Taking a Bite Out of

Food Allergy

Mark A. Posner, MD,

FAAAAI

Allergy and Asthma

Specialists, P.C.

Definitions

Adverse Food

Reactions

Toxic / Pharmacologic Non-Toxic / Intolerance

• Bacterial food

poisoning

• Heavy metal

poisoning

• Scombroid

fish poisoning

• Caffeine

• Alcohol

• Histamine

Non-immunologic

• Lactase

deficiency

• Galactosemia

• Pancreatic

insufficiency

• Gallbladder /

liver disease

• Hiatal hernia

• Gustatory

rhinitis

• Anorexia

nervosa

• Idiosyncratic

Adapted from Sicherer S, Sampson H. J

Allergy Clin Immunol 2006;117:S470-475.

• Eosinophilic

esophagitis

• Eosinophilic

gastritis

• Eosinophilic

gastroenteriti

s

• Atopic

dermatitis

Adverse Food

Reactions

IgE-Mediated

(most common)

Non-IgE

Mediated

Cell-

Mediated

Immunologic

• Systemic (Anaphylaxis)

• Oral Allergy Syndrome

• Immediate gastrointestinal allergy

• Asthma/rhinitis

• Urticaria

• Morbilliform rashes and flushing

• Contact urticaria

• Protein-

Induced

Enterocolitis

• Protein-

Induced

Enteropathy

• Eosinophilic

proctitis

• Dermatitis

herpetiformis

• Contact

dermatitis

Sampson H. J Allergy Clin Immunol 2004;113:805-9,

Chapman J et al. Ann Allergy Asthma & Immunol

2006;96:S51-68.

Pathophysiology

Allergens

• Proteins or glycoproteins (not fat or carbohydrate) – Generally heat resistant, acid

stable

• Major allergenic foods (>85% of food allergy)

– Children: milk, egg, soy, wheat,

peanut, tree nuts – Adults: peanut, tree nuts,

shellfish, fish, fruits and vegetables

CASE: Crustacean Allergy:

IgE Towards Protein in the

Food, NOT Iodine

• 79 year old man had anaphylaxis to

shrimp at age 20, 25

• Doctors told him he was allergic to iodine in seafood

• Avoided seafood, iodized salt for years

• Age 70: retirement dinner, hostess picked shrimp out of his portion and gave it to him --- ER visit for anaphylaxis

• At age 79, specific IgE measurement extremely high to shrimp: >100 kU/L

• On follow-up after education on avoidance, happily consuming foods with iodized salt because he didn’t have to screen salt source any more

Pan-allergens

• Proteins in food, pollen or plants that possess homologous IgE binding epitopes across species

• Tropomyosins: crustacea, dust mites, cockroach, mollusks

• Parvalbumins: fish

• Bovine IgG: beef, lamb, venison, cow’s milk

• Lipid transfer protein: fruits (peach, apple), vegetables, peanut, tree nuts

• Profilin: fruits, vegetables

• Class 1 chitinases: fruits, wheat, latex

Amino Acid Structural

Characteristics

• Allergenic proteins have been identified for common food allergens; genes have been cloned and sequenced for many of them

• Sequential vs conformational B

cell epitopes – IgE towards sequential epitopes

are associated with persistence of allergy

– Cross Reactivity: more likely if AA sequence homology >70%

IgE-Mediated

IgE-receptor

Histamine

Protein digestion

Antigen

processing

Some Ag enters

blood

Mast cell APC

B cell T cell

TNF-

IL-5

Non-IgE

Mediated

Immune Mechanisms

Risk Factors

Risk Factors for

Development of Food

Allergy

Local Factors

(Rodent

Models)

• Genetic

susceptibility

•Pepsin

digestion

•

Gastrointestin

al infections?

•

Malabsorption

Host

Factors

• Age (esp

neonates)

• Genetic

susceptibilit

y

• FHx of

atopy

• FHx of

food allergy

• Atopic

Chapman J et al. Ann Allergy Asthma & Immunol

2006;96:S51-68.

