Conflict of interest. Who am I? influence in the development of allergies. Babies feeding practices and their. Why the solid advice is. breastfeeding.

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1 Babies feeding practices and their influence in the development of allergies in children. Why the solid advice is breastfeeding. December 6 th, 2016 Varakis Nikos Pediatrician IBCLC Who am I? Conflict of interest A pediatrician, IBCLC, father of twins, husband of a wonderful wife, living in Rethymno I love my family, children and supporting breastfeeding I have no financial or any other kind of interest in companies selling breast milk substitutes

2 Babies feeding practices and their influence in the development of allergies in children. Why the solid advice is breastfeeding. December 6 th, 2016 Varakis Nikos Pediatrician IBCLC Αλλεργία = «άλλο έργο» Allergy = allo different+ ergo work If no family member with allergy 5-15% chance If sibling with allergy 25-35% If one parent with allergy 20-40% If both parents with allergy 40-60% If both parents with same allergy 50-70% drclemens von Pirquet 1905 Η αλληλεπίδραση γενετικών και περιβαλλοντικών παραγόντων στην εκδήλωση ατοπία :Θ.Παπαπασταύρου-Μαυρουδή;Παιδιτρ.Βορείου Ελλαδο, 17: ,2005 Children, having at least one first degree relative (parent or sibling) with allergy, are considered high risk Høst A, Halken S. Primary prevention of food allergy in infants who are at risk. Curr Opin Allergy Clin Immunol. 2005;5(3):

3 Most common food allergens: Cow s milk-dairy products Egg Fish Nuts Soy Most common allergic symptoms: Gastrointestinal: vomiting, diarrhea, severe colics, bloody stools Skin: eczema-dermatitis, urticaria Respiratory: runny nose, cough, asthma Diversity in clinical presentation due to combined allergies (Types I, III, IV)

4 Treatment? The only effective treatment is to avoid the allergen ( aller gy + gen erator ) Treat symptoms (antihistamines, adrenaline) Outgrown by age Desensitization What have we tried? Delay allergen introduction By delaying the allergens introduction.. The gastrointestinal tract matures and can digest food properly The immune system matures and it doesn t get confused Committee on Toxicity of Chemicals in Food, Consumer Products and the Environment (COT). Adverse reactions to food and food ingredients. London (United Kingdom): Committee on Toxicity of Chemicals in Food. Consum Prod Environ 1998; 11: American Academy of Pediatrics. Committee on Nutrition. Hypoallergenic infant formulas. Pediatrics 2000; 106:

5 What have we tried? Delay allergen introduction Global recommendations since 2000: Solid food introduction Exclusive breastfeeding for 6months Egg (yolk>10m, white>12m), Fish>12m If high risk baby: Exclusive breastfeeding for 6months Egg >2y Fish & nuts >3y The results: Allergy keeps marching on! Peanut allergy among african children doubled the last 10 years

6 Environmental factors responsible The prevalence of food allergy increasing over the past 2 decades (U.K., Canada, China). Given the short time frame, environmental factors, rather than genetic changes are likely to account for this increase. Observe without prejudice! (2008) Peanut allergy, serious and usually last for life Jewish children in UK have a prevalence of peanut allergy 10- fold higher than that of Jewish children in Israel! Common characteristics (genetic background, atopy, social class, peanut allergenicity) but different time of peanut introduction to baby s diet (U.K. avoid during weaning and Israel high amounts during infancy)

7 Should we introduce early? Poole JA, Barriga K, Leung DY, Hoffman M,Eisenbarth GS, Rewers M, et al. Timing of initial exposure to cereal grains and the risk of wheat allergy. Pediatrics 2006;117: No avoidance, no delay (2008) Consensus American College of Allergy, Asthma and immunology: dairy >12months, egg >24months, peanuts tree nuts and seafood >3years. ESPGHAN: there is no convincing scientific evidence that avoidance or delayed introduction of potentially allergenic foods such as fish and eggs, reduce allergies, either in infants considered at risk for the development of allergy or in those not considered to be at risk. Will you decide!

