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

2. 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

3. 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

4. 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

5. 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

6. 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?

7. 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

8. 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

9. 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”

10. 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

11. 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

12. 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

13. 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

14. 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

15. 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

16. 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

17. 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

18. 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

19. 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

20. 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

21. 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

22. 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

23. 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

24. 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

25. 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

26. 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

27. 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

28. 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

29. 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

30. 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

31. 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

32. 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

33. 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

34. 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

35. 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

36. 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

37. 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

38. 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

39. 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

40. 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

41. 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

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. 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. 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

45. 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

46. 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

47. 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

48. 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

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

50. 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

51. 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

52. 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.

53. 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

54. 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.

55. 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

56. 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

57. 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

58. Detailed Schedule for Introducing Solids to the Allergic Baby
Factsheets and FAQs: