Food allergy in children Food allergy in children the gastroenterologist the gastroenterologist

perspectiveperspectiveRon Shaoul MDRon Shaoul MD

Pediatric GastroenterologyPediatric GastroenterologyBnai Zion Medical CenterBnai Zion Medical CenterMaccabi Health ServicesMaccabi Health Services

Major food allergens

Common food antigens• Cow’s milk protein

– caseins, whey (beta-lactoglobulin, alpha-lactalbumin, bovine serum albumin, bovine immunoglobulins).

• Soy protein– 2S-globulin, soy tripsin inhibitor, soy

lectin

• Egg protein– Ovalbumin

• Fish, shrimp, beef, pork

Common food antigens-2

• Peanuts, nuts, beans.• Cocoa, chocolate.• Citrus fruits, apples, strawberries. • Wheat, cereals. • Spices, yeast.

Predisposing factors

• Positive family hx of atopic disease.

• GI mucosal barrier defect.

• Early antigen exposure during postnatal gut development

Epidemiology• Occurs in 0.3 to 7.5 percent of

otherwise normal infants• 82 percent of whom have symptoms

within four months of birth and 89 percent by one year of age.

Gastrointestinal manifestations

• Gastrointestinal food allergies are often the first form of allergy to affect infants and young children and typically present as irritability, vomiting or "spitting-up," diarrhea, and poor weight gain.

• Cell-mediated hypersensitivities predominate, making standard allergy tests such as prick skin tests and RAST tests of little diagnostic value

Food protein-induced enterocolitis syndrome

FPIES))• typically presents in the first several months of life

with irritability, protracted vomiting, and diarrhea, not infrequently resulting in dehydration.

• Vomiting generally occurs 1-3 hr after feeding, and continued exposure may result in bloody diarrhea, anemia, abdominal distention, and failure to thrive.

• Symptoms are most commonly provoked by cow's milk or soy protein-based formulas but occasionally result from food proteins passed in maternal breast milk.

Food protein-induced enterocolitis syndrome

• A similar enterocolitis syndrome has been reported in older infants and children from egg, wheat, rice, oat, peanut, nuts, chicken, turkey, and fish sensitivity.

• Hypotension occurs in about 15% of cases after allergen ingestion.

• Fourteen infants with FPIES caused by grains (rice, oat, and barley), vegetables (sweet potato, squash, string beans, peas), or poultry (chicken and turkey) were identified.

• Symptoms were typical of classical FPIES with delayed (median: 2 hours) onset of vomiting, diarrhea, and lethargy/dehydration.

• Eleven infants (78%) reacted to >1 food protein, including 7 (50%) that reacted to >1 grain.

• Nine (64%) of all patients with solid food–FPIES also had cow’s milk and/or soy-FPIES.

• Initial presentation was severe in 79% of the patients, prompting sepsis evaluations (57%) and hospitalization (64%) for dehydration or shock.

• We presented a series of four babies, previously suspected as having cow milk protein allergy that presented with severe life-threatening episodes, all related to unsupervised self-challenge with either a cow milk based formula or a dairy product.

• Parental decisions, physician recommendations, or inadvertent ingestion resulted in these serious clinical presentations.

Food protein-induced enteropathy

• Often presents in the first several months of life with diarrhea, not infrequently steatorrhea, and poor weight gain.

• Symptoms include protracted diarrhea, vomiting in up to two thirds of cases, failure to thrive, abdominal distention, early satiety, and malabsorption.

• Anemia, edema, and hypoproteinemia occur occasionally.

Cow's milk sensitivity• is the most frequent cause of this

syndrome in young infants, but it also has been associated with sensitivity to soy, egg, wheat, rice, chicken, and fish in older children.

Gastrointestinal anaphylaxis

• generally presents as acute abdominal pain and vomiting that accompany other IgE-mediated allergic symptoms

Allergic eosinophilic gastroenteritis

• occurs at any age and presents as symptoms similar to esophagitis as well as prominent weight loss or failure to thrive, which are the hallmarks of this disorder.

• Up to 50% of patients are atopic, and food-induced IgE-mediated reactions have been implicated in a minority of patients.

• Generalized edema secondary to hypoalbuminemia may occur in some infants with marked protein-losing enteropathy.

Allergic eosinophilic esophagitis

• may present from infancy through adolescence. • In young children, it is primarily cell-mediated and

presents as chronic gastroesophageal reflux (GER), intermittent emesis, food refusal, abdominal pain, dysphagia, irritability, sleep disturbance, and failure to respond to conventional reflux medications.