8 Should we change course? Data from 994 followed until 5 years: Late introduction of solid foods was associated with increased risk of allergic sensitization to food and inhalant allergens Bright I. et al Pediatrics 2010;125:50 59 Egg introduction: Data from 2073 children followed until 6years old: Delaying egg introduction doesn t protect from asthma, allergic rhinitis and sensitization to food or inhaled allergens at the age of 6 years Zutavern A. et al Pediatrics 2008 Data from 2589 infants: at 12monts old, there is a 5 fold decreased risk of having egg-allergy, when we introduce egg in the diet at 4-6 months,compared with introducing egg at 10 to 12months Kopplin Jj et al Allergy Clin Immunol 2010 Could it be that instead of delaying we should introduce early? Fish introduction: Less than 9months old => asthma at 8 years old (from 4.051children in Sweden) Goksoer et al: Pediatr.AllergyImmunol Between 6-12 months => episodes of wheezing when 4 years(7.210 childrnetherlands) Kiiefte-de Jong JC pediatrics 2012 Less than 12months => asthma, rhinitis, eczema at 12 years Magnusson et al Am J Clin Nutr 2013

9 Introducing solids 4-6months with parallel breastfeeding! DIPP study (Finland) Introducing fish < 6 months, egg < 11 months and cereals < 6 months was connected with less atopic sensitization at 5 year old Nwaru et al, Allergy 2013 PIFA study (U.K.) Introducing solids 4-6 months with parallel breastfeeding until at least 1 year old -> protection at 2 years old (123 children out of 1140 U.K.) Grimshaw et al, Pediatrics 2013 Window of opportunity! Seems that the positive interactions between mother s milk and the baby s gut micro-environment are effective and lead to tolerance during a limited period of time a window of opportunity which we try to use by following the latest instructions of solid introduction around 6 months (4-6months) Prescott S.et al PAI 2008 Breastfeeding combined with gradual solid introduction SichererSH,JACI 2008, Grimshaw KEC et al,pediatrics 2013

10 When you challenge what is considered common knowledge They randomly assigned 640 infants (4-11 months old) with severe eczema, egg allergy or both to consume or avoid peanuts: 530 had negative results on the skin-prick test 98 had positive results on the skin-prick test All children were followed up closely until they were 5 years old. Impressive results: Among the 530 infants in the intention-to-treat population who initially had negative results on the skin-prick test, the prevalence of peanut allergy at 5years: 13.7% avoidance group and 1.9% consumption group Among the 98 participants in the intention-to-treat population who initially had positive test results, the prevalence of peanut allergy was: 35.3% avoidance group and 10.6% consumption group

11 Early peanut introduction to prevent allergy! (Pediatrics, September 2015) 1American Academy of Allergy, Asthma & Immunology (AAAAI) 2American Academy of Pediatrics (AAP) 3American College of Allergy, Asthma & Immunology (ACAAI) 4Australasian Society of Clinical Immunology and Allergy (ASCIA) 5Canadian Society of Allergy and Clinical Immunology (CSACI) 6European Academy of Allergy and Clinical Immunology (EAACI) 7Israel Association of Allergy and Clinical Immunology (ISACI) 8Japanese Society for Allergology (JSA) 9Society for Pediatric Dermatology (SPD) 10World Allergy Organization (WAO) To EAT or not to eat, from 3months old?(2016) Enquiring About Toleracne ΕΑΤ study (U.K.) Introducing 6 allergenic foods (peanut, cooked egg, cow s milk, sesame, whitefish, and wheat) exclusively breast-fed infants who were 3 months of age and randomly assigned them to an early introduction group or to the current practice recommended in the U.K. of exclusive breastfeeding to approximately 6 months of age ( standard-introduction group)(1303 children U.K.) Editorial : Preventing Food Allergy in Infancy- Early Consumption or Avoidance? Gary W.K. Wong, The New England Journal of Medicine March 2016

