S101- Food Allergies and Formula Sensitivity

Vivian Hernandez-Trujillo, MD Director, Division of Allergy and Immunology

Director, Allergy-Immunology Fellowship Miami Children’s Hospital

Miami, Florida

Disclosure of Relevant Relationship • Dr. Hernandez-Trujillo (or spouse/partner) has disclosed the following commercial industry

affiliation and/or financial relationship in the past 12 months: • All COIs have been resolved prior to this presentation

• Dr. Hernandez-Trujillo will support this presentation and clinical recommendations with the “best

available evidence” from medical literature.

• Dr. Hernandez-Trujillo does not intend to discuss an unapproved/investigative use of a commercial product/device in this presentation.

Company/Organization Individual with COI Role

Baxter Self Speaker

Sanofi Self Advisory Board, Spokesperson

Claritin Council Self Spokesperson

CSL Self Advisory Board, Speaker

Merck/Bayer Self Advisory Board, Spokesperson

Meda Self Speaker

Milk Allergy

Vivian Hernandez-Trujillo, MD Director, Division of Allergy and

Immunology Miami Children’s Hospital

Disclosures

• In the last 12 months I have been:

• Speaker Baxter, CSL, Meda

• Advisory Board Sanofi, Merck/Bayer, CSL

• Claritin Council/Spokesperson Merck

• Spokesperson Sanofi

• Eosinophilic

esophagitis

• Eosinophilic

gastritis

• Eosinophilic

gastroenteritis

• Atopic dermatitis

Definitions: Adverse Reactions to Food

IgE-Mediated Non-IgE Mediated

Immunologic Spectrum

• Oral Allergy

Syndrome

• Anaphylaxis

• Urticaria

• Protein-Induced

Enterocolitis

• Protein-Induced

Enteropathy

• Eosinophilic

proctitis

IgE-mediated Food Allergy

• Prevalence: – 6 to 8% of children under 3 years

– 3 to 4% of adults

• More than 90% food allergy in children are caused by cow’s milk, soy, egg, peanuts, tree nuts, wheat, fish and shellfish – Majority of milk, egg, wheat, soy resolve by school age

– 20% children can outgrow peanut allergy • 7-9% can have recurrence especially if not ingested regularly

– 9% children outgrow tree nut allergy

Pathophysiology: Allergens

• Proteins (not fat / carbohydrate) – 10-70 kD glycoproteins – Heat resistant, acid stable

• Major allergenic foods (>85% of

allergy) – Children: milk, egg, soy, wheat and as

in adults – Adults: peanut, nuts, shellfish, fish

• Single food > many food allergies

Cross-reactivity

If allergic to… Risk of reaction to at least 1 other… Risk

Tree Nut Tree Nut 37%

Fish Fish 50%

Shellfish Shellfish 75%

Grain Grain 20%

Cow’s Milk Beef 10%

Cow’s Milk Goat Milk 92%

Cow’s Milk Mare Milk 4%

Peach Rosaceae Fruit 55%

Melon Other Fruit 92%

Legume Other Legume 5%

Pollen Fruits/Vegetables 55%

Cow’s Milk Allergy

• Most common food allergen affecting children (1 to 3%)

• Responsible for up to 13% of fatal food-induced anaphylaxis

• 1990- tolerance in 78% by age 6 years

• 2007- tolerance in 79% by age 16 years

Cow’s Milk Allergy

• Symptoms may be skin related- atopic dermatitis, urticaria, itching, GI-vomiting, diarrhea, Respiratory- nasal congestion, or anaphylaxis

• Some patients present with only persistent cough or nasal congestion/rhinorrhea and no skin symptoms

• Keep this in mind for children with cough who don’t respond to aerosolized bronchodilators or antihistamines and have history of “drinking lots of milk”

Diagnosis

• Gold standard- double blind placebo controlled (DBPC) oral food challenge (OFC)

• Skin prick testing (SPT)

• Measurement of specific IgE via blood

• **After anaphylaxis, if initial testing was done within a month of the reaction and is negative, repeat after one month time**

Allergy Testing

• Enzymatic assays- Specific IgE (formerly RAST) – 3 commercial detection assays FDA approved-

ImmunoCAP, TurboRAST, Immulite • Specific results cannot be compared across assays

– Advantage: no interference from antihistamines or dermatitis

– Disadvantage: increased discomfort from blood draw, delayed results

– Skin Prick Testing (SPT) – Advantage: immediate, visible results to patient/family

