foods - NYSOMS

Food Allergy
Marianne Frieri, M.D., Ph.D
Chief, Allergy Immunology
Nassau University Medical Center-Long
Island Jewish Health Care Systems (LIJHCS),
Dept of Medicine, Attending in
Pediatrics;Medicine,LIJHCS.
Faculty @ NYCOM/NYIT
Professor of Medicine & Pathology, State
University of New York at Stony Brook
Learning objectives
•
•
•
•
At the end of this presentation you will
be able to:
Recognise the main pathogenic food
allergens in adults and children
Differentiate between IgE-mediated,
cell-mediated and and mixed IgEmediated food-related diseases in
different organ systems
Discuss the diagnosis of food allergy
and the limitations of diagnostic
techniques
Review the treatment options
Adverse reactions to food:
Definition
Any abnormal clinical response
attributed to ingestion, contact or
inhalation of any food, a food derivative
or a food additive
•Toxic
•Non toxic or hypersensitivity
Adverse reactions to food
TOXIC
Nontoxic
Immune-mediated
Allergy
Non-IgE-mediated
IgE-mediated
Adverse Reactions to Food: Position
Paper. Allergy 1995; 50:623-635
Non-immune
mediated
Intolerance
Enzymatic
Pharmacologic
Undefined
Prevalence of food allergy
Precise prevalence is unknown, but
estimates are:
• Adults: 1.4% - 2.4%
• Children < 3 years: ~ 6%
• Atopic dermatitis (mild/severe): ~35%
• Asthmatic children: 6 - 8%
• Prevalence depends on: Genetic factors,
age, dietary habits, geography and
diagnostic procedures
Adapted from Sampson HA. Adverse Reactions to
Foods. Allergy Principles and Practice. 2003
“Second tier” foods
•
•
•
•
•
•
10% reactions to foods
160 foods
Fruits
Vegetables
Seeds (sesame, sunflower, poppy)
Spices
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, other
depending on geographical area
- Adult: peanut, nuts, shellfish, fish
• Single food (or related) > many food allergies
• Characterization of epitopes underway
- Linear vs conformational epitopes
- B-cell vs T-cell epitopes
Pathogenesis of food hypersensitivity: Gut barrier
•
•
•
The immune system is capable of discriminating
among harmless foreign proteins, commensal
organisms and dangerous pathogens
Food allergy is an abnormal response of the
mucosal immune system to antigens delivered
through the oral route
The immature state of the mucosal barrier might
play a role in the increased prevalence of
gastrointestinal infections and food allergy in
the first few years of life
Adapted from J Allergy Clin Immunol 2004;113:808-809; Frieri M Food Allergy. In: Current
Review of Allergic Diseases. Ed: Kaliner MA, Blackwell Science,1999. Food Hypersensitivity
and Adverse Reactions: A Practical Guide for Diagnosis and Management, Marcel Dekker,
Editors: Frieri M, Kettelhut B 1999.
Dual-allergen-exposure hypothesis for pathogenesis of food allergy. Tolerance occurs
as a result of oral exposure to food, and allergic sensitization results from cutaneous
exposure. GI, Gastrointestinal. Lack G J Allergy Clin Immunol121:1331-6, 2008.
Pathogenesis of food
hypersensitivity: Gut barrier
• About 2 % of ingested food antigens
are absorbed and transported
throughout the body in an
immunologically intact form, even
through the immature gut
• The underlying immunologic
mechanisms involved in oral tolerance
induction have not been fully
elucidated
Adapted from J Allergy Clin Immunol 2004;113:808-809
Pathophysiology: Immune Mechanisms
Protein digestion
Antigen processing
Some Ag enters blood
IgE-Mediated
IgE-receptor
APC
Mast cell
Non-IgEMediated
Histamine
B cell
T cell
TNF-
IL-5
Possible mechanisms of allergic sensitization to gastrointestinal antigen.Ag complex is sampled
by the gut-associated immune system via M cells or across enterocytes. Ag delivery to DCs, is
enhanced by antigen stability or compromised epithelial barrier. Intrinsic or associated features of
allergens activate DCs and other innate immune cells enhancing signals that instruct naive T
cells to a TH2 phenotype which may include membrane bound ligands expressed on DCs,
(OX40L, TIM-4, and jagged), that interact with their receptors on T cells, and soluble mediators
from other cells, as IL-4 and TSLP. Treg, Regulatory T cell.
Berin MC et al, J Allergy Clin Immunol 121:1311-20. 2008
Food Allergy: Clinical manifestations
IgE
IgE/Non-IgE
Urticaria/angioedema Atopic
Rhinitis /Asthma
dermatitis
Anaphylaxis
Oral allergic
syndrome
Gastrointestinal
symptoms (GIT)
Eosinophilic
gastrointestinal
disorders
Non-IgE
Protein-induced
proctocolitis/enterocolitis
Celiac disease
Contact dermatitis
Herpetiform dermatitis
Heiner´s syndrome
Adapted from J Allergy Clin Immunol. 1999;103:717-728
Cutaneous food hypersensitivity:Atopic eczema
• Generally begins in early infancy
• Characterized by typical distribution, extreme pruritus, and
chronically relapsing course
• Allergen-specific IgE antibodies bound to Langerhans cells
play a unique role as “non-traditional” receptors
• Double blind, placebo-controlled food challenges generally
provoke markedly pruritic,erythema,morbilliform rashes
• Food allergy plays a pathogenic role in about 35 % of
moderate-to-severe atopic dermatitis in children
Frieri M, et al. Association between CD62 ligand on naive and memory T cells; history of
cow’s milk hypersensitivity in atopic patients. Ann Allergy Asthma Immunol. 92:565-72,’04
Cutaneous food hypersensitivities
Acute Urticaria and Angioedema:
♦ The most common symptoms of food allergic reactions
♦ The exact prevalence of these reactions is unknown
♦ Acute urticaria due to contact with food is also common
Chronic Urticaria:
♦ Food allergy is an infrequent cause of chronic urticaria and
angioedema
IgE Mediated:Respiratory Manifestations
Asthma
• An uncommon manifestation of food allergy
• Usually seen with other food-induced symptoms
• Vapors or steam emitted from cooking food may
induced asthmatic reactions
• Food-induced asthmatic symptoms should be
suspected in patients with refractory asthma and
history of atopic dermatitis, gastroesophageal reflux,
food allergy or feeding problems as an infant, or history
of positive skin tests or reactions to food
Rhinoconjunctivitis
• Usually seen during positive controlled challenge tests,
but occasionally reported by patients
Bielory L Part II.J Allergy Clin Immunol 2000;106:1019-32. Chemosis
represents swelling of the conjunctiva in allergic conjunctivitis. This is
similar to an urticarial eruption on the conjunctival surface.
IgE Mediated: Systemic reaction
anaphylaxis/anaphylaxis syndrome
• Food-induced anaphylaxis
- Rapid-onset
- Multi-organ system involvement
- Potentially fatal
- Any food, highest risk:
peanut, nut, seafood, milk, egg
• Food-dependent - exercise-induced
- Associated with a particular food
- Associated with eating any food
ANAPHYLAXIS AND APS
• Four patients were reported with thrombosis
associated with APS and anaphylaxis to ingested
vegetal foods.
• All 4 had high specific IgE to certain food
allergens mostly to lentils, grains, rye grass,
chestnut, blackberry, strawberry, almond and
latex.
• A role of lipid transfer proteins (LTPs) as a
relevant panallergen was suspected as important
in food allergy cross reactivity
• A recent consensus on APS encourages studies to
document features of this syndrome.
Armentia A et al. Ann Allergy Asthma Immunol 2001:27-54-59; Wilson Wa et al,
Arthritis Rheum 1999; 42:1309-1311
Selected cases of Anaphylaxis
Puglisi G, Frieri M. Allergy Asthma Proc, 28:634-639, 2007
• A case of anaphylactic shock due to inadvertent ingestion of a
hidden carrot allergen contained in ice cream. Carrot allergy
confirmed by in vivo and in vitro assays. Other ingredients of
the ice cream was excluded through DBPCC.1
• DM-sensitive female with dyspnea twice after ingesting
pancakes and anaphylaxis on the second episode. Microscopic
examination of the mix revealed DM, and skin-prick test was
positive to the pancake mix.2; similar cases by MF 10 years ago
and this year 3 .
