Prevention of Allergy Janice M. Joneja, Ph.D., RD 2006

Approach to Infant Allergy Prediction Identification of the atopic baby before initial allergen exposure may allow prevention of allergy Prevention Measures to prevent initial allergic sensitization of potentially atopic infant Identification Methods for identification of an established food allergy Management Strategies for avoiding the allergenic food and providing complete balanced nutrition from alternative sources to ensure optimum growth and development J.M.Joneja 2006

Prevention of Food Allergy in Clinical Practice Requirement: Practice guidelines for: Prevention of sensitization to food allergens Prevention of expression of allergy Consensus for practice guidelines using evidence-based research Current status: Lack of consensus

Possible Confounding Variables in Studies and Subjects Variability in genetic predisposition of infant to allergy Mother’s allergic history Role of in utero environment Exposure to allergens Exclusivity of breast-feeding Inclusion of infant’s allergens in mother’s diet Dietary exposure not recognized in infant or mother Exposure to inhalant and contact allergens

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 2006

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?

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

Does Atopic Disease Start in Fetal Life? (continued) IgG1 and IgG3 are the more “protective” subtypes of IgG IgG1 and IgG3 tend to be lower than normal in allergic mothers In allergic mothers, IgE and IgG4 are abundant In mothers with allergy and asthma, IgE is high at the fetal/maternal interface Fetus of allergic mother may thus be primed to respond to antigen with IgE production

Significance in Practice Food proteins demonstrated to cross the placenta and can be detected in amniotic fluid Allergen-specific T cells in fetal blood demonstrated to: Ovalbumin Alpha-lactalbumin Beta-lactoglobulin 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”

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 fetal IgE However – there is no convincing evidence that sensitization to specific food allergens is initiated prenatally

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

Pregnancy Diet and Fish Intake 2006 study Frequent maternal intake (2–3 times/wk or more) of fish reduced the risk of food sensitizations by over a third A similar trend (not significant) was found for inhalant allergies In the whole study population, i.e. allergic group plus non-allergic group: correlation between increased consumption of fish and decreased prevalence of SPT positivity for foods Reduced incidence of allergic sensitization thought to be due to the omega-3 content of fish _______________ Calvani et al 2006

The Neonate: Conditions That Predispose to Th2 Response Inherited allergic potential (maternal and paternal) Intrauterine environment Immaturity of the infant’s immune system Major elements of the immune system are in place, but do not function at a level to provide adequate protection against infection The level of immunoglobulins (except maternal IgG) is a fraction of that of the adult Secretory IgA (sIgA) absent at birth: provided by maternal colostrum and breast milk throughout lactation J.M.Joneja 2006

The Neonate: Conditions That Predispose to Th2 Response Increased uptake of antigens: Hyperpermeablilty of the immature digestive mucosa Immaturity of the gut-associated lymphoid tissue (GALT) means reduced effectiveness of antigen processing at the luminal interface Inflammatory conditions in the infant gut (infection or allergy) that interfere with the normal antigen processing pathway

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 Mother eliminates highly allergenic foods from her diet Reduced risk of asthma in the first 24 months of life

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

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

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

TGF-1 in mothers of infants who developed IgE-mediated CMA Immunological Factors in Human Milk that may be Associated with Allergy: TGF-1 (continued) TGF-1 in mothers of infants who developed IgE-mediated CMA (+challenge; + SPT) lower than in: Mothers of infants with non-IgE CMA (+ challenge; - SPT) Mothers of infants without CMA (- challenge; - SPT) __________________ Saarinen et al 1999

Implications of Research Data Exclusive breast-feeding with exclusion of infant’s known allergens will protect the child against allergy if it is inherited from the father 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 Other benefits of breast-feeding far outweigh any possible negative effects on allergy: exclusive breast-feeding for 4-6 months is strongly encouraged

Current Recommendations for Practice Preventive Measures Mother is atopic: Mother eliminates all sources of her own allergens prior to and during pregnancy to reduce IgE and IgG4 in the uterine environment Continues to avoid her own allergens during lactation Exclusive breast-feeding without exposure of infant to external sources of food allergens for 6 months