(~$15 per SPT) – Disadvantage: need to withhold antihistamine medications

for testing, need rash free skin

Allergy Testing- selection and interpretation

• Useful to confirm specific trigger • Positive serum IgE or SPT denotes sensitization

only • Sensitization is not equivalent to clinical

diagnosis of allergy • Many children with positive tests have no clinical

illness when exposed to the allergen • Avoid testing food allergens clearly tolerated

with selection of specific suspicious foods*** • I do not order food allergy panels****

Allergy testing- selection and interpretation

• Interpretation of results

– Allergen panels without consideration of above may lead to irrelevant positive results****

• Over interpretation can lead to costly, socially, emotionally, nutritionally detrimental actions of unnecessary allergen avoidance

• Patients should not be told they are allergic based on positive testing alone without consideration of history

• Size of SPT or level of specific IgE do not predict severity of allergic reaction

Food Allergy Testing

• Screening panels of food allergens without consideration of history- not recommended – 8% of patients screened will have positive result for peanut

but only 1% are clinically allergic

• Negative SPT or serum IgE does not entirely rule out food allergy in the setting of convincing history – Medically supervised oral food challenge may be

indicated

• Cross-reactivity may result in more positive test results than clinical reactivity – > 50% with peanut allergy test positive to other legumes

but < 5% have clinical symptoms

Food Allergy Testing

• Total IgE is often elevated in atopic individuals and does not identify specific allergens

• Measuring IgG antibodies to diagnose allergic disease is not recommended- does not denote sensitization***

• Intradermal (ID) testing is not recommended due to increased risk of severe allergic reaction***

Treatment

• Dietary elimination and avoidance

• Nutrition eval- calcium

• Anaphylaxis plan in writing – Auto-injectable epinephrine (first line)

• EpiPen Jr 0.15 mg <30 kg

• EpiPen 0.3 mg >30 kg

– Immediate follow up in ED or call 911

– 4 to 6 hours of observation

• Re-evaluation in children every 6-12 months – Potential for OFC

Substitute Infant Formulas for patients with IgE mediated CMA • Soy (confirm soy IgE negative)

– <15% soy allergy among IgE-CMA – Good option in many patients above 6 months age

• Cow’s milk protein extensively hydrolyzed – >90% tolerance in IgE-CMA, especially urticaria and

atopic derm

• Partial hydrolysates – Not hypoallergenic! – Not a good option for CMA

• Elemental amino acid-based formulas (AAF_ – Lack allergenicity – Best option for anaphylaxis

* CMA=cow’s milk allergy

Question to consider

Can infants with cow’s milk allergy have an allergy to human breast milk ?

Jarvinen KM, Geller L, Bencharitiwong R, et al

Presence of functional, autoreactive human milk-specific IgE in infants with cow’s milk allergy.

Clin and Exp Allergy; 2012(42): 238-247.

Human Milk Allergy: Background

• Some exclusively breastfed infants with CMA are symptomatic despite strict maternal CM avoidance

• Objective: Determine whether sensitization to endogenous human milk proteins, similar to bovine proteins, occurs

Human Milk Allergy : Methods

Peptides from Bovine milk IgE-binding epitopes

And homologous human milk peptides labelled

with sera

15 breastfed infants with CMA

Ages: 3 weeks to 12 months

10 older children Ages: 5-15 yrs

Milk IgE > 100 kU/L DBPCFC or recent rxn

Human Milk Allergy : Results

• All infants with CMA reacted clinically- AD or urticaria

• SPT and serum IgE

• Maternal restriction diet

• 60% infants asymptomatic during maternal diet

• 40% symptomatic- all resolved when breastfeeding stopped

Asymptomatic

Symptomatic

Percent

Breastfed

Infants

All 15 breastfed infants reacted during OFC to cow’s milk formula

Human Milk Allergy : Results

• In all 15 CMA infants, IgE binding to at least one bovine peptide seen

• Most also reacted to homologous human peptide******

• At least one human milk peptide was recognized by IgE from 5/6 symptomatic and 4/9 asymptomatic

Human Milk Allergy : Results

• Trend of IgE to more human milk peptides in infants symptomatic compared those responded to diet

• Older CMA patients also showed binding to bovine and homologous human peptides

• Controls (nonatopic and atopic non-milk allergic) were negative

Human Milk Allergy : Conclusions

• Endogenous human milk epitopes are recognized by specific IgE from most infants and children with CMA

• Autoreactive human milk-specific IgE functional in vitro

• Role in allergic symptoms remains unclear

Take Home Message

• Primary sensitization to endogenous human milk protein appears possible

• Breastfed infants with CMA and maternal CM restricted diet who remain symptomatic may benefit from cessation of breastfeeding

Enterocolitis Enteropathy Proctitis Age Onset: Infant Infant/Toddler Newborn Duration: 12-24 mo ? 12-24 mo 9 mo-12 mo Characteristics: Failure to thrive Malabsorption Bloody stools Shock Villous atrophy No systemic sx Lethargy Diarrhea Eosinophilic Vomit Diarrhea

Non-IgE-mediated, typically milk and soy induced

Spectrum may include colic, constipation and occult GI

blood loss

Pediatric Gastrointestinal Syndromes

FOOD PROTEIN INDUCED ENTEROCOLITIS (FPIES)

“Non-IgE mediated gastrointestinal food hypersentitivity that manifests as profuse, repeated vomiting, often with diarrhea that leads to acute dehydration and lethargy or weight loss with failure to thrive if chronic.”

FPIES

• 75% of infants appear acutely ill

• 15% develop hypotension requiring hospitalization

• Chronic symptoms generally improve within 3 to 10 days of switching to casein hydrolysate-based formula

• Symptoms typically present early infancy (1 to 3 months old) but can be seen up to 1 year old

FPIES

• Most commonly milk or soy with several studies showing reactivity in 50% of patients to both

– 1/3 will also develop solid food FPIES

• Usually presents 1 to 4 weeks after introduction of milk or soy (can be later onset in breast fed babies with delayed introduction)

• Other associated foods: rice (most common), oat, barley, chicken, turkey, egg, green pea, peanut, sweet potato, white potato, fruit, fish, mollusks

Diagnosis

• Infants often present with multiple reactions and extensive evaluations before FPIES is considered

• > 90% have negative skin prick tests and undetectable food-specific IgE antibodies

Treatment

• Strict avoidance for minimum 18 to 24 months – Majority (60-90%) resolve by age 3 years for milk and soy,

less for solid food

• Introduction of yellow fruits and vegetables instead of cereal when infants are ready for semi-solids

• Solid FPIES infants may have cow’s milk or soy introduced after at least 1 year of age if no prior history of reactivity to these specifically

• Tolerance to one food from each high-risk group increases the likelihood of tolerance to others of the same group (oat from grains, soy from legumes)

Substitute Infant Formulas for patients with non IgE mediated CMA

• Soy – ~50% soy allergy among non-IgE CMA

– Not a good option

• Cow’s milk protein extensively hydrolyzed – Only considered if amino-acid based formulas

not available or refused- recommend supervised oral challenge

• Partial hydrolysates – Not a good option for CMA

• Elemental amino acid-based formulas

-Excellent choice

* CMA=cow’s milk allergy

Evaluation for Resolution

• OFC necessary to evaluate for resolution of symptoms – Considered a high-risk procedure given symptoms

in a positive reaction

– Should be conducted in a setting where IV access can be secured with rapid fluid resuscitation if a reaction occurs

– Epinephrine does not improve symptoms of emesis or lethargy but should be available for potential hypotension and shock

GALACTOSE-Α-1,3-GALACTOSE (ALPHA-GAL)

IgE-mediated reaction to mammalian oligosaccharide

Alpha-gal

• Discovered due to significant number of patients in TN, NC, AK, VA, MO having hypersensitivity reactions to their first infusion of cetuximab – Reactions occurring in patients with IgE to alpha-gal

• Delayed anaphylaxis, angioedema or urticaria after consumption of red meat – Symptoms occur 3 to 6 hours after ingestion of beef, pork

or lamb due to digestion and/or processing

• Reactions did not start until after receiving multiple tick bites – Studies implicate Amblyomma americanum (Lone Star

Tick)

Alpha-gal

• SPT with commercial extracts are often negative

• SPT with fresh meat directly also negative

• SPT with extract prepared from fresh meat are positive as well as ID tests with commercial extract – Intradermal testing to food allergens not routinely

performed due to high risk of anaphylaxis

• Specific IgE to alpha-gal typically elevated

Alpha-gal

• Patients need to have caution if bit by ticks, as sensitization appears to increase

• Symptoms may appear upon consumption of meat one day, but not another

• Risk of allergy to gelatin as well

Diagnosis: Elimination Diets and Food Challenges

• Elimination diets (1 to 6 weeks) – Eliminate suspected food(s), or – Prescribe limited “eat only” diet, or – Elemental diet

• Oral challenge testing (MD supervised, ER meds available) – Open – Single-blind – Double-blind, placebo-controlled

(DBPCFC)

Diagnostic Approach: Non-IgE-Mediated Disease

• Includes disease with unknown mechanisms – Food additive allergy

• Elimination diets (may need elemental diet) • Oral Challenges

– Timing/dose/approach individualized for disorder • Enterocolitis syndrome can elicit shock • Enteropathy / eosinophilic gastroenteritis may

need prolonged feedings to develop symptoms

– DBPCFCs preferred – May require ancillary testing

(endoscopy / biopsy)