Food Allergy Disorders

Anaphylaxis Syndromes

• Food-induced anaphylaxis – Food allergy = #1 cause of

anaphylaxis in the ED

– Rapid-onset, up to 30% biphasic

– May be localized (single organ) or generalized

– Potentially fatal

– Any food, highest risk:

• peanut, tree nut, seafood (cow’s milk and egg in young children)

• Food-dependent, exercise-induced: 2 forms

– Specific foods (wheat, celery most common)

– Any food (post-prandial)

Fatal Food

Anaphylaxis

• Frequency: ~ 150 deaths / year

• Clinical features:

– Biphasic reaction can contribute –initially better, then recurs

– Cutaneous symptoms may not be present

– Respiratory symptoms prominent

• Risk factors:

– Underlying asthma – Delayed epinephrine

– Symptom denial – Previous severe reaction

– Adolescents, young adults

• History: known food allergen

• Key foods: peanuts and tree nuts dominate (~90% of fatalities), fish,crustaceans

• Most events occurred away from home

Bock SA, et al. J Allergy Clin Immunol

2001;107:191-3.

Cutaneous Reactions

• Acute urticaria/angioedema – common

• Contact urticaria - common

• Food allergy rarely causes chronic urticaria/angioedema

• 1/3 of children with moderate to severe atopic dermatitis may have food allergy (especially cow’s milk, egg, soy, wheat). Morbilliform rashes may be seen in these children upon food challenge.

• Contact dermatitis (food handlers)

Respiratory Responses

• Upper and lower respiratory

tract symptoms may be seen

(rhinoconjunctivitis, laryngeal

edema, asthma)

• Rarely isolated, usually

accompany skin and GI

symptoms

• Inhalational exposure may

cause respiratory symptoms

that can be severe • Occupational

• Restaurants

• Kitchen/Home Examp

le:

crabs

to be

boiled

Birch Apple, carrot, celery,

cherry, pear, hazelnut

Ragweed Banana, cucumber,

melons

Grass Melon, tomato, orange

Mugwort Melon, apple, peach,

cherry

Pollen-Food

Syndrome or Oral

Allergy Syndrome

• Clinical features: rapid onset oral

pruritus, rarely progressive

• Epidemiology: prior sensitization to

pollens

• Key foods: raw fruits and vegetables

• Allergens: Profilins and pathogenesis–

related proteins

– Heat labile (cooked food usually

OK)

• Cause: cross reactive proteins

pollen/food

Latex-Fruit

Syndrome

• 30-50% of those with latex allergy are sensitive to some fruits due to cross-reactive IgE

• Most common fruits: banana, avocado, kiwi, chestnut but other fruits and nuts have been reported

• Can clinically present as anaphylaxis to fruit

• Warn latex-sensitive patients of potential cross-reactivity

• Some fruit-allergic patients may be at risk for latex allergy

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

Fully reviewed in: Sicherer SH. Pediatrics

2003;111:1609-1616.

GI Syndromes of Children

and Adults:

Celiac Disease (Gluten-sensitive enteropathy) – In children:

• FTT, or weight loss

• Malabsorption, diarrhea, abdominal pain

• May be subtle

– In adults, average 10 years of nonspecific symptoms:

• Diarrhea, abdominal pain

• GERD

• Malabsorption

• May present atypically with osteoporosis, infertility, neurologic sx

Pathophysiology: an immune-mediated enteropathy triggered by gluten peptides in genetically predisposed patients (DQ2 or DQ8)

– Lymphocytic infiltration of small bowel

– Villus atrophy

Celiac Disease

(Gluten-sensitive

enteropathy) Cont’d: • Diagnosis

– ~1/133 people in US have celiac disease – many are currently undiagnosed

– IgA anti-tissue transglutaminase (IgG if IgA-deficient), anti-endomysial Ab, little role for anti-gliadin Ab currently due to poor specificity

– Upper endoscopy with biopsy; refer to gastroenterologist

• Management – Strict, lifelong, gluten avoidance

(wheat, barley, rye)

– Rare risk of GI lymphoma

– Oats almost always OK

– Link with resources: dietician, local support groups, national organizations (listed at www.celiac.nih.gov)

GI Syndromes of Children

and Adults

Gastrointestinal Anaphylaxis

or Immediate

Gastrointestinal Allergy

– IgE-mediated

– Acute

emesis/diarrhea/abdominal pain

– Can present without other signs

or symptoms of an allergic

reaction to food

GI Syndromes of Children

and Adults Eosinophilic Gastrointestinal

Disorders: eosinophilic esophagitis/gastritis/gastroenteritis

• Prevalence increasing, eosinophilic esophagitis is the most common syndrome, all rare in adults

• Symptoms

– Post-prandial N/V/D/abdominal pain, weight loss

– FTT in infants and young children, irritability, sleep disturbance

– GER, often refractory, may be seen

– In teens/adults: dysphagia, food impaction

Eosinophilic Gastrointestinal

Disorders: eosinophilic

esophagitis/gastritis/gastroente

ritis cont’d:

• Diagnosis

– Biopsy: eos infiltration (mucosa

serosa): >20/HPF

– Presence of eos doesn’t necessarily

invoke food allergy

– May affect esophagus to rectum

• Response to specific food elimination

found in a subset of patients

(especially eosinophilic esophagitis):

can screen for food allergy with

prick/in vitro IgE, patch testing with

food is currently under investigation

Prevalence and Natural

History

Prevalence of

Food Allergy

• Perception by public: 20-25%

• Confirmed allergy (oral challenge) – Adults: 2-3.5%

– Infants/young children: 6-8%

• Specific Allergens – Dependent upon societal eating and

cooking patterns

• Prevalence higher in those with: – Atopic dermatitis

– Certain pollen allergies

– Latex allergy

• Prevalence seems to be increasing

Estimated Prevalence of

Food Allergy

Food Children

(%)

Adults

(%)

Cow’s

milk

2.5 0.3

Egg 1.3 0.2

Soy 0.3-0.4 0.04

Peanut 0.8 0.6

Tree nut 0.2 0.5

Crustace

ans

0.1 2.0

Fish 0.1 0.4 Sampson H. J Allergy Clin

Immunol;113:805-19.

Prevalence of Clinical

Cross Reactivity Among

Food “Families”

Food Allergy

Prevalence of Allergy to

> 1 Food in Family

Fish 30% -100%

Tree Nut 15% - 40%

Grain 25%

Legume 5%

Any 11%

Sicherer SH. J Allergy Clin Immunol. 2001

Dec;108(6):881-90.

Natural History

• Dependent on food &

immunopathogenesis

• ~ 85% of cases of cow milk,

soy, egg and wheat allergy

remit by age 3 yrs

– Declining/low levels of

specific-IgE predictive

– IgE binding to conformational

epitopes predictive

• Non-IgE-mediated GI allergy

– Infant forms resolve in 1-3

years

– Toddler / adult forms more

persistent

Natural History

(cont’d) • Allergies to peanuts,

tree nuts, seafoods, and seeds typically persist

• ~20% of cases of peanut allergy resolve by age 5 years.

Prognostic factors include: – PST <6mm

– ≥2 years avoidance

– History of mild reaction

– Few other atopic diseases

– Low levels of peanut-specific IgE

– Rarely re-develop allergy: role for regular ingestion?

Evaluation

Evaluation of Food

Allergy • Suspect IgE-mediated

– Panels/broad screening should NOT be done without supporting history because of high rate of false positives.

– Prick skin tests (prick-prick with fresh food if pollen-food syndrome)

– In vitro tests for food-specific IgE

• Suspect non-IgE-mediated – Consider biopsy of gut, skin

• Suspect non-immune, consider: – Breath hydrogen

– Sweat test

– Endoscopy

Evaluation:

Interpretation of

Laboratory Tests

• Positive prick test or specific IgE – Indicates presence of IgE

antibody NOT clinical reactivity

– ~90% sensitivity

– ~50% specificity

– ~50% false positives

– Larger skin tests/higher IgE correlates with likelihood of reaction but not severity

• Negative prick test or specific IgE – Essentially excludes IgE

antibody (>95% specific)

Evaluation:

Elimination Diets & Food

Challenges

• Elimination diets (1 - 6 weeks) most useful for chronic disease (eg. AD, GI syndromes) – Eliminate suspected food(s)

or – Prescribe limited “eat only”

diet or – Elemental diet

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

controlled (DBPCFC) * Unless convincing history warrants supervised challenge

Diagnostic Approach: IgE-

Mediated Allergy

• If test for specific-IgE

antibody is

– Negative: reintroduce food*

– Positive: start elimination diet

• If elimination diet is

associated with

– No resolution: reintroduce

food*

– Resolution

• Open / single-blind

challenges to “screen”

• DBPCFC for equivocal open

challenges

Diagnostic Approach: Non-IgE-

Mediated Disease or those with

unclear mechanism

• Elimination diets (may need elemental diet)

• Oral Challenges – Timing/dose/approach

individualized for disorder

• Enterocolitis syndrome can induce shock

• Eosinophilic gastroenteritis may need prolonged feedings before symptoms develop

– DBPCFCs preferred

– May require ancillary testing (endoscopy/biopsy)

Management

Management of Food

Allergy

• Complete avoidance of

specific food trigger

• Ensure nutritional needs

are being met

• Education

• Anaphylaxis Emergency

Action Plan if applicable

– most accidental exposures

occur away from home

This frozen dessert

could have peanut,

tree nut, cow’s milk,

egg, wheat

Management: Dietary

Elimination • Hidden ingredients in

restaurants/homes (peanut in

sauces,egg rolls)

• Labeling issues (“spices”,

changes, errors)

• Cross contamination (shared

equipment)

• Seeking assistance

– Food allergy specialist

– Registered dietitian:

(www.eatright.org)

– Food Allergy & Anaphylaxis

Network (www.foodallergy.org;

800-929-4040) and local support

groups

Contain cow’s milk: Artificial butter flavor, butter, butter fat, buttermilk, casein, caseinates (sodium, calcium, etc.), cheese, cream, cottage cheese, curds, custard, Half&Half®, hydrolysates (casein, milk, whey), lactalbumin, lactose, milk (derivatives, protein, solids, malted, condensed, evaporated, dry, whole, low-fat, non-fat, skim), nougat, pudding, rennet casein, sour cream, sour cream solids, sour milk solids, whey (delactosed, demineralized, protein concentrate), yogurt. MAY contain milk: brown sugar flavoring, natural flavoring, chocolate, caramel flavoring, high protein flour, margarine, Simplesse®.

AS of January 1, 2006, all food containing “Big Eight Allergens” (cow’s milk, peanut, tree nut, hen’s egg, soy, wheat, fish, crustacean) in the U.S. MUST declare the ingredient on the label in COMMON language. Does NOT apply to non-Big 8 allergens (e.g., sesame).

Label reading used to be very

challenging!

Example: Cow’s Milk

Food Allergen Labeling and Consumer

Protection Act of 2004 (P.L. 108-282)

(FALCPA)

Management: Infant

Formulas

• Soy (confirm soy IgE negative)

– <15% soy allergy among IgE-CMA

– ~50% soy allergy among non-IgE CMA

• Cow’s milk protein extensive hydrolysates

– >90% tolerance in IgE-CMA

• Partial hydrolysates

– Not hypoallergenic!

• Elemental amino acid-based formulas

– Lack allergenicity

* CMA=cow’s milk allergy

Management:

Emergency Treatment of

Anaphylaxis • Epinephrine: drug of choice

– Self-administered epinephrine readily available at all times

– If administered, seek medical care IMMEDIATELY

– Train patients, parents, contacts: indications/technique

• Antihistamines: secondary therapy only: WILL NOT STOP ANAPHYLXAXIS

• Written Anaphylaxis Emergency Action Plan

– Schools, spouses, caregivers, mature sibs / friends

• Emergency identification bracelet

MYTH: Prior Episodes

Predict Future Reactions

• No predictable pattern

• Severity depends on:

– Sensitivity of the individual

– Dose of the allergen

– Other factors (e.g., food matrix

effects, exercise, concurrent

medications, airway

hyperresponsiveness)

• Must always be prepared for an emergency

.

Key Point: Diphenhydramine

will not block anaphylaxis

• Unfortunately, reaction

severity CANNOT be

predicted to again be mild with

the next episode

– In a United Kingdom series of

anaphylaxis fatalities, 1/3 of

food allergy deaths were in

patients with such mild

reactions to foods (mainly

peanuts/tree nuts) that they

had not been prescribed self-

injectable epinephrine*

– Consider self-injectable

epinephrine for all at risk of

anaphylaxis *Pumphrey RS. Clin Exp Allergy. 2000

Aug;30(8):1144-50.

This is

available for

download.

Parents can

add their

child’s photo

on the plan

and review it

with

caregivers/sch

ools.

Available at:

www.aaaai.org

The form was adapted from J

Allergy Clin Immunol

1998;102:173-176 and J Allergy

Clin Immunol 2006;117:367-

377.

