Infant Food Allergies Where Are We Now? Janice Joneja Ph.D., RD J.M.Joneja PhD, RD 2010

Food Allergy in the Past 7 Years Nearly 4% of North Americans have food allergies, many more than recorded in the past Incidence of food allergy much higher in children (>8%) than adults (<2%) Prevalence of peanut allergy doubled in American children younger than 5 years of age in the years 2002 - 2007 J.M.Joneja PhD, RD 2010

Food Allergy in the Past 7 Years Prevalence of food allergy highest in infants and toddlers Cow’s milk allergy incidence: 2.5% of infants Up to 8% of children under 3 years have allergy to a limited number of foods: Cow’s milk  Wheat Egg  Shellfish Soy  Fish Peanut  Tree nuts For every child who actually had a food allergy, over three more children were believed wrongly by their parents to suffer from the condition ______________ Venter et al 2008 J.M.Joneja PhD, RD 2010

Age Relationship Between Food Allergy and Atopy Effect of Food Allergens Effect of Air-borne Allergens Asthma Rhinitis Eczema Food Allergy Anaphylaxis Relative Incidence 1 2 2 3 3 4 5 6 7 8 9 10 11 12 13 14 15 16 Age (in years) J.M.Joneja PhD, RD 2010

Historical Perspective Sensitization to food allergens was thought to be the start of the “allergic march” Food allergy Atopic dermatitis/eczema Asthma Rhinitis Reducing sensitization to foods was therefore considered the essential first step in allergy prevention J.M.Joneja PhD, RD 2010

Historical Perspective Measures of prevention were all designed to avoid sensitization to allergens during what were considered the most vulnerable periods: Intra-uterine life From birth to 2-3 years This meant reduction in exposure to highly allergenic foods: Mother’s diet during pregnancy and lactation Delay in introduction of highly allergenic foods during weaning In spite of these stringent measures to prevent allergy, incidence of all types of allergies have increased significantly J.M.Joneja PhD, RD 2010

Change in Direction During the Past Five Years Understanding of the importance of immunological sensitization and tolerance Recognition that tolerance not sensitization is the critical step in allergy prevention Finding that exposure to the allergenic food at an optimum stage is probably a critical step in allergy prevention Recognition that tolerance can be induced after allergy has been established – leading to important measures for allergy management J.M.Joneja PhD, RD 2010

Allergy is a Response of the Immune System Our immune systems are designed to protect the body from invasion by foreign materials All foods contain proteins – derived from plants and animals – all of which are foreign to the human body In order for food to be absorbed, metabolized, and utilized by the body, the immune system needs to be “educated” that the foreign material is safe ________ Herz 2008 J.M.Joneja PhD, RD 2010

Education of the Immune System Involves a complex series of immunological reactions controlled by T cell lymphocytes (T cells) T helper (Th) cells detect foreign proteins (antigens) in any form T cells then trigger a series of immunological reactions, mediated by cytokines (the “control chemicals” of the immune system) _________ Joneja 2007 J.M.Joneja PhD, RD 2010

T-helper Cell Subclasses There are two subclasses of T-helper cells Th1 Th2 Each Th cell type produces its own specific set of cytokines The types of cytokines generated determine the resulting immune response Th1 principally INF- Th2 principally IL-4 J.M.Joneja PhD, RD 2010

Role of T-helper Cell Subtypes Th1 triggers the protective response to a pathogen such as a virus or bacterium IgM, IgG, IgA antibodies are produced Th2 is responsible for the allergic (hypersensitivity) reaction IgE antibodies are produced J.M.Joneja PhD, RD 2010

T cells involved in Oral Tolerance T cell response depends on the type of T helper cell that is activated Latest research indicates that T cells that produce a cytokine called TGF- are important in inducing oral tolerance Sometimes called Th3 cells T cells that produce IL-10 and IL-13 may also be involved in tolerance These also regulate immune response to resident microflora, preventing the usual immune inflammatory response to microorganisms ___________________ Strobel and Mowat 2006 J.M.Joneja PhD, RD 2010