Current Recommendations for Practice (continued) Father and or siblings atopic; mother is non-atopic: No recommendations for mother to restrict her diet during pregnancy No recommendations for mother to restrict her diet during lactation unless the baby shows signs of allergy Exclusive breast-feeding for 4-6 months

Current Recommendations for Practice (continued) Some studies suggest that maternal avoidance of the most highly allergenic foods during lactation may reduce sensitization of infant with family history of allergy Foods to be avoided: Peanuts - Shellfish - Eggs Tree nuts - Fish - Milk Benefits of this remain to be proven; the strategy is recommended by some authorities Hypoallergenic infant formulae if breast-feeding not possible

Current Recommendations for Practice (continued) No family history of allergy: Good nutrition practices for mother from preconception onwards Good nutrition practices for early infant feeding Breast-feeding is the best possible source of nutrition and protection Allergen avoidance is unnecessary unless the infant demonstrates signs of allergy

Current Recommendations for Practice (continued) If infant demonstrates overt signs of allergy (eczema; gastrointestinal complaints; rhinitis; wheeze) Identify specific food trigger by elimination and challenge Exclusive breast-feeding with mother excluding her own and baby’s food allergens If breast-feeding is not possible, extensively hydrolyzed casein formula Careful monitoring of mother’s diet during lactation for nutritional adequacy, especially of vitamins and trace elements

Foods Most Frequently Causing Allergy in Babies and Children 6. Fin fish 7. Wheat 8. Soy 9. Beef 10. Chicken 11. Citrus fruits 12. Tomato 1. Egg white yolk 2. Cow’s milk 3. Peanut 4. Nuts 5. Shellfish J.M.Joneja 2006

Suggested Sources of Sensitizing Food Allergens Present thinking is that sensitization occurs predominantly from external sources The antigens in mother’s milk then elicit symptoms in the previously sensitized infant Exposure to food antigens in breast milk normally tolerizes infant to foods However, recent research suggests that sensitization via breast milk may occur in the atopic mother and baby pair: this remains to be proven

Suggested Sources of Sensitizing Allergens (continued) Food sources of allergens Via placenta prenatally (unproven) Mother’s diet via breast milk during lactation Infant formulae, especially in the new-born nursery before first feeding of colostrum Solid foods Covertly by caretakers Accidentally

Introduction of Solid Foods Disagreement among authorities about: At what age to introduce solids Which solids to introduce Which foods should be delayed until later age

Introduction of Solid Foods Results of studies are confounded by: Genetic factors may influence development of tolerance or sensitization Th1 or Th2 response may be influenced by environmental exposure Some initial evidence that “window of opportunity” in maturation of systems may play a role

Supplemental formula feeding no earlier than 6 months Recommendations for Introduction of Solids to High Risk for Allergy Infants Most recent US consensus document recommends for infant at risk for allergy: Optimal age for introduction of solids is six months Dairy products introduced at 12 months Eggs at 24 months Peanut, tree nuts, fish, seafood delayed until at least 36 months Supplemental formula feeding no earlier than 6 months __________________ Fiocchi et al July 2006

Recommendations for Introduction of Solids to High Risk for Allergy Infants 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

Recent Evidence for Early Introduction of Solids? “Delaying initial exposure to cereal grains until after 6 months may increase the risk of wheat allergy”1 Based on questionnaires and parental report of wheat allergy Excluded children with celiac disease 16 children reported to have wheat allergy by parents Four had wheat-specific IgE These four were reported to have been first exposed to wheat grains after 6 months of age Previous studies: “The possibility of cereal allergy after the introduction of cereal formula during the lactation period should not be underestimated”2 ________________ 2Armentia et al 2002 _________________ 1Poole et al June 2006