• A surgical resident with latex hypersensitivity who developed
systemic anaphylaxis to snacks adjacent to a bowl of
guacamole.4
1.Schiappoli M, et al. Allergol Immunopathol(Madr.) 30:243–244, 2002;2 Ott NL.Ann Allergy.Asthma Immunol 92:169a, 2004
3.Frieri M. Personal observation, 2008;4.Therattil JM, Kumar N, and Frieri M. Ped Allergy Asthma Immunol 11:141–146, 1997.
Fatal food anaphylaxis
Frieri M. Anaphylaxis. In: Manual of Critical Care,
Philadelphia, Pa. American College of Physicians, 2009
• Frequency: ~ 100 deaths/yr
• Risk:
- Underlying asthma - Delayed
epinephrine
- Symptom denial
- Previous severe
reaction
• History: known allergic food
• Biphasic reaction
• Lack of cutaneous symptoms
BIPHASIC/LATE-PHASE REACTION
Cellular infiltrates: 3 to 6 hours (LPR)
Eosinophil
Histamine
IL-4, IL-6
Allergen
3 to 6 hours
(CysLTs, PAF,
IL-5)
CysLTs, GM-CSF,
TNF-, IL-1, IL-3, PAF,
ECP, MBP
Basophil
Histamine,
CysLTs,
TNF-, IL-4, IL-5, IL-6
Monocyte
PGs
CysLTs
Proteases
Mast cell
EPR 15 min
(Early-Phase Reaction)
CysLTs, TNF-,
PAF, IL-1
Lymphocyte
IL-4, IL-13, IL-5,
IL-3, GM-CSF
Return
of
Symptoms
Hidden Sources of Food Allergens
Cross-Contact
Serving utensils
Food manufacturing equipment
Handling of foods
Ingredient switching
Cross-reactivity
Allergenic foods not covered by the FALCPA
Undeclared allergenic foods
Loopholes in labeling regulations
Contamination of foods with allergens not intended
to be foods
Additives
Preservatives
Antigenic substances
Puglisi G, Frieri M. Allergy Asthma Proc, 28:634-639, 2007
Food-dependent, exercise-induced
anaphylaxis
Exercise
Wheat
Temperature
Gastrin
Mediator release
- Histamine
- Others (LTD4,PAF, etc)
ANAPHYLAXIS
Adapted from Adverse Reactions to Foods Committee. Spanish Society of Allergy and
Clinical Immunology
IgE-mediated: GIT manifestation
Oral allergy syndrome (OAS)
• Elicited by a variety of plant proteins that
cross-react with airborne allergens
• Pollen allergic patients may develop symptoms
following the ingestion of vegetable foods:
- Ragweed allergic patients: Fresh melons and
bananas
- Birch pollen allergic patients: Raw potatoes,
carrots, celery, apples, pears, hazelnuts and
kiwi
• Immunotherapy for treating the pollen-induced
rhinitis may reduce/eliminate oral allergy
symptoms
Adapted from J Allergy Clin Immunol. 2004;
113:808-809
Food allergy prevalence in specific disorders
Disorder
Food Allergy Prevalence
Anaphylaxis
Oral allergy syndrome
35 - 55 %
25 - 75% in pollen allergic
patients
Atopic dermatitis
35% in children
(rare in adults)
Urticaria
20% in acute
(rare in chronic)
5 - 6% in asthmatic or food
allergic children
Rare
Asthma
Chronic rhinitis
Mixed IgE/Non-IgE mediated: GIT
allergic eosinophilic disorders
• Characterized by infiltration of the esophagus, stomach
and/or intestinal walls with eosinophils, basal zone
hyperplasia, papillary elongation, absence of vasculitis and
peripheral eosinophilia in about 50 % of patients
• AEE can occur in children and adults. Increasing yearly
incidence (23/100.000 population in Switzerland)
• In children symptoms similar to gastroesophageal reflux
and in adults dysphagia and impaction is common
• Almost 50% of patients have other atopic diseases
• Diagnosis is based on endoscopic findings and biopsy
(>15-20 eosinophils per High Power Field)
Adapted from J Allergy Clin Immunol. 2006; 118:1054-9
Mixed IgE/non-IgE mediated: GIT
allergic eosinophilic esophagitis (AEE)
 Dysphagia
 Abdominal pain
 Poor response to anti - reflux
drugs
 Biopsy:Eosinophils ++++
>20 eosinophils / HPF
 Eotaxin – 3 tissue
expression correlates with
eosinophilia – crucial in
pathogenesis of this
Bullock et J Pediatr Gastroenterol Nutr. 2007
Allergic eosinophilic esophagitis
endoscopic findings
Rings
White plaques
(eosinophils)
Mixed IgE/non-IgE Mediated: GIT
Allergic Eosinophilic Gastroenteritis (AEG)
Vomiting, diarrhea (post-prandial)
Blood loss
Iron deficiency
Protein/iron- losing enteropathy
↑ TH2 in blood and mucosa
↑ Mast cells, Eosinophils in mucosa
Eotaxin - 3
Persistent food hypersensitivity at 5yr FU.