Treatment: Dietary Elimination

• Hidden ingredients (peanut in sauces or egg rolls)

• Labeling issues (“spices”, changes, errors)

• Cross contamination (shared equipment)

• “Code words” (“Natural flavor” may be CM)

• Seeking assistance – Registered dietitian: (www.eatright.org)

– Food Allergy Network (www.foodallergy.org; 800-929-4040)

Prevention of Atopy

• Lack of evidence that maternal dietary restriction during pregnancy plays significant role in prevention of atopic disease in infants

• Exclusive breastfeeding for at least 4 months compared with cow milk formula decreases cumulative incidence of AD and cow milk allergy in first 2 yrs of life

• Exclusive breastfeeding for at least 3 months protects against wheezing in early life but not beyond 6 yrs old

• Infants at high risk who are not exclusively breastfeed or are formula fed- modest evidence use of extensively or partially hydrolyzed formula

Pediatrics 2008; 121;183-191

Prevention of Atopy

• No convincing evidence for use of soy-based formula in allergy prevention

• No current evidence supporting delayed introduction of solid foods beyond 4 to 6 months in protection against atopic disease

Pediatrics 2008; 121;183-191

Functions Primary MD

Initial diagnosis

Definitive diagnosis

Single food diet

Multi food diet

MMR

Natural history

Food Allergy Management Primary MD/Allergist Partnership

Allergist

Prevention

Summary

• Allergy testing should be focused and specific based on history

• Alpha-gal is an IgE-mediated carbohydrate allergy

• FPIES is a form of a non-IgE mediated allergic reaction

• Restriction of introduction of foods to infants not shown to prevent atopy

References • Allen KJ, Koplin JJ. The Epidemiology of IgE-Mediated Food Allergy and

Anaphylaxis. The Immunology and Allergy Clinics of North America. 2012 (32): 35-50.

• Cianferoni A, Muraro A. Food-Induced Anaphylaxis. The Immunology and Allergy Clinics of North America. 2012 (32): 165-195.

• Commins SP, et al. Delayed anaphylaxis, angioedema, and urticaria after consumption of red meat in patients with IgE antibodies specific for galactose-α-1,3-galactose. Journal of Allergy and Clinical Immunology. 2009(123)2: 426-433.

• Commins SP, et al. The relevance of tick bites to the production of IgE antibodies to the mammalian oligosaccharide galactose-α-1,3-galactose. Journal of Allergy and Clinical Immunology. 2011(127)5: 1286-1293.

• Fiocchi A, et al. WAO DRACMA Guidelines WAO Journal April 2010 • Fleischer DM, et al. Oral Food Challenges in Children with a Diagnosis of Food

Allergy. The Journal of Pediatrics. 2011(158)4: 578-583 • Greer FR, Sicherer SH, Burks AW. Effects of Early Nutritional Interventions on the

Development of Atopic Disease in Infants and Children” The Role of Maternal Dietary restriction, Breastfeeding, Timing of Introduction of Complementary Foods, and Hydrolyzed Formulas. Pediatrics. 2008(121): 183-191.

• Hofmann A, Burks AW. Pollen Food Syndrome: Update on the Allergens. Current Allergy and Asthma Reports. 2008 (8): 413-417.

References

• Keck LE, Simpson EL, Berry TM, Hanifin JM. Is Food Allergy Testing Reliable in Pediatric Atopic Dermatitis? A Population-Based Study. Chemical Immunology and Allergy. 2012 (96): 108-112.

• Kim JS, Nowak-Wegrzyn A, Sicherer SH, Noone S, Moshier EL, Sampson HA. Dietary baked milk accelerates the resolution of cow’s milk allergy in children. Journal of Allergy and Clinical Immunology. 2011 (128) 125-131.

• Leonard SA, Nowak-Wegrzyn A. Food protein-induced enterocolitis syndrome: an update on natural history and review of management. Annals of Allergy, Asthma, and Immunology. 2011 (107): 95-101.

• Licouras CA, et al. Eosinophilic esophagitis : Updated consensus recommendations for children and adults. Journal of Allergy and Clinical Immunology. 2011(128): 3-20.

• Nowak-Wegrzyn A, et al. Work Group report: Oral food challenge testing. Journal of Allergy and Clinical Immunology. 2009(123)6:S365-S383.

• Sicherer SH, Wood RA. Allergy Testing in Childhood: Using Allergen-Specific IgE Tests. Pediatrics. 2012(129)193: 193-197.

• Sicherer SH. Clinical implications of cross reactive food allergens. Journal of Allergy and Clinical Immunology. 2001(108)6: 881-890.