Introduction of Solid Foods in Relationship to Diabetes and Celiac Disease DAISY1 and BABYDIAB2 studies suggest that the age at which an at-risk for diabetes infant is fed cereal is important in determining his or her risk of type 1 diabetes mellitus (DM) Autoantibody directed against pancreatic islet cells used for detecting DM, not onset of the disease Both studies indicate that early introduction of gluten-containing cereals is a risk factor in DM DAISY shows similar risk from early introduction of rice-based (non-gluten) cereals ______________ ______________ 2Zeigler et al 2003 1Norris et al 2003

Introduction of Solid Foods in Relationship to Diabetes and Celiac Disease Previous studies had implicated early introduction of cow’s milk as a precipitating factor BABYDIAB actually suggested early exposure to cow’s milk may be protective DAISY results suggest that high risk for celiac disease occurs if gluten-containing grains are introduced before 3 months or after 7 months Final conclusions: “Current infant feeding practices should not be changed” _______________ Norris et al 2005

Measures to Reduce Food Allergy in Infants with Symptoms of Allergy or at High Risk Because of Genetic Background 1. Exclusive breast-feeding for the first 6 months 2. Total maternal avoidance of: any food inducing allergy symptoms in the infant any food inducing allergy symptoms in mother Eggs Cow’s milk and milk products Peanuts Nuts Shellfish As a preventive measure initially if not avoided in above categories {clinicians disagree about this} _________________ Zeiger S. 2003 Muraro et al 2004 J.M.Joneja 2006

Measures to Reduce Food Allergy in Infants (continued) 3. Colostrum as soon after birth as possible: provides sIgA which is absent in newborn 4. Avoid infant formulae in the newborn nursery: NO exposure to formulae in the hospital Avoid small supplemental feedings of infant formulae at widely spaced intervals If formula is unavoidable introduce in incremental doses over a 3-4 week period J.M.Joneja 2006

Measures to Reduce Food Allergy in Infants (continued) 7. Introduce solid foods after 6 months starting with the least allergenic. Use incremental dose introduction to promote oral tolerance 8. Delay the most allergenic foods until after 12 months: Cow’s milk  Eggs Shellfish  Fish Delay peanuts and nuts until after 2-3 years 10. Other foods are not specified, but it may be beneficial to delay introducing the following foods if the child shows signs of allergy: Citrus Fruits  Tomatoes Beef  Chicken Soy  Wheat

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 Extensively hydrolysed (ehf) casein based formula if milk allergy is proven

Development of Tolerance 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 have become intolerant to other foods in the meantime Tolerance of specific foods : After 1 year: 26% decrease in allergy to: Milk  Soy  Peanut Egg  Wheat 2% decrease in allergy to other foods ________________ Bishop et al 1990 J.M.Joneja 2006

Prognosis Age at which milk was tolerated by milk-allergic children: 28% by 2 years of age 56% by 4 years of age 78% by 6 years of age About 25% of allergic children develop respiratory allergies Allergy to some foods more often than others persists into adulthood: Peanut  Tree nuts Shellfish  Fish J.M.Joneja 2006

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

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

Probiotics Microorganisms in the Bowel The healthy large bowel sustains a resident microbiota of bacteria, fungi, and other harmless microorganisms Beneficial effects include: Synthesis of vitamins: Vitamin K Biotin Thiamin Folic acid Vitamin B12 Interaction with immune cells to maintain a healthy epithelium Positive competition with invading pathogens to resist disease J.M.Joneja 2006

Resident Microbiota An individual’s bowel microflora is established after weaning Remains stable throughout life unless events intervene Individuals in the same household, eating the same diet, may have a vastly different bowel microflora After oral antibiotics several microbial species will be killed, but after about 6 months the previous strains become re-established and microflora returns to its pre-antibiotic state Probiotics may alter the gut microenvironment by changing the types of microorganisms present and the cytokines produced by the local immune cells

Bowel Microflora and Allergy The type of gut colonization during the first weeks of life may predispose an individual to atopic disease Microflora of the bowel of a breastfed infant is different from that of a formula-fed baby The gut microflora influences: Resistance to infection Immunological environment for subsequent challenges, including food allergens May influence predominance of Th1 or Th2 response _________________ Kirjavainen et al 1999