Oral Tolerance “Education” of the T cells to not respond to that food protein when it enters via the oral route – called oral tolerance Contrasts with the active immune responses needed to protect the gut against continual bombardment by invading pathogens and their products (toxins, etc) Also contrasts with the reduced responsiveness to the millions of microorganisms that are permanent residents of the large bowel T cells involved in these processes are called regulator T cells (Treg) J.M.Joneja PhD, RD 2010

Prevention of Food Allergy in Clinical Practice Significant change in directives within the past 5 years: Previously: Avoidance of allergen to prevent sensitization (allergen-specific IgE) Current: Active stimulation of the immature immune system to induce tolerance of the antigens in food ________________ Rautava et al 2005 J.M.Joneja PhD, RD 2010

Factors Predictive of Allergy: High and Low risk Groups Many factors investigated as possible predictive markers for allergy Only significant variable in studies: Family history of allergy (all types) High risk for allergy: One first degree relative with diagnosed allergy (IgE-mediated) of any type First-degree relative: parent or sibling J.M.Joneja PhD, RD 2010

Does Atopic Disease Start in Fetal Life? Fetal cytokines are skewed to the Th2 type of response Suggested that this may guard against rejection of the “foreign” fetus by the mother’s immune system IgE occurs from as early as 11 weeks gestation and can be detected in cord blood _____________ Jones et al 2000 J.M.Joneja PhD, RD 2010

Does Atopic Disease Start in Fetal Life? (continued) At birth neonates have low INF- and tend to produce the cytokines associated with Th2 response, especially IL-4 So why do all neonates not have allergy? J.M.Joneja PhD, RD 2010

Does Atopic Disease Start in Fetal Life? (continued) New research indicates that the immune system of the mother may play a very important role in expression of allergy in the neonate and infant IgG crosses the placenta; IgE does not Certain sub-types of IgG (IgG1; IgG3) can inhibit IgE response J.M.Joneja PhD, RD 2010

Significance in Practice Food proteins demonstrated to cross the placenta and can be detected in amniotic fluid Exposure to small quantities of food antigens from mother’s diet thought to tolerize the fetus, by means of IgG1 and IgG3, within a “protected environment” J.M.Joneja PhD, RD 2010

Immune Response of the Allergic Mother Atopic mother’s immune system may dictate the response of the fetus to antigens in utero The allergic mother may be incapable of providing sufficient IgG1 and IgG3 to downregulate (depress) fetal IgE There is no convincing evidence that sensitization to specific food allergens is initiated prenatally J.M.Joneja PhD, RD 2010

Diet During Pregnancy Current directive: the atopic mother should strictly avoid her own allergens and replace the foods with nutritionally equivalent substitutes There are no indications for mother to avoid other foods during pregnancy A nutritionally complete, well-balanced diet is essential Authorities recommend avoidance of excessive intake of highly allergenic foods such as peanuts and nuts to prevent “allergen overload”, but there is no scientific data to support this _______________ Kramer et al 2006 J.M.Joneja PhD, RD 2010

Breast-feeding and Allergy Studies indicating that breast-feeding is protective against allergy report: A definite improvement in infant eczema and associated gastrointestinal complaints when baby is exclusively breast-fed Reduced risk of asthma in the first 24 months of life __________________ Kirjavainen et al 2002 J.M.Joneja PhD, RD 2010

Breast-feeding and Allergy Other studies are in conflict with these conclusions: Some report no improvement in symptoms Some suggest symptoms get worse with breast-feeding and improve with feeding of hydrolysate formulae Japanese study suggests that breast-feeding increases the risk of asthma at adolescence Why the conflicting results? _______________ Miyake et al 2003 J.M.Joneja PhD, RD 2010

Immunological Factors in Human Milk that may be Associated with Allergy: Cytokines and Chemokines Atopic mothers tend to have a higher level of the cytokines and chemokines associated with allergy in their breast milk Those identified include: IL-4 IL-5 IL-8 IL-13 Some chemokines (e.g. RANTES) Atopic infants do not seem to be protected from allergy by the breast milk of atopic mothers ___________________________ Snijders et al 2007 KOALA study J.M.Joneja PhD, RD 2010