• A study of children younger than 1 yr of age presenting with GER found that 40% had cow's milk-induced reflux.

Reflux and milk allergy• On the basis of studies using cow milk

elimination and challenge, it is clear that a subset of infantile GER is attributable to cow milk allergy

• The magnitude of the problem is not well-defined; it has been estimated that in 16% to 42% of infants, GER is attributable to CMA.

• Risk factors for milk’s being causal seem to include esophagitis, malabsorption, diarrhea, and atopic dermatitis.

Reflux and milk allergy• Thus, for many infants with cow milk-

associated GER, the reflux is not an isolated symptom.

• One group identified that in infants with CMA-induced GER, the pH probe shows a “phasic” pattern with a gradual and prolonged fall in pH after milk ingestion.

• However, the phasic pattern has not been demonstrated by other investigators.

• Taking the studies together, it is evident that CMA accounts for GER in some infants.

Sicherer SH Pediatrics 2003;111:1609 –1616

Oral allergy syndrome• Is an IgE-mediated hypersensitivity that occurs in many

older children with birch pollen and ragweed-induced allergic rhinitis.

• Symptoms are usually confined to the oropharynx and consist of the rapid onset of pruritus, tingling, and angioedema of the lips, tongue, palate, and throat, and occasionally a sensation of pruritus in the ears and/or tightness in the throat.

• Symptoms are generally short-lived and are due to local mast cell activation by fresh fruit and vegetable proteins that cross react with birch pollen (apple, carrot, potato, celery, hazel nuts, and kiwi) and ragweed pollen (banana and melons-watermelon, etc.).

• They hypothesized that intolerance of cow’s milk can also cause severe perianal lesions with pain on defecation and consequent constipation in young children.

• They performed a double-blind, crossover study comparing cow’s milk with soy milk in 65 children with chronic constipation.

• All had previously been treated with laxatives without success; 49 had anal fissures and perianal erythema or edema.

• After 15 days of observation, the patients received cow’s milk or soy milk for 2 weeks. After a one-week washout period, the feedings were reversed.

• A response was defined as eight or more bowel movements during a treatment period.

• Forty-four of the 65 children (68 percent) had a response while receiving soy milk. Anal fissures and pain with defecation resolved.

• None of the children who received cow’s milk had a response.

• In all 44 children with a response, the response was confirmed with a double-blind challenge with cow’s milk.

• Children with a response had a higher frequency of :– coexistent rhinitis, dermatitis, or bronchospasm – anal fissures and erythema or edema at base line – evidence of inflammation of the rectal mucosa on biopsy – signs of hypersensitivity, such as specific IgE antibodies to

cow’s-milk antigens

Other GI manifestations ?

• Recurrent oral aphtae• Bowel edema and obstruction• Occult GI bleeding• Infantile colic

Clinical applications

• In infants with IgE-mediated CMA, most (86%) will tolerate a soy formula, but the rate of tolerance is lower (50%) for most of the cell-mediated disorders.

• Infants with true CMA would be expected also to react to partially hydrolyzed formula, lactose-free cow milk-based formula, and most mammalian milks (eg, sheep, goat), so none of these is a good alternative.

• In most cases (95%), infants with CMA will tolerate extensively hydrolyzed cow milk formula, but for the few who continue to react (presumably as a result of residual allergens), an amino acid-based formula is required for therapy.

Any need for amino acid formula ?

Intolerance to protein hydrolysate infant formulas: An underrecognized cause of

gastrointestinal symptoms in infants • The purpose of this study was to determine the

effectiveness of an amino acid–based infant formula in infants with continued symptoms suggestive of formula protein intolerance while they were receiving casein hydrolysate formula (CHF).

• Twenty-eight infants, 22 to 173 days of age, were enrolled; each had received CHF for an average of 40 days (10 to 173 days) and continued to have bloody stools, vomiting, diarrhea, irritability, or failure to gain weight, or a combination of these symptoms.

Intolerance to protein hydrolysate infant formulas: An underrecognized cause of gastrointestinal symptoms in infants

• Sigmoidoscopy with rectal biopsy was performed in all infants.

• The infants then received an amino acid–based infant formula, Neocate, for 2 weeks.

• After 2 weeks of treatment, 25 of the infants demonstrated resolution of their symptoms and underwent challenge with CHF.