Weight loss, FTT+/_oedema
Chehade M et al JPGN 2006;42;516-521
AEE and AEG
• Food antigens have been implicated as
one of the main etiologies
• Skin prick test and atopy patch tests can
be useful for food allergy diagnosis
• Elimination diets or even amino-acid
formula can be instituted on the basis of
allergy testing, clinical history, biopsy and
treatment response
• Pharmacologic treatment: oral steroids
and/or swallowed aerosolized fluticasone
• ? Anti-IL-5 therapy
Adapted from J Allergy Clin Immunol. 2006; 118:1054-9
A proposed model to explain molecular and cellular mechanisms involved in EE pathogenesis, eotaxin-3–associated
eosinophil recruitment, and treatment. Aeroallergen, food allergen, and skin sensitization have been implicated in EE
pathogenesis (J Allergy Clin Immunol 2006;118:1054-9.)
Non-IgE mediated: GIT food protein induced
syndromes (typically milk & soy induced)
# Solid foods implicated: fish, corn, chicken, turkey, vegetables
Enterocolitis #
Enteropathy
Proctocolitis
Age Onset:
Infant
Infant/Toddler
Newborn
Duration:
12-24 mo
? 12-24 mo
< 12mo
Characteristics: Failure to thrive
stools
Shock
sx
Lethargy
Eosinophil
Diarrhea
Nowak-Wegrzyn et al Pediatrics 2003
Zapatero Remon L et al. Allergol Immunopathol 2005
Malabsorption
Villous atrophy
Diarrhea
Bloody
No systemic
Non IgE mediated: GIT food proteininduced enterocolitis syndrome
• Occurs in infants prior to 8-12 months of age, but may be
delayed in breast-fed babies (milk or soy protein-based
formulas are implicated)
• Symptoms may include irritability, protracted vomiting 13 hours after feeding, bloody diarrhoea (leading to
dehydration), anaemia, abdominal distension, failure to
thrive
• In adults and older children, fish, shellfish and cereals
hypersensitivity may provoke a similar syndrome with
delayed onset of severe nausea, abdominal cramps and
protracted vomiting
• Resolved: 50% at 18 months, 90% at 36 months
Adapted from J Allergy Clin Immunol. 2004;113:808-809
Non-IgE Mediated: GIT food protein
induced enteropathy (excluding celiac )
• Occurs from 0 - 24 months
• Diarrhea (mild to moderate steatorrhea in about
80% of cases)
• Food implicated: milk, cereals, egg, fish
• Poor weight gain
• Diagnosis:
-Biopsy shows patchy villous atrophy with
prominent
mononuclear round cell infiltrate,
few eosinophils,
-Response to exclusion diet,
-Challenge test
• Resolved at 2 - 3 years old
Adapted from J Allergy Clin Immunol. 2004;113:808-809
Non-IgE Mediated: GIT food
protein-induced protocolitis
• Usually presents in the first few months of life
and is thought to be due to food proteins passed
to the infant in maternal breast milk, or to milk or
soy-based formulas
• Rectal bleeding is common
• Diagnosis: endoscopy and colonic biopsy
(eosinophils in epithelium and lamina propia)
• Good response to extensively hydrolized
formulas. Diet without dairy product in mother if
lactating
• Good prognosis with resolution at 12 months of
life
Adapted from J Allergy Clin Immunol. 2004;
113:808-809
Non-IgE Mediated:GIT Celiac disease
• Extensive enteropathy leading to
malabsorption
• Associated with an immune reaction to gliadin
peptides (wheat, rye and barley)
• Highly associated with HLA-DQ2 1 *0501. 1
*0201)
• Serology: anti-transglutaminase IgA, Antigliadin IgA (asymptomatic and +ve serology is
common)
• Treatment: Elimination of gluten-containing
foods
Adapted from J Allergy Clin Immunol. 2004;113:808-809
Celiac Disease for the Allergist.