12 What went wrong after all? Seems that we ve treated children as grown ups In adults the treatment for allergy is to avoid the allergen In fetuses, neonates and babies things seem to be different Avoidance of possible allergens from the pregnant woman, the breastfeeding mother and the high risk baby did not offer the protection expected Recent studies suggests exactly the opposite: desensitizing at-risk children by introducing possible allergen early in their diet Tolerance The key word for facing allergy seems to be tolerance : a natural procedure trough which our immune system distinguishes friends from enemies, like for example a food-protein (ex b-lactoglobulin ), or a non pathogenic micro-organism (ex bifidobacerium), from viruses (ex Rota), and pathogens (ex E.Coli) Our gastro-intestinal tract plays the most important role in the development of tolerance (oral tolerance) introduction of many different dietary & microbiological allergens protection from intestinal inflammatory diseases, food allergies and celiac disease Valerie Verhasselt: Oral tolerance in neonates: from basics to potential prevention of allergic disease. Mucosal Immunology 3: (2010)

13 Breastfeeding and oral tolerance: Breast-milk offers a protective effect against allergy by: promoting the growth and maturation of baby s gut forming a proper micro-environment immunomodulating factors promoting oral tolerance! A baby cannot be allergic to the milk of his own mother Milk is species-specific Both the mother and her baby share 50% of the same genetic material There is no report of an antibody reaction to mother s milk Secretory IgA (siga) abundant in human s milk, blocks food allergens from invading baby s gut, until its maturation and production of baby s own siga in significant amounts The only case of a baby being allergic to the milk of his own mother is when he is allergic to allergens that the mother consumed and appear in her milk Core Curriculum for Lactation Consultant Practice ; R.Mannel, P.J.Martens, Mwalker; 2 nd ed. 2007, pg 310

14 Promoting the growth and maturation of baby s gut ( gut closure ) The gut acts as a gate. Intestinal maturation takes place in human, during the first days of life, when intestinal permeability decreases ->decrease transport of macromolecules across intestinal barrier (gut closure) Maternal colostrum and milk contain gut epithelium growth factors, such as epidermal growth factor and transforming growth factor, that stimulate intestinal growth and development, accelerate gut closure, and might affect antigen transfer. Studies suggest that increased permeability in conjunction with other activating factors of the immune system, such as gut infection or antibiotics might favor allergy development. Promoting the growth and maturation of baby s gut Epidermal Growth Factor high amount in colostrum and declines during first months of lactation. In milk of mothers with pre-term babies much higher, than milk of mothers full-term (protection against necrotizing enterocolitis). Also in breast milk we have Erythropoetin, Insulin like Growth Factor, hepatocyte growth factor and basic fibroblast growth factors. Gut closure normally occurs before birth, but the intestinal surface barrier may be inadequate up to 2 years of age There is no Epidermal Growth Factor in formula milk!

15 Promoting the growth and maturation of baby s gut The allergen needed to sensitize or even initiate an allergic reaction is minor: just 1 ng (nanogram = one billionth of a gram) of β-lactoglobulin ( cow s milk protein not found in human milk ) is enough. In breast milk we may have traces of b-lactoglobulin (0.5 to 32 ng/l) depending on mother s dairy consumption. 40 ml formula contains the amount of b-lactoglobulin that a baby would get through his mother s milk if he would be breastfeeding for 21 years! Businco, Bruno, & Giampietro 1999 What if we offer cow s milk instead of mother s milk before gut closure? Promoting the growth and maturation of baby s gut For the first 6 months of life main food for the baby is milk: Formula fed: exclusively large amounts of cow s milk antigens Exclusively breastfed: daily, from birth until weaning, minute amounts of numerous antigens ingested by the mother