• Of the 25 who were challenged, eight tolerated the CHF and the remainder had recurrence of their symptoms.

• The histologic features in these infants varied from eosinophilic infiltration to normal.

Intolerance to protein hydrolysate infant formulas: An underrecognized cause of gastrointestinal symptoms in infants

• They concluded that not all infants with apparent formula protein–induced colitis respond to CHF

(J Pediatr 1997;131:741-4)

Natural history of food allergy

• Most food allergy is acquired in the first 1 to 2 years of life.

• The prevalence of food allergy peaks at 6% to 8% at 1 year of age and then falls progressively until late childhood, after which the prevalence remains stable at 1% to 2%.

• Most food allergy is indeed lost over time.

• The process of outgrowing food allergies, varies a great deal for different foods and among individual patients.

• It is also important to note that the process of outgrowing a food allergy may be helped by strict avoidance of the offending food, in that repeated exposures to even small quantities may delay the development of tolerance in some patients

Early intervention to prevent food allergy

Can we do it ???

• Aim: To assess the preventive effect of differently hydrolyzed formulas compared with cow’s milk formula (CMF) in high-risk infants.

• Methods: 2252 infants with a hereditary risk for atopy were enrolled in the German Infant Nutritional Intervention Study and randomly assigned at birth to one of 4 blinded formulas: CMF, partially hydrolyzed whey formula, extensively hydrolyzed whey formula, and extensively hydrolyzed casein formula (eHF-C).

• The primary end point at 1 year of age was the presence of allergic manifestation, which was defined as atopic dermatitis (AD), gastrointestinal manifestation of food allergy, allergic urticaria, or a combination of these factors.

• Results: The incidence of allergic manifestation was significantly reduced by using eHF-C compared with CMF (9% vs 16%; adjusted OR, 0.51; 95% CI, 0.28-0.92),

• The incidence of AD was significantly reduced by using eHF-C (OR, 0.42; 95% CI, 0.22-0.79) and partially hydrolyzed whey formula (OR, 0.56; 95% CI, 0.32-0.99).

• Family history of AD was a significant risk factor and modified the preventive effect of the hydrolysates.

• Conclusions: Prevention of allergic diseases in the first year of life is feasible by means of dietary intervention but influenced by family history of AD.

• The preventive effect of each hydrolyzed formula needs to be clinically evaluated.

• Seven studies compared prolonged feeding of hydrolysed formula to cow's milk formula for allergy prevention.

• Meta-analysis of 4 studies (386 infants) found a significant reduction in allergy incidence in infancy (RR 0.63)

• One study reported a significant reduction in allergy incidence in childhood (RR 0.54).

• Significant reductions were found in – asthma prevalence in childhood– eczema incidence in infancy and

prevalence in childhood – food allergy prevalence in childhood– CMA incidence in infancy.

• Main results: Five eligible studies were found, all enrolling infants at high risk of allergy on the basis of a family history of allergy in a first degree relative.

• Conclusions: Feeding with a soy formula should not be recommended for the prevention of allergy or food intolerance in infants at high risk of allergy or food intolerance.

• Conclusions: In breast-fed infants with atopy, gut barrier function is improved after cessation of breast-feeding and starting of hypoallergenic formula feeding.

• Objective: a systematic review with meta-analysis of prospective studies that evaluated the association between exclusive breast-feeding during the first 3 months after birth and atopic dermatitis.

• Methods: 18 prospective studies that met the predefined inclusion criteria.

J Am Acad Dermatol 2001;45:520-7

• Results: The summary odds ratio (OR) for the protective effect of breast-feeding in the studies analyzed was 0.68 (95% confidence interval [CI], 0.52-0.88).

• This effect estimate was higher in the group of studies wherein children with a family history of atopy were investigated separately (OR = 0.58; CI, 0.41-0.92) than in those of combined populations (OR = 0.84; CI, 0.59-1.19).

• Conclusion: Exclusive breast-feeding during the first 3 months of life is associated with lower incidence rates of atopic dermatitis during childhood in children with a family history of atopy.

• This effect is lessened in the general population and negligible in children without first-order atopic relatives.

• Results: The summary odds ratio (OR) for the protective effect of breastfeeding was 0.70 (95% CI 0.60 to 0.81).

• The effect estimate was greater in studies of children with a family history of atopy (OR = 0.52) than in studies of a combined population (OR = 0.73).

