Pediatric Allergy Prevention and Management

Change in Direction During the Past Three Years Understanding of the importance of immunological sensitization and tolerance Understanding of the importance of immunological sensitization and tolerance Recognition that tolerance not sensitization is the critical step in allergy prevention Recognition that tolerance not sensitization is the critical step in allergy prevention Finding that exposure to the allergenic food at the optimum age is probably a critical step in allergy prevention Finding that exposure to the allergenic food at the optimum age 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 Recognition that tolerance can be induced after allergy has been established – leading to important measures for allergy management 2

Prevention of Food Allergy in Clinical Practice Significant change in directives within the past 3 years: Previously: Previously: Avoidance of allergen to prevent sensitization (allergen-specific IgE) Current: Current: Active stimulation of the immature immune system to induce tolerance of the antigens in food ________________ Rautava et al

Diet During Pregnancy Current directive: the atopic mother should strictly avoid her own allergens and replace the foods with nutritionally equivalent substitutes 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 There are no indications for mother to avoid other foods during pregnancy A nutritionally complete, well-balanced diet is essential 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 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

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 Exclusive breast-feeding with exclusion of mother’s and baby’s allergens will reduce signs of allergy in the first 1-2 years 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 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 Other benefits of breast-feeding far outweigh any possible negative effects on allergy: exclusive breast- feeding for 4-6 months is strongly encouraged 5

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 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 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 There is a lack of evidence that exclusive breast-feeding has any positive effect on the development of asthma in older children There is a lack of evidence that exclusive breast-feeding has any positive effect on the development of asthma in older children _____________ Greer et al 2008 ____________________ Sicherer and Burks

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 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 Extensively hydrolyzed formulas have a greater protective effect than partially hydrolyzed formulas Extensively hydrolyzed formulas have a greater protective effect than partially hydrolyzed formulas 7

Summary of 2008 AAP Guidelines continued There is no good evidence that soy-based infant formulas have any preventive effect on the development of allergy There is no good evidence that soy-based infant formulas have any preventive effect on the development of allergy There is little evidence that delaying the timing of the introduction of solid foods beyond 4-6 months of age prevents the occurrence of allergy There is little evidence that delaying the timing of the introduction of solid foods beyond 4-6 months of age prevents the occurrence of allergy _____________________ Thygaran and Burks

Infant Formulae for the Allergic Baby Current Recommendations Modest evidence that allergy may be delayed or prevented by the use of hydrolyzed formulas compared with formula of intact cow’s milk proteins Modest evidence that allergy may be delayed or prevented by the use of hydrolyzed formulas compared with formula of intact cow’s milk proteins Cow’s milk based formula if there are no signs of milk allergy 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 Partially hydrolysed (phf) whey-based formula if there are no signs of milk allergy Extensively hydrolysed (ehf) casein based formula if milk allergy is proven Extensively hydrolysed (ehf) casein based formula if milk allergy is proven _________________ Greer et al AAP 2008 Von Berg et al

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 Little evidence that delaying the introduction of complementary foods beyond 4-6 months of age prevents allergy Introduction of solid foods should be individualized Introduction of solid foods should be individualized Foods should be introduced one at a time in small amounts 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 Mixed foods containing various potential food allergens should not be given unless tolerance to each ingredient has been assessed __________________ Greer et al AAP ___________________________________ European Food Safety Authority EFSA 2009

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 CD 1 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 CD 1 Introduction of gluten while breast-feeding offers protection or delays onset of celiac disease in at-risk infants 2 Introduction of gluten while breast-feeding offers protection or delays onset of celiac disease in at-risk infants 2 Recommendations: Recommendations: Introduce gluten grains in small amounts between 4 and 6 months while infant is breastfed Introduce gluten grains in small amounts between 4 and 6 months while infant is breastfed Continue breast-feeding for a further 2-3 months Continue breast-feeding for a further 2-3 months _______________ 1 Norris et al 2005 _____________ 2 Guandalini

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

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

Introduction of Fish Historically, fish consumption during infancy was considered to be a risk factor for allergy Historically, fish consumption during infancy was considered to be a risk factor for allergy Recent research indicates otherwise: 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 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 pregnancy 2 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 pregnancy 2 _____________ 1 Kull et al 2006 _______________ 2 Calvani et al

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 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 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 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 Breast-feeding did not have any significant impact on development of eczema ____________ Alm et al

The Natural History of Food Allergy Food allergy most often begins in the first 1 to 2 years of life 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 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 Sensitization does not necessarily mean that the child will develop symptoms when that food is eaten Over time most food allergy is lost Over time most food allergy is lost _________ Wood

Development of Tolerance 25% of infants lost all food allergy symptoms after 1 year of age 25% of infants lost all food allergy symptoms after 1 year of age Most infants will outgrow milk allergy by 3 years of age, but may become intolerant to other foods Most infants will outgrow milk allergy by 3 years of age, but may become intolerant to other foods Tolerance of specific foods : Tolerance of specific foods : After 1 year: 26% decrease in allergy to: 26% decrease in allergy to: Milk Soy Peanut Milk Soy Peanut Egg Wheat Egg Wheat 2% decrease in allergy to other foods 2% decrease in allergy to other foods 17

Prognosis Age at which milk was tolerated by milk-allergic children: 28% by 2 years of age 28% by 2 years of age 56% by 4 years of age 56% by 4 years of age 78% by 6 years of age 78% by 6 years of age About 25% of food allergic children develop respiratory allergies About 25% of food allergic children develop respiratory allergies Allergy to some foods more often than others persists into adulthood: Allergy to some foods more often than others persists into adulthood: Peanut Tree nuts Seeds Peanut Tree nuts Seeds Shellfish Fish Shellfish Fish 18

19 University of Portsmouth UK Milk allergy outgrown: Milk allergy outgrown: ¾ by 3 years ¾ by 3 years Egg allergy outgrown: Egg allergy outgrown: ½ by 3 years ½ by 3 years Of 272 allergic babies, only 60 (22%) were allergic at age 3 years Of 272 allergic babies, only 60 (22%) were allergic at age 3 years In these the most common allergies were: In these the most common allergies were: Peanuts (11) Peanuts (11) Eggs (9) Eggs (9) Milk (4) Milk (4) Wheat, Brazil nut; Almond (2 each) Wheat, Brazil nut; Almond (2 each) Hazelnut, Cashew, Corn (1 each) Hazelnut, Cashew, Corn (1 each) None were allergic to tomato or fish at age 3 years None were allergic to tomato or fish at age 3 years _____________ Savage et al 2007

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” 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) Designated (SOTI: specific oral tolerance induction) Starting with very low dosages Starting with very low dosages Gradually increasing daily dosage up to the equivalent of the usual daily intake Gradually increasing daily dosage up to the equivalent of the usual daily intake Followed by daily maintenance dose Followed by daily maintenance dose __________________ Niggemann et al

Desensitization to Cow’s Milk 18 children with confirmed CMA >4 years of age underwent SOTI 18 children with confirmed CMA >4 years of age underwent SOTI Starting dose 0.05 ml cow’s milk Starting dose 0.05 ml cow’s milk Increased to 1 ml on first day Increased to 1 ml on first day Increasing dosage weekly up to a daily dose of ml Increasing dosage weekly up to a daily dose of ml Results: 16/18 tolerated ml milk Results: 16/18 tolerated ml milk Length of process median 14 weeks (range weeks) Length of process median 14 weeks (range weeks) Tolerance has been maintained for >1 year Tolerance has been maintained for >1 year _______________ Zapatero et al

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 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: 4 peanut-allergic children underwent SOTI: Daily doses of peanut flour starting at 5 mg peanut protein Daily doses of peanut flour starting at 5 mg peanut protein 2-weekly dosage increase up to 800 mg 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 challenge 2 All subjects tolerated at least 10 whole peanuts (2.38 g protein) on post-intervention challenge 2 ______________ 1 Staden et al 2007 ____________ 2 2 Clark et al

Progression of Peanut Allergy Peanut allergy, like many early food allergies, can be outgrown 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 allergy 1 In 2001 pediatric allergists in the U.S. reported that about 21.5 per cent of children will eventually outgrow their peanut allergy 1 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 allergy 2 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 allergy 2 Only about 9% of patients are reported to outgrow their allergy to tree nuts 3 Only about 9% of patients are reported to outgrow their allergy to tree nuts 3 __________________ 1 Skolnick et al Fleischer et al Fleischer et al

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 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 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

Take Home Message Allergy prevention emphasizes inducing tolerance rather than avoiding sensitization Allergy prevention emphasizes inducing tolerance rather than avoiding sensitization Beginning of tolerance to foods may occur in utero or during breast-feeding 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 Restriction of maternal diet to avoid highly allergenic foods during pregnancy or lactation is contraindicated Unless either mother or baby is allergic to them Unless either mother or baby is allergic to them 25

Take Home Message Exclusive breast-feeding should continue to 4-6 months of age Exclusive breast-feeding should continue to 4-6 months of age Complementary foods (solids) should be introduced no later than 6 months of age Complementary foods (solids) should be introduced no later than 6 months of age Gluten-containing foods should be introduced not later than 6 months of age while breast- feeding continues Gluten-containing foods should be introduced not later than 6 months of age while breast- feeding continues

Take Home Message Management of established food allergy includes : Management of established food allergy includes : Accurate identification of the allergenic food(s) Accurate identification of the allergenic food(s) Careful avoidance of the food allergens – especially if there is any risk of anaphylaxis Careful avoidance of the food allergens – especially if there is any risk of anaphylaxis Avoidance of unnecessary food restrictions Avoidance of unnecessary food restrictions 27

Take Home Message Provision of complete balanced nutrition by substituting foods of equal nutritional value 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 Monitoring the child’s response at intervals to determine when the food allergy has been outgrown Maintenance of tolerance by feeding tolerated foods regularly Maintenance of tolerance by feeding tolerated foods regularly 28

29 Invitation to Further Information Joneja, J.M.Vickerstaff Dealing with Food Allergies in Babies and Children Bull Publishing Company, Boulder, Colorado. October 2007