Immunological Factors in Human Milk that may be Associated with Allergy: TGF-1 Cytokine, transforming growth factor-1 (TGF-1) promotes tolerance to food components in the intestinal immune response TGF-1 in mother’s colostrum may influence the type and intensity of the infant’s response to food allergens A normal level of TGF-1 is likely to facilitate tolerance to food encountered by the infant in mother’s breast milk and later to formulae and solids ______________ Rigotti et al 2006 J.M.Joneja PhD, RD 2010

Implications of Research Data Exclusive breast-feeding with exclusion of mother’s and baby’s allergens will reduce signs of allergy in the first 1-2 years; specifically: Cow’s milk allergy Eczema Reduction or prevention of early food allergy by breast-feeding does not seem to have long-term effects on the development of asthma and allergic rhinitis Other benefits of breast-feeding far outweigh any possible negative effects on allergy: exclusive breast-feeding for 4-6 months is strongly encouraged J.M.Joneja PhD, RD 2010

Summary of 2008 AAP Guidelines for Allergy Management [Greer et al 2008] There is no convincing evidence that women who avoid highly allergenic foods, or other foods during pregnancy and breast-feeding lower their child’s risk of allergies For high-risk for allergy infants (one first-degree relative with established allergy), exclusive breast-feeding for at least 4 months prevents or delays the occurrence of atopic dermatitis (eczema), cow’s milk allergy, and wheezing in early childhood _____________ Greer et al 2008 ____________________ Sicherer and Burks 2008 J.M.Joneja PhD, RD 2010

Preventive Effect of Breast-feeding: KOALA Study Longer duration of breastfeeding is associated with lower risk for eczema in non-atopic mothers Slightly lower risk for mothers with allergy but no asthma Longer duration of breastfeeding reduced risk for wheezing in infants: possibly due to reduction in respiratory infections There is a lack of evidence that exclusive or prolonged breast-feeding has any positive effect on the development of asthma in older children ___________________________ Snijders et al 2007 KOALA study J.M.Joneja PhD, RD 2010

Summary of 2008 AAP Guidelines continued In infants at high risk for allergy who are not exclusively breast-fed for 4-6 months there is modest evidence that the onset of atopic disease (allergy), especially eczema, may be delayed or prevented by the use of hydrolyzed formulas There is no good evidence that soy-based infant formulas have any preventive effect on the development of allergy J.M.Joneja PhD, RD 2010

Preventive Effect of Hydrolyzed Infant Formulae No evidence of any reduction in allergy with hydrolyzed formula compared to breastfeeding Limited evidence that prolonged feeding with hydrolyzed formula compared to cow’s milk reduces incidence of CMA and eczema No evidence that hydrolyzed formulas have any effect on the development of rhinitis and asthma later Extensively hydrolyzed cow’s milk (Ehf) formulas marginally better than partially hydrolyzed whey (Phf) in prevention _________________________________ Osborn and Sinn 2009 Cochrane Review __________________________ Von Berg et al GINI Study 2009 J.M.Joneja PhD, RD 2010

Infant Formulae for the Allergic Baby Current Recommendations Cow’s milk based formula if there are no signs of milk allergy Partially hydrolysed (phf) whey-based formula if there are no signs of milk allergy in high risk for allergy group Extensively hydrolysed (ehf) casein based formula if milk allergy is proven _________________ Greer et al AAP 2008 Von Berg et al 2007 J.M.Joneja PhD, RD 2010

Recommendations for Introduction of Solids to High Risk for Allergy Infants Little evidence that delaying the introduction of complementary foods beyond 4-6 months of age prevents allergy Introduction of solid foods should be individualized Foods should be introduced one at a time in small amounts Mixed foods containing various potential food allergens should not be given unless tolerance to each ingredient has been assessed _____________________ Thygaran and Burks 2008 ____________________ Greer et al AAP 2008 J.M.Joneja PhD, RD 2010