Management: Follow-

Up

• Re-evaluate for tolerance

periodically

• Interval and decision to re-

challenge:

– Type of food allergy (IgE vs non-

IgE)

– Severity of previous symptoms

– Allergen/Prognosis (cow’s milk vs

peanut)

• Ancillary testing

– Skin prick test/in vitro specific IgE

may remain positive

– Decline in concentration of food

specific-IgE is suggestive of

development of tolerance

Prevention

Food Allergy Prevention

• Expect revisions – research

is ongoing

( American Academy of Pediatrics

recommendations for children at risk of

food allergy include a delay in

introduction of certain foods:

– Solid foods: after age

6 mos

– Cow’s milk/dairy: after age

1 yr

– Egg: after age

2 yrs

– Peanut, tree nut, seafood: after age

3-4 yrs)

(2008 Committee report states that there

is NO CONVINCING EVIDENCE that

delaying solids beyond 4-6 mos has a

significant protective effect on

American Academy of Pediatrics Committee on Nutrition.

Pediatrics 2000;106:346-9.

Food Allergy Prevention

• Exclusive breastfeeding for at least 4 months decreases eczema and cow milk allergy in the first 2 years of life in infants at high risk for atopy

• Recent studies (Fox) show early oral intake of peanuts decreases peanut allergy while env. exposure alone increases the risk

• Du Toit showed that peanut allergy was 10-fold higher in Jewish children in the UK vs. Israel where peanut is introduced early

Fox AT, et al. J Allergy Clin Immunol 2009;123:417-23.

Du Toit G, et al. J Allergy Clin Immunol 2009;122:984-91.

Ongoing Studies

• The Food Allergy Research

Consortium-NIH sponsored

consortium to study food

allergy

• Now underway:

Observational study of solids in

infants>4mo

Egg oral immunotherapy

Peanut sublingual

immunotherapy

Recombinant peanut vaccine

safety study

Future Approaches

Future Immunomodulatory

Approaches

• Recombinant anti-IgE antibody

• Gene (naked DNA) immunization

• Mutated B-cell epitopes

• Minimal T-cell epitopes

• Immune-modulating adjuvants (ISS)

• Probiotics

• T lymphocyte manipulation to induce

tolerance

• Chinese herbal remedies (Food

Allergy Herbal Formula)

TH0 TH1

TH2

TH2

TH1

Tolerance (immune deviation)

Sensitization

“atopics”

“Non-

atopics”

antigen

IgE

cDNA, Probiotics Peptides/Epitopes

Immune

Modulation

Anti-IgE Sicherer SH, unpublished

Role of the Allergist

Reasons for Allergy

Referral

• Persons who have limited their diet based upon perceived adverse reactions to foods or additives.

• Persons with a diagnosed food allergy

• Atopic families with, or expecting, a newborn who are interested in identifying risks for, and preventing, allergy.

• Persons who have experienced allergic symptoms in association with food exposure.

• Persons who experience an itchy mouth from raw fruits and vegetables.

Leung D, et al. J Allergy Clin Immunol

2006;117:S495-523.

Reasons for Allergy

Referral (Cont’d)

• Infants with recalcitrant gastroesophageal reflux or older individuals with recalcitrant reflux symptoms, particularly if they experience dysphagia.

• Infants with gastrointestinal symptoms including vomiting, diarrhea (particularly with blood), poor growth, and/or malabsorption whose symptoms are otherwise unexplained, not responsive to medical management, and/or possibly food-responsive (even if screening allergy tests are negative).

• Persons with known eosinophilic inflammation of the gut.

Leung D, et al. J Allergy Clin Immunol

2006;117:S495-523.

Role of the Allergist

• Identification of causative food

• Institution of elimination diet

• Education on food avoidance

• Development of an Anaphylaxis

Emergency Action Plan

• Prevention of other allergies

• Follow-up to ascertain tolerance

Summary and

Conclusions • IgE & non-IgE-mediated

conditions exist

• The history and physical are

paramount

• Elimination diets, skin testing, in

vitro assays, and food challenges

also have roles in diagnosis

• Avoidance, education, and

preparation for emergencies are

the pillars of current management

• Periodic re-challenge to monitor

tolerance as indicated by history,

allergen, and level of food-

specific IgE is an important part

of ongoing follow-up