Hoffenberg EI. Allergy Asthma Proc 28:20-24,’07
Celiac disease is unique among autoimmune diseases in that three elements, a
genetic predisposition, environmental exposure and an autoantigen, are known.
Allergy Asthma Proc 28:20 –24, 2007
Differential diagnosis presentation
Malabsorption Abdominal Pain Growth
Vomiting
Pubertal Delay
Crohn’s disease
Acid-peptic disease
Intestinal parasite
Food allergy
H. pylori
Food allergy
Crohn’s disease
Nonspecific
Complaints
Depression
Growth hormone Irritable bowel
deficiency
Thyroid disease
Malignancy
Pancreatitis
Lactose intolerance Gall bladder disease
DH _ Dermatitis herpetiforms.
DH
Eczema
FA
Nutritional deficiency:
B12, folate, iron
Non-IgE-mediated syndromes
affecting the skin and lung
• Dermatitis Herpetiformis
- Vesicular, pruritic eruption
- Gluten-sensitive
- Associated with Celiac Disease
• Heiner’s Syndrome
- Infantile pulmonary hemosideroisis
- Anemia, failure to thrive
- Cow’s milk-associated
- Precipitating antibodies to cow’s milk
Gastrointestinal food hypersensitivity?
Infantile colic
• Syndrome of paroxysmal fussiness
characterized by inconsolable,
agonized crying
• Generally develops in the first 2 to 4
weeks of life and persists through the
third to fourth months
• Diagnosis can be established by the
implementation of several brief trials
of hypoallergenic formula
Adapted from J Allergy Clin Immunol. 2004;113:808-809
Disorders not proven to be
related to food allergy
• Migraines ?
• Behavioral/Developmental
disorders
• Arthritis
• Seizures
• Inflammatory bowel disease ?
Food Allergy Referrral Guidelines
Journal of
Allergy Clin Immunol S117 #2, 2006; Frieri M. A Preliminary Study of IL-4 detection in Atopic
Pediatric; Adult Patients: Effect of Dietary Modification Annals of Asthma Allergy Immunol 7; 27-35,
1993; Frieri M. Food Hypersensitivity and Adverse Reactions.A Practical Guide for Diagnosis and
Management, Marcel Dekker,1999;Food Allergy..Current Rev of Allergic Diseases. Ed: Kaliner MA,
Blackwell ‘99
• Patients with a diagnosed food allergy or oral
allergy syndrome
• Patients who have limited their diet
• Atopic families expecting a newborn interested
in identifying risks
• Patients with urticaria, angioedema, wheezing,
gastrointestinal responses with food exposure
• Infants with recalcitant gastrointestinal refux or
other symptoms, vomiting, diarrhea,
eosinophilic inflammation
Diagnosis: History / Examination
• History: symptoms, timing, reproducibility
Acute reactions vs chronic disease
• Diet details / symptom diary
Specific causal food/s
“Hidden” ingredient/s
• Physical examination: Evaluate disease
severity
• Identify general approach
Allergy vs intolerance
IgE-mediated vs non-IgE mediated
Diagnosing food hypersensitivity
disorders: IgE-mediated
 Identification and relationship with the food:
Medical history
 To identify specific IgE: Skin tests/serum
specific IgE
 To demonstrate that IgE sensitization is
responsible for the clinical reaction: Controlled
challenge tests
 Diagnosis is based on the medical history,
supported by identification of specific IgE
antibodies to the incriminated food allergen
and confirmed by challenge
Adapted from Adverse Reactions to Foods Committee.