Introduction of Solid Foods in Relationship to Celiac Disease Results suggest that in high risk for celiac disease infants introduction of gluten-containing grains before 3 months or after 7 months increases incidences of development of CD1 Introduction of gluten while breast-feeding offers protection or delays onset of celiac disease in at-risk infants2 Recommendations: Introduce gluten grains in small amounts between 4 and 6 months while infant is breastfed Continue breast-feeding for a further 2-3 months Similar results for wheat allergy3 _______________ 1Norris et al 2005 ______________ 2Guandalini 2007 ____________ 3Poole et al 2006 J.M.Joneja PhD, RD 2010

Introduction of Peanuts Directives from pediatric societies (1998 - 2007) recommended avoidance of peanuts by mothers during pregnancy and lactation, and delaying introduction of peanuts until after 2 or even 3 years of age Research indicates that incidence of peanut allergy in children rose dramatically in the years following release of these directives Recent research suggests: Avoidance of peanuts reduced development of tolerance Early exposure leads to reduced incidence of peanut allergy _________________ Hourihane et al 2007 J.M.Joneja PhD, RD 2010

Introduction of Peanuts Study (n=10,786) among primary school age Jewish children in UK and Israel Prevalence of peanut allergy (PA): In UK: 1.85% In Israel: 0.17% Median monthly consumption of peanut in infants aged 8 – 14 months: In UK: 0 In Israel: 7.1 g Difference not due to atopy, genetic background, social class, or peanut allergenicity Israeli infants consume peanuts in high quantities during the first year of life ______________ Du Toit et al 2008 J.M.Joneja PhD, RD 2010

Introduction of Fish Historically, fish consumption during infancy was considered to be a risk factor for allergy Recent research indicates otherwise: Regular fish consumption during the first year of life associated with a reduced risk for allergic disease by age 4 years (n=4089)1 Babies of mothers who frequently consumed fish (2-3 times per week or more) during pregnancy had one third less food sensitivities than those whose mothers did not consume fish during pregnancy2 _____________ 1Kull et al 2006 _______________ 2Calvani et al 2006 J.M.Joneja PhD, RD 2010

Introduction of Fish Study (n= 5,000); 20.9% developed eczema by 1 year: Babies who were fed fish before nine months of age were 24% less likely to develop eczema by age 1 year Omega-3 content of fish did not seem to influence the outcome The age at which egg and milk were introduced did not affect development of eczema Breast-feeding did not have any significant impact on development of eczema ____________ Alm et al 2009 ____________________________ Hibbeln et al 2007 ALSPAC study J.M.Joneja PhD, RD 2010

The Natural History of Food Allergy Food allergy most often begins in the first 1 to 2 years of life Child is sensitized to the food protein by the immune system developing allergen-specific IgE to that protein Sensitization does not necessarily mean that the child will develop symptoms when that food is eaten Over time most food allergy is lost _________ Wood 2003 J.M.Joneja PhD, RD 2010

Prognosis Most children outgrow early food allergy John’s Hopkins Children’s Center USA Milk allergy outgrown: 20% by 4 years 42% by 8 years 79% by 16 years Egg allergy outgrown: 4% by 4 years 37% by 10 years 68% by 16 years Allergy to some foods more often than others persists into adulthood: Peanut  Tree nuts  Seeds Shellfish  Fish ______________ Skripak et al 2007 J.M.Joneja PhD, RD 2010

Induction of Oral Tolerance Tolerance to a specific food can be induced by oral administration of the offending food by process of “low dose continuous exposure” Designated (SOTI: specific oral tolerance induction) Starting with very low dosages Gradually increasing daily dosage up to the equivalent of the usual daily intake Followed by daily maintenance dose __________________ Niggemann et al 2006 _____________ Calvani et al 2010 40 J.M.Joneja PhD, RD 2010 40

Desensitization to Cow’s Milk 18 children with confirmed CMA >4 years of age underwent SOTI Starting dose 0.05 ml cow’s milk Increased to 1 ml on first day Increasing dosage weekly up to a daily dose of 200-250 ml Results: 16/18 tolerated 200-250 ml milk Length of process median 14 weeks (range 11-17 weeks) Tolerance has been maintained for >1 year _______________ Zapatero et al 2008 41 J.M.Joneja PhD, RD 2010 41