• Conclusions: Exclusive breast-feeding during the first months after birth is associated with lower asthma rates during childhood.

• Aim to assess long-term outcome of asthma and atopy related to breastfeeding in a New Zealand birth cohort.

• Methods: the cohort consisted of 1037 of 1139 children born in Dunedin, New Zealand.

• Children were assessed every 2–5 years from ages 9 to 26 years with respiratory questionnaires, pulmonary function, bronchial challenge, and allergy skin tests.

• History of breastfeeding had been independently recorded in early childhood

• Conclusions: Prescription of an antigen avoidance diet to a high-risk woman during pregnancy is unlikely to reduce substantially her child's risk of atopic diseases, and such a diet may adversely affect maternal and/or fetal nutrition.

• Prescription of an antigen avoidance diet to a high-risk woman during lactation may reduce her child's risk of developing atopic eczema, but better trials are needed.

When to add solids ? • The relationship between early solid feeding

practices and risks of recurrent or chronic eczema in childhood was examined in a birth cohort of New Zealand children studied to the age of 10.

• By the age of 10 years, 7.5% of children had chronic or recurrent eczema.

• There were clear and consistent associations between the diversity of the child's diet during the first 4 months and risks of eczema.

• children exposed to four or more different types of solid food before 4 months had risks of recurrent or chronic eczema that were 2.9 times those of children who were not exposed to early solid feeding. Fergusson DM et al Pediatrics. 1990 Fergusson DM et al Pediatrics. 1990

Age of Introduction of Complementary Foods

• The optimal age of introduction of complementary foods remains controversial.

• The appropriate time may represent a compromise between 2 competing health issues. On one hand, if complementary foods are introduced too late when breast milk alone no longer meets all the infant's energy and nutrient needs nutrient deficiencies and growth faltering may occur.

• On the other hand, because these foods are often contaminated with microbial pathogens, premature introduction carries an unnecessary risk of transmission of infection. WHO/UNICEF Review on Complementary Feeding

Pediatrics 2000

Age of Introduction of Complementary Foods

• A sizeable number of observational studies and 2 randomized trials have failed to identify any benefit of complementary foods for infant growth before 6 months of age, even in low birth weight term infants.

• By contrast, several studies have documented a twofold or greater risk of enteric and other infections when these foods are provided before 6 months.

• Hence, the authors of the WHO/UNICEF report concluded that the optimal age of introduction of complementary foods is about 6 months.

Thank you

Soy story

S

• Study design: Children <3.5 years with documented IgE-associated CMA (n = 93) were evaluated for soy allergy by double-blind, placebo-controlled food challenge, open challenge, or convincing previous history of an anaphylactic reaction to soy.

• Results: Of this IgE-associated CMA cohort (ages 3 to 41 months), 14% were determined to have soy allergy,

• Conclusions: Soy allergy occurs in only a small minority of young children with IgE-associated CMA.

• As such, soy formula may provide a safe and growth-promoting alternative for the majority of children with IgE-associated CMA shown to be soy tolerant at the time of introduction of soy formula.

• Study design: Infants (n = 170) with documented cow’s milk allergy were randomly assigned to receive either a soy formula or an extensively hydrolyzed formula.

• If it was suspected that the formula caused symptoms, a double-blind, placebo-controlled challenge (DBPCFC) with the formula was performed.

• The children were followed to the age of 2 years, and soy-specific IgE antibodies were measured at the time of diagnosis and at the ages of 1 and 2 years.

• Results: An adverse reaction to the formula was confirmed by challenge in 8 patients (10%) randomly assigned to soy formula and in 2 patients (2.2%) randomly assigned to extensively hydrolyzed formula.

• Adverse reactions to soy were similar in IgE-associated and non–IgE-associated cow’s milk allergy (11% and 9%, respectively).

• IgE to soy was detected in only 2 infants with an adverse reaction to soy.

• Adverse reactions to soy formula were more common in younger (<6 months) than in older (6 to 12 months) infants (5 of 20 vs 3 of 60, respectively, P = .01).

• Conclusions: Soy formula was well tolerated by most infants with IgE associated and non–IgE-associated cow’s milk allergy.

• Development of IgE-associated allergy to soy was rare.

• Soy formula can be recommended as a first-choice alternative for infants ≥6 months of age with cow’s milk allergy.

Probiotics for treatment

Atopic dermatitis• The Idea:

– In the hygiene hypothesis the progressive increase in frequency of atopic disease is attributed to reduced microbial exposure in early life.

