of stratum corneum chymotryptic enzyme
    Etc
  • 2. 이차 예방 감작된 후의 질병 발생을 억제 한다 . Allergy prevention 1. 일차예방
      • 항원에 대해 감작 (IgE-mediated) 이 되지 않도록 하는 것
    3. 삼차예방
      • 알레르기 질환 발생 후 증상을 경감시킨다 .
  • Pediatr Allergy Immunol 2004: 15 (Suppl. 16): 9–32 Development of allergic disease Allergy Prevention Primary prevention Secondary prevention
    • Development of the immune system
      • Lymphocytes in thymus at 8-9 week
      • IgE in 11 week
      • T cell migrate into fetal circulation at 15-16 weeks
    • Fetal exposure to allergen
      • Allergen in maternal circulation -> placenta by passively diffusion -> fetus
      • Allergens with maternal IgG actively across the placenta
      • Allergens are detected in amniotic fluid at 16 week and fetal circulation at term
      • Proliferation of fetal cell to allergen in 2 nd trimester.
    • Cord blood IgE and sensitization
      • IgE not cross the placenta, low sensitivity, fetal igE
      • Predisposing factor for atopy
    Intrauterine environment
    • 태아감작 : 2nd trimeser 태반 통해
    • 항원은 수용성 형태 혹은 IgG-complexed 펩타이드 분획형태로 태반을 통과
    • 제대혈 T 세포 : 흡인항원이나 식품항원에 모두 증식반응
    • : 아토피가족력 있거나 후에 아토피가 발생하는 환아에서 더욱 강 한 반응을 보이나 ,
    • 비아토피 신생아도 제대혈 T 세포가 항원에 증식반응 ; 모든 신생아 이미 태내에서 항원에 감작이 일어남을 시사
    • 임신중 태아와 모체는 Th1 반응이 억제 , 상대적 Th2 우세 반응 : 태아 T 세포가 알레르겐에 노출시 자연스럽게 Th2 반응을 일으킬 수 있는 환경
    태내감작의 증거들
  • Th2 type reactivity before and after birth . Potential pathway of IgE-mediated antigen focusing occurring via interaction of foetal gastrointestinal tract and amniotic fluid. Hypothesis ( 엄마의 특이 IgE + 산모를 통한 항원 노출 ) -> 두 위험요소가 결합하여 아기의 면역을 Th2 로 유지하게 하여 출생 후 아토피 질환에 영향을 미칠 것이다 . Holloway JA. Warner JO. Does atopic disease start in foetal life?. Allergy. 55(1):2-10, 2000
  • Th2 type reactivity before and after birth . ( Bjorksten,1998 ) Primary immune responses to allergens encountered early in life include TH 1- and TH 2-like immunity. ( Bjorksten,1998 ) Allergy Prevention
  • Correa JMM et alii J Pediatr (Rio J) 2001; 77 (6): 441-46 Allergy Prevention X X X
  • Prevention Primary prevention
    • Prediction of allergy
      • Allergy genes : 11q13, 5q31-33
      • Family history : 60-80% in a child born to two allergic patients
      • Cord blood IgE : 26% sensitive, 74% specific
    • Dietary manipulation during pregnancy : peanut avoidance
    • Breastfeeding : exclusive breastfeeding for 6 mo
    • Maternal avoidance diets during lactation : peanuts and nuts (consider avoiding eggs, cow’s milk, fish)
    • Protein hydrolysate formula
    Secondary prevention
    • To prevent progression of the “atopic march” : in research
    Tertiary prevention
    • Avoidance of offending food, teaching action plan
    • Allergen avoidance, skin care for atopic dermatitis
    Allergy Prevention
  • 아토피 유병율 알레르기 질환에서 Lactobacillus GG 투여 효과 31/68 (46%) 15/64 (23%) Probiotics in primary prevention of atopic disease, Lancet. 2001;357:1076-9 Probiotics
    • 장내 세균총의 균형 유지 , 살아있거
    • 나 비활성화시킨 미생물
    • : Lactobacilli, Bifidobacteria
    • Metchinikoff : 사람의 건강과 장수
    • 위장관 , 알레르기 질환 , 암 :
    • 위장관 면역조절 > 예방및 치료
    • 장내 항상성 유지
    • 식품항원에 대한 면역 관용
    • 위장관 병적세균 제거
    Allergy Prevention
  • Dietary prevention recommendations /comments from several professional organizations J Allergy Clin Immunol 2008;122:29-33 Allergy Prevention
    • 임신 3 기 , 계란 우유 섭취 제한
    • - 알레르기 질환의 예방효과 미약
    • 영양면 체중감소 등 부작용
    • 미국 (AAP), 유럽
    • 필수 영양소 섭취 제한의 알레르겐 회피식은
    • 권유되지 않는다 .