Oral Tolerance Induction to Milk, Egg, and Peanut 36% of children with IgE-mediated allergy to cow’s milk and hen’s egg developed permanent tolerance of the foods after a median 21 months specific oral tolerance induction (SOTI)1 4 peanut-allergic children underwent SOTI: Daily doses of peanut flour starting at 5 mg peanut protein 2-weekly dosage increase up to 800 mg protein All subjects tolerated at least 10 whole peanuts (2.38 g protein) on post-intervention challenge2 ______________ 1Staden et al 2007 ______________ 2Clark et al 2009 42 J.M.Joneja PhD, RD 2010 42

Progression of Peanut Allergy Peanut allergy, like many early food allergies, can be outgrown In 2001 pediatric allergists in the U.S. reported that about 21.5 per cent of children will eventually outgrow their peanut allergy1 Those with a mild peanut allergy, as determined by the level of peanut-specific IgE in their blood, have a 50% chance of outgrowing the allergy2 Only about 9% of patients are reported to outgrow their allergy to tree nuts3 __________________ 1Skolnick et al 2001 2Fleischer et al 2003 3Fleischer et al 2005 43 J.M.Joneja PhD, RD 2010 43

Maintaining Tolerance of Peanut When there is no longer any evidence of symptoms developing after a child has consumed peanuts, it is preferable for that child to eat peanuts regularly, rather than avoid them, in order to maintain tolerance to the peanut Children who outgrow peanut allergy are at risk for recurrence, but the risk has been shown to be significantly higher for those who continue to avoid peanuts after resolution of their symptoms _________________ Fleischer et al 2004 44 J.M.Joneja PhD, RD 2010 44

Probiotics and Allergy Prevention Probiotics and prebiotics may change the colonic microflora of the neonate Theory: Change from Th2 to Th1 response in the neonatal period is required to reduce potential for allergy This change is mediated by contact with micro-organisms Non-allergic children have a predominance of lactobacilli and bifidobacteria Atopic children tend to have more clostridia and lower levels of bifidobacteria Probiotics could be used to change the “atopic” to a more “non-atopic flora” ____________ Ozdemir 2010 J.M.Joneja PhD, RD 2010

Studies on Probiotics in Allergy Prevention Some studies indicate a positive outcome in reducing the incidence of allergy: Lactobacillus F19 in cereals fed to infants from 4 to 13 months of age reduced the incidence of eczema1 Other studies showed no effect: Bifidobacterium + Lactobacillus rhamnosus daily for the first 6 months in at risk infants had no effect compared to placebo2 ____________________ 1 West et al 2009 ___________________ 2 Soh et al 2009 J.M.Joneja PhD, RD 2010

Current Status of Probiotics in Allergy Prevention Beneficial effects of probiotic therapy depends on: Type of bacteria selected Dosage of the bacteria delivered to the digestive tract Method of delivery of the bacteria to the GI tract (in formulae; in cereals) Age of the individual Length of duration of delivery Conclusion at the current state of research: Probiotics cannot be recommended generally for primary prevention of atopic disease _____________ Ozdemir 2010a J.M.Joneja PhD, RD 2010

Take Home Message Allergy prevention emphasizes inducing tolerance rather than avoiding sensitization Beginning of tolerance to foods may occur in utero or during breast-feeding Restriction of maternal diet to avoid highly allergenic foods during pregnancy or lactation is contraindicated Unless either mother or baby is allergic to them J.M.Joneja PhD, RD 2010

Take Home Message Management of established food allergy includes: Accurate identification of the allergenic food(s) Careful avoidance of the food allergens – especially if there is any risk of anaphylaxis Avoidance of unnecessary food restrictions J.M.Joneja PhD, RD 2010

Take Home Message Provision of complete balanced nutrition by substituting foods of equal nutritional value Monitoring the child’s response at intervals to determine when the food allergy has been outgrown Maintenance of tolerance by feeding tolerated foods regularly J.M.Joneja PhD, RD 2010

Invitation to Further Information www.allergynutrition.com Joneja, J.M.Vickerstaff Dealing with Food Allergies in Babies and Children Bull Publishing Company, Boulder, Colorado. October 2007 J.M.Joneja PhD, RD 2010