Spanish Society of Allergy and Clinical ImmunologyAlergol Inmunol Clin 1999; 14: 50-62.
Diagnosing IgE-mediated food
hypersensitivity disorders
Medical history: Symptoms
 Symptoms described by patient
 Length of time between ingestion and
development of symptoms
 Severity of symptoms
 Frequency of symptoms
 Time from last episode
Adapted from Adverse Reactions to Foods Committee.
Spanish Society of Allergy and clinical Immunology
Alergol Inmunol Clin 1999; 14: 50-62.
Diagnosing IgE-mediated food
hypersensitivity disorders
Medical history: Timing of reaction
An immediate reaction (1- 2
hours) is suggestive of an IgE
mediated reaction to foods
 It may be preceded by
previous tolerance of
minimal symptoms
 It may occur apparently
after the first contact
Adapted from Adverse Reactions to Foods Committee, Spanish Society of Allergy and
Clinical Immunology Alergol Inmunol Clin 1999; 14: 50-62.
Diagnosing IgE-mediated food
hypersensitivity disorders
Medical history: food






Identification of food
How food was prepared
Quantity ingested
Previous tolerance
Cross-reactions with other food
Hidden foods, additives, contaminants
Adapted from Adverse Reactions to Foods Committee.Spanish Society of Allergy and
clinical Immunology Alergol Inmunol Clin 1999; 14: 50-62.
Diagnosing IgE-mediated food
hypersensitivity disorders
Medical history: Patient
 Age at onset of symptoms
 Other factors (eg, brought on by exercise)
 Personal and family history of atopic
diseases
 Risk factors
 Physical examination: Atopic dermatitis,
dermographism, nutritional status
Adapted from Adverse Reactions to Foods Committee. Spanish Society of Allergy and
clinical Immunology Alergol Inmunol Clin 1999; 14: 50-62.
Diagnosing IgE-mediated food
hypersensitivity disorders
 The diagnosis of food allergy cannot be
performed on the basis of a noncompatible medical history
 No diagnostic analysis (skin tests,
specific IgE in serum, etc) is of value if
it is interpreted without reference to
medical history
Adapted from Adverse Reactions to Foods Committee. Spanish Society of Allergy and
Clinical Immunology Alergol Inmunol Clin 1999; 14: 50-62.
Diagnosing IgE-mediated food
hypersensitivity disorders
Skin tests
Prick:
Reproducible, sensitive, not irritant
Prick-prick:Use raw or cooked food. Highly
recommended for fruits and vegetables
(commercially prepared extracts are generally
inadequate because of the lability of the
allergens, so the fresh food must be used for
skin testing)
Diagnosing IgE-mediated food
hypersensitivity disorders
 Skin Prick Tests are used to
screen patients for sensitivity to
specific foods
 Allergens eliciting a wheal of at
least 3 mm > the negative
control are considered positive
 Overall positive predictive
accuracy is < 50 %
 Negative predictive accuracy >
95 % (negative skin tests
essentially confirm the absence
of IgE-mediated reactions)
+
Diameter
 3 mm
Diagnosing IgE-mediated food
hypersensitivity disorders
Skin tests
 Atopy Patch test (APT): Atopic dermatitis, delayed
reactions
Recommended
Fresh food or dry food
Non-standardized
Intradermal:
Not indicated
Difficult to interpret
Specific IgE to food
(CAP / Radioallergosorbent tests)




*Sensitivity similar to skin prick tests
*Good correlation with other procedures
*Efficiency: Depends on the allergen
*Indicated if SPT are contraindicated (eg, skin disease,
medications)
 *Useful if discrepancy exists between history and SPT
 *The use of quantitative measurements has shown to be
predictive, for some allergens, of symptomatic IgEmediated food allergy
 *Possibility to perform component-resolved diagnosis
very useful in cross-reactivity reactions: profilins (Bet
v2, Phl p12), polcalcins (Bet v4, Phl p7), LPT (Pru p3,
Cor a8), Gly m4, Cross-reactive Carbohydrate
Determinants or CCDs
Diagnostic food-specific IgE values (CAPsystem fluorescent enzyme immunoassay) of
greater than 95% positive predictive value
Food
Egg
≤ 2 yr old
Milk
≤ 2 yrs old
Peanut
Fish
Tree nuts
Serum IgE Value (kU/L)
≥7.0
≥2.0*
≥15.0
≥5.0**
≥14.0
≥20.0
≥15.0
From Sampson HA: JACI 107:891-896,2001.