    • 땅콩 : 태아감작으로 출생후 땅콩알레르기 발생 , 고위험군
    • 산모에서 제한 권유 (AAP), 최근 연구 결과는 차이 없다 쪽으로
    임신중 모체의 식이제한 Allergy Prevention
  • Dietary prevention
  • Studies
    • A birth cohort study consisting of a baseline of 4,146
      • frequency of consumption of fruit, vegetables, fish, egg, milk, milk products, nuts, and nut products during the last month
      • followed until 8 years of age
      • assess associations between maternal diet during pregnancy and childhood asthma outcomes over 8 years.
      • an increased risk of daily versus rare consumption of nut products during pregnancy on childhood asthma outcomes
      • Am J Respir Crit Care Med Vol 178. pp 124–131, 2008
    • 2641 children at 2 y of age, German prospective birth cohort study (LISA) Maternal diet during the last 4 wk of pregnancy , a semiquantitative food-frequency questionnaire
      • Intake of allergenic foods and foods rich in n6 polyunsaturated fatty acids during pregnancy may increase and foods rich in n3 polyunsaturated fatty acids may decrease the risk of allergic diseases in the offspring
      • Am J Clin Nutr 2007;85:530 –7
  • Studies
    • To investigate the relationship between allergen specific cord blood (CB) IgE levels, parental sensitization, CB cytokine production, and environmental influences.
    • 922 neonates, 922 mothers, and 835 fathers
      • allergen-specific IgE antibodies against 20 common seasonal, perennial, and food allergens
      • Supernatants from stimulated CB cells, the production of IL-5, IFN-g, IL-10, and TNF-a.
      • Contamination with maternal serum was excluded by several means of analyses, including the absence of IgA antibodies
    • Allergen-specific IgE antibodies were detectable in 23.9% of newborns
    • Clear correlation between maternal and fetal IgE was found only for hen’s egg, cow’s milk, and soybean allergen
    • Fetal IgE correlated negatively with the level of IFN-g production
    • Conclusion: Allergen-specific IgE antibodies most probably of fetal origin are detectable in CB and correlate with a lowered CB IFN-g production
    • (J Allergy Clin Immunol 2008;122: 711-6.)
  • I Pregnancy: physiological T helper type 2 priming; intrauterine allergen exposure. II Neonatal period: the establishment of gut microbiota and neonatal antigen exposure. III Critical windowcounterregulatory mechanisms. IV Early symptoms of allergic disease: V Fully established allergic disease: European journal of gastroenterology & hepatology17(12), December 2005 Allergen free Nutrients
  • Conclusions
    • Individual variation in the responses to foods
    • & aeroallergens. : high- risk group.
    • Dietary antioxidant & lipid intake during pregnancy
    • : immunomodulation effect,
    • Limits the ability to draw firm conclusions regarding
    • pregnancy and lactation avoidance diets and the timing
    • of introducing specific allergenic foods
    • : lack of convincing evidence.
    • Further research : in particular the role of dietary
    • intervention to individual susceptibility
    Allergy Prevention