Probiotic Living micro-organisms within a food that is designed to provide health benefits beyond the food’s inherent nutritional value The types of micro-organisms used have certain characteristics to be of any value: Must be capable of living within the human bowel without causing any harm to the host Produce metabolites to improve the health of the body Have a beneficial interaction with the local immune cells ______________ Thompson 2001

Probiotic Characteristics Probiotic micro-organisms alter the gut microflora by competitively interacting with the existing flora by: Production of antimicrobial metabolites Modulating the local immune response to the indigenous micro-organisms _____________ Shanahan 2000

Forms of Probiotic Agents Examples of food supplements containing live culture: Yogurts Fermented milks Fortified fruit juice Powders Capsules Tablets Sprays

Prebiotics Non-digestible food ingredients that selectively stimulate a limited number of bacteria, to improve health Examples: Fructo-oligosaccharides (FOS) Lactulose Galacto-oligosaccharides (GOS) Provided in: Beverages and fermented milks Health drinks and spreads Cereals, confectionery, cakes Food supplements

Synbiotics Combine prebiotics and probiotics Prebiotic substrate should enhance survival of probiotic bacteria Example: Bifidobacteria + fructo-oligosaccharide (FOS) In order to establish the new species, need to continue to provide live culture, and appropriate substrate

Probiotics and Lactose Intolerance Lactobacilli, bifidobacteria and Streptococcus thermophilus, assist in reducing the symptoms of lactose intolerance Produce the enzyme beta-galactosidase (lactase) in yogurt Microbial lactase breaks down lactose The fermented milk itself delays gastrointestinal transit, thus allowing a longer period of time in which both the human and microbial lactase enzyme can act on the milk lactose.

Microflora and Lactose Intolerance Lactose tolerance in people who are deficient in lactase may be improved by continued ingestion of small quantities of milk Does not improve or affect the production of lactase in the brush border cells of the small intestine Continued presence of lactose in the colon contributes to the establishment and multiplication of bacteria capable of synthesizing the beta-galactosidase enzyme over time Resident micro-organisms will break down the undigested lactose in the colon Reduces the osmotic imbalance within the colon that is the cause of much of the distress of lactose intolerance _________________ de Vrese et al 2001

Clinical Trials of Probiotics Not all probiotics have been tested in clinical studies with regard to allergy prevention or treatment L. bulgaricus seemed to have no effect on immune parameters, whereas it was associated with lower frequency of allergies L. acidophilus consumption accelerated recovery from food allergy symptoms These effects have also been observed in infants with eczema and cow's milk allergy using infant formulas supplemented with L. rhamnosus.

Trials on Probiotics and Eczema Prevention Pregnant women took capsules containing Lactobacillus rhamnosus GG (LGG) during the last two to four weeks of pregnancy The newborn infants were given the same microorganism from birth to six months Breast-feeding mothers continued to take the capsules during lactation The babies were given the bacteria mixed with water by spoon Subjects taking the probiotic had a reduced risk of developing atopic dermatitis (eczema) compared to controls up to 4 years of age Other studies found no reduced incidence of eczema in babies treated with probiotics _________________ Kalliomaki et al 2003

Prebiotics and Eczema A few preliminary studies suggested increased bifidobacteria may be associated with a decreased incidence of atopic dermatitis Stool of infants fed formula containing oligosaccharides (FOS and GOS) in comparison to infants not fed the test formula had: Increased numbers of bifidobacteria and lactobacilli Increased amount of short chain fatty acids Increased proportion of acetate Decreased proportion of propionate Lower stool mean pH This is closer to that seen in breast-fed babies compared to those fed usual infant formulae _______________ Ben XM et al 2004 ____________ Knol et al 2005

Status of Probiotics as Therapy Great care must be taken in transferring data from laboratory and experimental animal studies into human use Applies also to the use of known probiotics, some of which are already present in human nutrition, such as yoghurt Not all strains of bacteria in use as probiotics are completely harmless Their immune-modifying effects and possible antiallergic and anti-cancer actions require large clinical studies

Detailed Schedule for Introducing Solids to the Allergic Baby Factsheets and FAQs: www.allergynutrition.com