16 Forming a proper micro-environment (hygiene hypothesis) Baby s contact with non pathogenic micro-organisms of the normal flora, early in life, protects against allergies. Natural birth, skin to skin breastfeeding, breast-milk helps creating a normal gut flora. Our modern sterile way of living have deprived infants of adequate, natural immunological stimuli. Forming a proper microenvironment (gut microbiota) Neonatal GI tract is sterile (free of micro-organisms) at birth and it is colonized soon after birth (complete after 1 week, but the number and species of bacteria fluctuate <1 year). Once established, the microbiota is surprisingly stable, and they are specific to each individual! The changes in the gut microbiota influences both immunity and tolerance. Normal flora promotes oral tolerance and protects from inflammation, autoimmunity and allergy Factors influencing baby s gut microbiota: Maternal microbiota, Method of delivery, Incidental microbial encounters, Baby s diet (breast milk: pre & probiotics + mother s flora growth of health promoting bacteria)

17 Immunomodulating factors promoting oral tolerance: Immunoglobulin E (IgE) IgE is elevated in allergic people High levels of IgE in a baby indicates high probability for atopy in the future Fecal IgE levels (corresponds to blood s) in 1 month old babies fed with formula, are higher when compared to exclusively breastfed babies of the same age Furukawa et al., 1994 Immunomodulating factors promoting oral tolerance: Secretory IgA (siga) In adults, siga represents the predominant antibody class in intestinal secretions: Nonimflammatory antibody Inhibits the adherence of bacteria and viruses to mucosal surfaces and microbial colonization Trap food antigens immune exclusion of dietary antigens + favors their degradation by pancreatic enzymes Antigens that have been translocated through the epithelial barrier induce the synthesis of antigen-specific secretoryiga, -> antigens are captured bound to IgA -> actively transported from the lamina propria back to the lumen Adults IgA-deficient are more susceptible to allergies Neonates are deficient in IgA synthesis, but maternal IgA in breast milk can substitute efficiently for this lack of endogenous synthesis. Studies have shown an inverse correlation between the levels of IgA in breast milk and further allergy development in breast-fed children, supporting a possible role of IgA in oral tolerance.

18 Immunomodulating factors promoting oral tolerance Immunoglobulin IgG Our babies, receive maternal passive immunity both before birth (by transplacental transfer of IgG) and after birth (through mother s milk) There is a specific FcRn (neonatal Fc receptor) expressed in the proximal small intestine (not only in neonates) responsible for antigen transport (allows antigen bound to IgG to cross the intestinal barrier without being degraded) Milk-borne antigen IgG immune complexes FcRn transported across the intestinal barrier induction of regulatory T cells(tregs) potent tolerance induction and protection from allergic airway disease Mosconi, E. et al.: Breast milk immune complexes are potent inducers of oral tolerance in neonates and prevent asthma development. Mucosal Immunol. ( 2010 ). Immunomodulating factors promoting oral tolerance (other defense mechanism) From birth, we find in our G.I. tract lymph nodes, Peyer s patches and Dendritic Cells (DC), all affected by the microbioma and factors in breast-milk that regulate immune and tolerance development Dendritic Cells subpopulations (CD103) specialized in tolerance induction in the gut: local production of retinoic acid(vita from breast milk) mesenteric lymph nodes Tregs Thelper 2 -> allergic predisposition (pregnancy, skin) Tregs 1 -> tolerance and protection from allergy