*
Boyano-Martinez T, Garcia-Ara C, Diaz-Pena JM, et al: Clin Exp Allergy 31:1464-1469,2001.
** Garcia-Ara C, Boyano-Martinez T, Diaz-Pena JM, et al: JACI 107:185-190,2001.
Diagnosing IgE-mediated food
hypersensitivity disorders
Serum specific IgE (CAP / RAST)
Advantages
 Quantitative and comparable measurements
 Use of recombinant allergens
 Component-resolved diagnosis
Disadvantages
 Multiple determinations with one blood sample
 Cost
 Results delayed
Interpretation of laboratory tests
• Positive prick test or RAST / CAP
- Indicates presence of IgE antibody NOT
clinical reactivity (~50% false positive)
• Negative prick test or RAST
- Essentially excludes IgE antibody (>95%)
• Intradermal skin test with food
- Risk of systemic reaction & not predictive
Cross-reactivity among foods
• Patients often have positive SPTs or RAST results to other
members of a plant family or animal species immunological reactivity – does not always correlate with
clinical reactivity
• Cross reactions caused primarily by “Type 1” sensitization
Legumes, tree nuts, fish, shellfish, cereal grains,
mammalian and avian food products
• Cross reactions caused by “Type 2” sensitization
- Pollen-food allergy syndrome (oral allergy syndrome),
- Latex- food syndrome
• Proper clinical evaluation (ideally by double-blind placebocontrolled challenge testing) is necessary in patients who
demonstrate immunological cross-reactivity to foods and
when tolerance to food is unknown (to avoid unnecessary
restriction of certain foods)
Cross reactions with foods:
Clinical implications
• If the patient is diagnosed with allergy to a
food, assessment of clinical sensitization to
foods with known cross reactivity is
recommended
• If the patient is diagnosed with allergy to a
food with known cross reactivity with
another food which he / she is not eating
(unknown tolerance) that food must be
challenged to assess tolerance
Diagnosing IgE-mediated food
hypersensitivity disorders
Other Techniques
 *Histamine release with foods:
Similar sensitivity and specificity to serum
specific IgE
 *Sulphidoleukotrienes released from basophils
with food: Not well studied
 *For monitoring food challenges:
- Plasma and urinary histamine: High sensitivity,
low specificity
- Serum tryptase: High specificity, low sensitivity
Unproven / experimental tests (useless)
•
•
•
•
•
Provocation / neutralization
Cytotoxic tests
Applied kinesiology
Hair analysis
IgG4
Diagnosis: Elimination Diets
and Food Challenges
• Elimination diets (1 - 6 weeks):
- Eliminate suspected food/s, or
- Prescribe limited “eat only” diet, or
- Elemental diet
• Oral challenge testing:
- Physician supervised
- Emergency room medications must be
available
Basic elimination diet:
ALLOWED foods
•
•
•
•
Rice
Fruit: Pear, Apple, Grape
Meat: Lamb, Chicken
Vegetables: Asparagus, Beetroot, Carrots,
Lettuce, Sweet potatoes, Butternut Squash
• Other: Black Tea, Rooibos
• Olive oil, Sunflower oil, Sugar, Salts
NB: No Preservatives, no tinned or packet
foods
Types of challenge testing
• Double -blind
• Single-Blind
• Open
• Exercise + oral challenge
• Inhalation challenge
Double-blind, placebo-controlled
food challenge testing: Limitations
• Tedious
• Time-consuming and expensive
• Potential risk requires specialist unit
(research)
• IgE-mediated or non-IgE-mediated?