– Probiotics further degrade the food and antigens.

– Regulation of the immune response and reduction of IgE secretion

– Reduction of bowel permeability

Isolauri et al. Clin Exp Allergy 2000

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2

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14

before therapy after two months

CFBB-12LGG

SCORAD

Atopic dermatitis• Improvement is noted within 1 month

of treatment and is further improved over the next 6 months

Probiotics in primary prevention of atopic disease: a randomized placebo-controlled trial

Kalliomaki M et al. Lancet 2001;357:1076-9

• Purpose: To assess the effect on prevention of atopic disease of Lactobacillus GG given early in life.

• Design: Double-blind, randomized, placebo-controlled trial.

Probiotics in primary prevention of atopic disease: a randomized placebo-controlled trial

Kalliomaki M et al. Lancet 2001;357:1076-9

• Patients: Mothers who had at least one first-degree relative (or partner) with atopic eczema, allergic rhinitis, or asthma, and their infants.

• Intervention: Oral Lactobacillus GG was given for 2 to 4 weeks prenatally to the mothers, and postnatally for 6 months to their infants.

• Main outcome measures: Chronic recurring atopic eczema evaluated at age 2 years.

Probiotics in primary prevention of atopic disease: a randomized placebo-controlled trial

Kalliomaki M et al. Lancet 2001;357:1076-9

• Results: Atopic eczema was diagnosed in 35% children aged 2 years.

• The frequency of atopic eczema in the probiotic group was half that of the placebo group [23%] vs. [46%].

Kalliomaki et al Lancet 2001 age= -1-24m P< 0.008

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60

80

100

LGG Plaebo

atopic eczema

n=64 n=68

+

אחזתינוקות

Probiotics in primary prevention of atopic disease: a randomized placebo-controlled trial

Kalliomaki M et al. Lancet 2001;357:1076-9

• Conclusions: Lactobacillus GG was effective in the prevention of early atopic disease in children at high risk.

• Thus, gut microflora may be a hitherto unexplored source of natural immunomodulators and probiotics for prevention of atopic disease.

• To investigate whether the preventive effect of lactobacillus on atopic disease extends beyond infancy, they reexamined the cohort at the age of 4 years.

• Atopic eczema was diagnosed in 14 of the 53 (26%) children on lactobacillus, compared with 25 of the 54 (46%) on placebo (relative risk 0·57, 95% CI 0·33–0·97).

• Five of 54 children in the placebo group and ten of 53 in the lactobacillus group had developed seasonal allergic rhinitis (p=0·15)

• One in the placebo group and three in the lactobacillus group had developed asthma (p=0·30).

Not preventing all allergies

• Objectives: The aim of this study was to assess the efficacy of oral probiotic bacteria in the management of atopic disease and to observe their effects on the composition of the gut microbiota.

• Methods: The study population included 35 infants with atopic eczema and allergy to cow’s milk.

• At a mean age of 5.5 months, they were assigned in a randomized double-blind manner to receive either extensively hydrolyzed whey formula (placebo group) or the same formula supplemented with viable (viable LGG group) or heat-inactivated Lactobacillus GG (heat-inactivated LGG group).

J Pediatr Gastroenterol Nutr, Vol. 36, No. 2, February 2003

• The changes in symptoms were assessed by the SCORAD method.

• Results: The treatment with heat-inactivated LGG was associated with adverse gastrointestinal symptoms and diarrhea.

• Consequently, the recruitment of patients was stopped after the pilot phase.

• Within the study population, atopic eczema and subjective symptoms were significantly alleviated in all the groups;

• The SCORAD scores decreased from 13 to 8 units in the placebo group, from 19 to 5 units in the viable LGG group, and from 15 to 7 units in the heat-inactivated LGG group.

• The decrease in the SCORAD scores within the viable LGG group tended to be greater than within the placebo group.

• Conclusions: Supplementation of infant formulas with viable but not heat-inactivated LGG is a potential approach for the management of atopic eczema and cow’s milk allergy.

Thank you

• Infants (n = 52) allergic to cow’s milk protein and extensively hydrolyzed formulas received an amino acid–based formula.

• The amino acid–based formula proved to be safe, with infants exhibiting an overall gain in length and weight.

• Children with allergy restricted to extensively hydrolyzed formulas were diagnosed earlier and tolerated cow’s milk protein earlier than children with multiple food allergy. (J Pediatr 2002;141:271-3)