19 Immunomodulating factors promoting oral tolerance ( overlap effect) Immunomodulating factors in breast milk indicate that breastfeeding is important in tolerance development, especially when there is simultaneous introduction of allergen transforming growth factor-β, IL-10 key to immune tolerance homeostasis, produced by the intestine epithelial cells, endogenous levels low at birth and increase toward weaning. Breast milk is rich in TGF-β & IL-10 soluble CD14 the more found in mother s milk the less chance the child developing exzema at 6 months lysosyme antimicrobial action lactoferrin reducing free iron => reducing pathogen development, antimicrobial (bacteriocide, fungicide) blastocytes transform into different tissues according needs Oligosaccharides glucanes, prebiotics-probiotics growth of protective microbiota, gut mucosal maturation, protection from pathogens and allergens Mother s important role in oral tolerance even for aero-allergens Before appearing in mothers milk, allergens, are being handled by her digestive tract, a process that transforms them into a tolerogenic form. Most of aeroallergens (95%) are also detected in the gut The environment inside an adults stomach is acidic (ph 1-2) while in a baby more alkaline (ph 3-5) The pancreas is immature during the first few months of life, and produces small amounts of enzymes (essential for proper digestion, included into breast milk) An antigen appears to breast milk, both if it is introduced to mother p.os (by mouth), or i.v. (through vein) only when introduced p.os tolerance develops to the breastfed baby! Verhasselt, unpublished data

20 Valerie Verhasselt: Oral tolerance in neonates: from basics to potential prevention of allergic disease. Mucosal Immunology 3: (2010) Allergens = tolerogens in infancy Is that enough? In less than a decade we went from: delaying or even avoiding some foods (especially if allergen and especially in high risk baby) introduce with no restrictions (any food to even high risk baby) early introduce (3 month old) allergic food to high risk baby All studies addressed to breastfeeding babies!

21 Some food for thoughts Could early solid introduction reduce the number of babies breastfeeding until at least 6 months? Is there an upper time-limit for breastfeeding? Should we delay introducing solids for the first 6 months in order to protect breastfeeding? The window of opportunity opens at around 6 months 4-6 months : neurodevelopment indicates baby ready to eat (reduction of neonatal reflexes, motor coordination everything to mouth-, head control, sitting-up position 4-6 months : pancreatic enzymes, maturation of gut, acidity in stomach 4-6 months : renal function

22 Could it be that it closes when breastfeeding stops?... By delaying to introduce certain foods we may have deprived our children from the protection of breastfeeding ( I wonder how many children were still breastfeeding for 3 years when the nut introduction for high risk children use to be the guideline ) It seems wise to focus on the benefits of breast-milk For how long? Could it be that it closes when breastfeeding stops?... In Greece, as in most places all over the world, fresh food (vegetables, fruits, cereals, fish etc) has a seasonal growth for around a year. So, waiting minimum for a year after beginning introducing solids in our baby s diet, seems a logical target to reach, in order to experiment new foods while still under the protection of mother s milk.

23 Science constantly evolves, dispute about everything and changing what for sometime seemed to be concrete knowledge! Maybe after all, the only solid advice is something Aristotle once said: «φύσι ουδέν ποιεί μάτην» Nature makes nothing in vain! And what nature has provide us is mother s milk Thank you very much for your attention

