S101- Food Allergies and Formula Sensitivity - Vivian Hernandez-Trujillo, MD Director, Division of Allergy and Immunology
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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:
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
• 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.
Milk Allergy
Vivian Hernandez-Trujillo, MD
Director, Division of Allergy and
Immunology
Miami Children’s HospitalDisclosures • In the last 12 months I have been: • Speaker Baxter, CSL, Meda • Advisory Board Sanofi, Merck/Bayer, CSL • Claritin Council/Spokesperson Merck • Spokesperson Sanofi
Definitions: Adverse Reactions to Food
Immunologic Spectrum
IgE-Mediated Non-IgE Mediated
• Oral Allergy • Eosinophilic • Protein-Induced
Syndrome esophagitis Enterocolitis
• Anaphylaxis • Eosinophilic • Protein-Induced
• Urticaria gastritis Enteropathy
• Eosinophilic • Eosinophilic
gastroenteritis proctitis
• Atopic dermatitisIgE-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 allergyPathophysiology: 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 allergiesCross-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 skinAllergy 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 reactionFood 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 symptomsFood 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
– Immediate follow up in ED or call 911
– 4 to 6 hours of observation
• Re-evaluation in children every 6-12 months
– Potential for OFCSubstitute Infant Formulas for
patients with IgE mediated CMA
• Soy (confirm soy IgE negative)
– 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 allergyQuestion 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 10 older children
with CMA Ages: 5-15 yrs
Ages: 3 weeks to Milk IgE > 100 kU/L
12 months DBPCFC or recent rxnHuman Milk Allergy : Results
• All infants with CMA reacted Percent
clinically- AD or urticaria Breastfed
• SPT and serum IgE Infants
• Maternal restriction diet
• 60% infants asymptomatic Asymptomatic
Symptomatic
during maternal diet
• 40% symptomatic- all resolved
when breastfeeding stopped
All 15 breastfed infants reacted during OFC to cow’s milk formulaHuman 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
Pediatric Gastrointestinal Syndromes
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 GIFOOD 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 allergyEvaluation 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 shockGALACTOSE-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 elevatedAlpha-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;183-191Prevention 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;183-191Food Allergy Management Primary
MD/Allergist Partnership
Functions Primary MD Allergist
Initial diagnosis
Definitive diagnosis
Single food diet
Multi food diet
MMR
Natural history
PreventionSummary • 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.You can also read
