S101- Food Allergies and Formula Sensitivity - Vivian Hernandez-Trujillo, MD Director, Division of Allergy and Immunology

S101- Food Allergies and Formula Sensitivity - Vivian Hernandez-Trujillo, MD Director, Division of Allergy and Immunology
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
S101- Food Allergies and Formula Sensitivity - Vivian Hernandez-Trujillo, MD Director, Division of Allergy and Immunology
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.
S101- Food Allergies and Formula Sensitivity - Vivian Hernandez-Trujillo, MD Director, Division of Allergy and Immunology
Milk Allergy

 Vivian Hernandez-Trujillo, MD
Director, Division of Allergy and
   Miami Children’s Hospital
• 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 dermatitis
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
  – Children: milk, egg, soy, wheat and as
    in adults
  – Adults: peanut, nuts, shellfish, fish

• Single food > many food allergies
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
• 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
• 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
   – 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
• Useful to confirm specific trigger
• Positive serum IgE or SPT denotes sensitization
• 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 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
• 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
• 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 OFC
Substitute 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 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

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

Clin and Exp Allergy; 2012(42): 238-247.
Human Milk Allergy: Background
• Some exclusively breastfed infants with CMA
  are symptomatic despite strict maternal CM

• 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 rxn
Human 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
  during maternal diet

• 40% symptomatic- all resolved
  when breastfeeding stopped

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

• 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
    Non-IgE-mediated, typically milk and soy induced
    Spectrum may include colic, constipation and occult GI
“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.”
• 75% of infants appear acutely ill
• 15% develop hypotension requiring
• 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
• 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
• Infants often present with multiple reactions
  and extensive evaluations before FPIES is

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

IgE-mediated reaction to mammalian oligosaccharide
• 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
• SPT with commercial extracts are often
• SPT with fresh meat directly also negative
• SPT with extract prepared from fresh meat are
  positive as well as ID tests with commercial
  – Intradermal testing to food allergens not routinely
    performed due to high risk of anaphylaxis
• Specific IgE to alpha-gal typically elevated
• 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
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
   – DBPCFCs preferred
   – May require ancillary testing
     (endoscopy / biopsy)
Treatment: Dietary Elimination
• Hidden ingredients (peanut in sauces or egg
• 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-
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
Food Allergy Management Primary
          MD/Allergist Partnership
Functions              Primary MD   Allergist
Initial diagnosis

Definitive diagnosis

Single food diet

Multi food diet


Natural history

• Allergy testing should be focused and specific
  based on history
• Alpha-gal is an IgE-mediated carbohydrate
• FPIES is a form of a non-IgE mediated allergic
• Restriction of introduction of foods to infants
  not shown to prevent atopy
•   Allen KJ, Koplin JJ. The Epidemiology of IgE-Mediated Food Allergy and
    Anaphylaxis. The Immunology and Allergy Clinics of North America. 2012 (32): 35-
•   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.
•   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-
•   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.
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