24 Special thanks to my colleagues and friends Stefanaki Evaggelia pedo-allergiologist and IBCLC Xepapadaki Paraskevi pedo-allergiologist Worth's reading: Brandtzaeg P. Food allergy: separating the science from the mythology. REVIEW Nat Rev Gastroenterol Hepatol 2010;7: V Verhasselt: Oral tolerance in neonates: from basics to potential prevention of allergic disease REVIEW Mucosal Immunology 2010; 3, Brian Symon, Michael Bammann: Feeding in the first year of life. Emerging benefits of introducing complementary solids from 4 months Australian Family Physician Vol. 41, No. 4, april 2012 N. Sansotta: Timing of introduction of solid food and risk of allergic disease development: Understanding the evidence REVIEW Allergol Immunopathol (Madr). 2013;41(5): Consensus Communication on Early Peanut Introduction and the Prevention of Peanut Allergy in High-risk Infants PEDIATRICS Volume 136, number 3, September 2015 Michael R. Perkin,: Randomized Trial of Introduction of Allergenic Foods in Breast-Fed Infants March 4, 2016, NEJM.org. Arnon Elizur; Yitzhak Katz: Timing of Allergen Exposure and the Development of Food Allergy. Treating Before the Horse Is Out of the BarnCurr Opin Allergy Clin Immunol. 2016;16(2): Valerie Verhasselt: Neonatal tolerance under breastfeeding influence Current Opinion in Immunology 2010, 22: George Du Toit: Randomized Trial of Peanut Consumption in Infants at Risk for Peanut Allergy N Engl J Med 2015;372: George Du Toit et al: Effect of Avoidance on Peanut Allergy after Early Peanut Consumption March 4, 2016, at NEJM.org. A. Muraro: EAACI Food Allergy and Anaphylaxis Guidelines. Primary prevention of food allergy. POSITION PAPER Allergy 2014; 69: Gary W.K. Wong: Preventing Food Allergy in Infancy Early Consumption or Avoidance? Editorial March 4, 2016, NEJM.org Valerie Verhasselt: Is infant immunization by breastfeeding possible? REVIEW 2015 Published by the Royal Society. Worth's reading: Medical Position Paper Complementary Feeding: A Commentary by the ESPGHAN Committee on NutritionJournal of Pediatric Gastroenterology and Nutrition 46: # 2008 Kate E.C. Grimshaw et al: Introduction of Complementary Foods and the Relationship to Food Allergy Pediatrics 2013;132:e1529 e1538 George Du Toit et al: Early consumption of peanuts in infancy is associated with a low prevalence of peanut allergy 2008 American Academy of Allergy, Asthma & Immunology Koplin J, Osborne N, Martin P, et al. Can early introduction of egg prevent egg allergy in infants? A population based study of an infant cohort. J Allergy Clin Immunol. 2010;126: Zutavern A, Brockow I, Schaaf B, et al. Timing of solid food introduction in relation to eczema, asthma, allergic rhinitis, and food and inhalant sensitization at the age of 6 years: results from the prospective birth cohort study LISA. Pediatrics. 2008;121(1). B. I. Nwaru, M. Erkkola, S. Ahonen et al., Age at the introduction of solid foods during the first year and allergic sensitization at age 5 years, Pediatrics, vol. 125, no. 1, pp , Bright I. Nwaru et al.: Age at the Introduction of Solid Foods During the First Year and Allergic Sensitization at Age 5 Years, Pediatrics 2010;125:50 59 Jessica C. Kiefte-de Jong, et al : Fish Consumption in Infancy and Asthma-like Symptoms at Preschool Age Pediatrics 2012;130: Emma Goks or, et al Early fish introduction and neonatal antibiotics affect the risk of asthma into school age Pediatr Allergy Immunol 2013: 24: Jessica Magnusson, et al : Fish consumption in infancy and development of allergic disease up to age 12 y Am J Clin Nutr 2013;97: Takeshi Yamamoto, et al: Oral Tolerance Induced by Transfer of Food Antigens via Breast Milk of Allergic Mothers Prevents Offspring from Developing Allergic Symptoms in a Mouse Food Allergy Model Clinical and Developmental Immunology Volume 2012, Article ID Robert S. Zeiger,: Food Allergen Avoidance in the Prevention of Food Allergy in Infants and Children PEDIATRICS Vol. 111 No. 6 June 2003 Frank R. Greer,: Effects of Early Nutritional Interventions on the Development of Atopic Disease in Infants and Children: The Role of Maternal Dietary Restriction, Breastfeeding, Timing of Introduction of Complementary Foods, and Hydrolyzed Formulas PEDIATRICS Volume 121, Number 1, January 2008 Stefano Luccioli Infant Feeding Practices and Reported Food Allergies at 6 Years of Age Pediatrics 2014;134:S21 S28 Zrinjka Misˇak: Symposium II: Infant and childhood nutrition and disease Infant nutrition and allergy, 70 th Anniversary Conference on Nutrition and health: from conception to adolescence Glasgow on 5 6 April 2011Proceedings of the Nutrition Society (2011), 70,