Diagnostic approach:
Non-IgE-Mediated disease
• Includes disease with unknown mechanisms
- Food additive intolerance
• Elimination Diets (may need elemental diet)
• Oral Challenges
- Timing / dose / approach individualized for
disorder
- Enterocolitis syndrome can elicit shock
- Enteropathy / eosinophilic gastroenteritisprolonged feedings to develop symptoms
• May require ancillary testing (endoscopy /
biopsy)
Food allergy: Treatment
•
•
•
•
•
•
•
Correct diagnosis
Treatment of reactions
Avoidance
Role of dietician
Tolerance assessment
Prevention
Immunotherapeutic strategies
Adapted from Adverse Reactions to Foods Committee. Spanish Society of Allergy and
Clinical Immunology
Treatment emergency medicines
• Epinephrine: drug of choice for reactions
- Self-administered epinephrine readily available
- Train patients: Indications / technique
• Antihistamines: Secondary therapy
• Emergency plan in writing
- Schools, spouses, caregivers, mature siblings
/ friends
• Emergency identification bracelet
Treatment: Avoidance
• Mainstay of treatment
• Must be considered as a therapeutic
approach
• Risk-benefit must be assessed
- Correct diagnosis is essential
- Very restrictive diets can lead to
malnutrition
• Dietician’s role is crucial
Vitamins and minerals which will be
affected by restricted diet
Allergen
Vitamin and Minerals
Milk
Vitamin A, vitamin D, riboflavin, pantothenic acid,
vitamin B12, calcium, & phosphorus
Egg
Vitamin B12, riboflavin, pantothenic acid, biotin, &
selenium
Soy
Thiamin, riboflavin, pyridoxine, folate, calcium,
phosphorus, magnesium, iron, & zinc
Wheat
Thiamin, riboflavin, niacin, iron, & folate if fortified
Peanut
Vitamin E, niacin, magnesium, manganese, &
chromium
Treatment: Dietary elimination
•
•
•
•
Hidden ingredients
Labelling issues
Cross contamination (shared equipment)
“Code words” (“Natural flavor” may be
cow’s milk)
• Seeking assistance
Registered dietician: (www.eatright.org)
• Food Allergy Network
(www.foodallergy.org) (800-929-4040)
Hidden foods
READ LABELS IN PREPARED FOOD!!! Puglisi G, Frieri M. Allergy
Asthma Proc, 28:634-639, 2007
Some foods (allergens) are masked and may be taken
un-noticed during diagnostic procedure:
– Spices: Mustard, pepper, sesame
– Legumes and tree nuts: Peanut, soy
– Milk protein (protein supplements): Caseine,
caseinates
– Vaccines
– Kitchen tools, volatile allergens
– Transgenic foods with new proteins
Parasitized food:
– Mites in flour ( pasta, pizzas)
– Anisakis simplex in fish
Natural history
• Dependent on food & immunopathogenesis
• IgE-mediated allergy:
- CM 85% remit by 8 yrs
Saarinen et al JACI 2005
- Egg 66% remit after 5 yrs
Bovano-Martinez et al JACI 2002
- Peanut 20% may remit (8% may recur)
Fleischer et al JACI 2004
- Tree nut, seafood typically persist
• Declining/low levels of specific-IgE predictive
• Non-IgE-associated GI allergy
- Infant forms resolve 1- 3 years
- Toddler/adult forms more persistent
Treatment: Follow-up
• Re-evaluate for tolerance periodically
• Interval and decision to re-challenge:
- Type of food allergy
- Severity of previous symptoms
- Allergen
• Ancillary testing
- Skin prick test/RAST/CAP may
remain positive
- Reduced concentration specific-IgE
encouraging
Food specific IgE cut off levels which
predict 50% pass rate for challenge
Food
Milk
Egg
Peanut
Wheat
Soy
Perry et al. JACI 2004
IgE level (KUA/l)
2
2
2
?
?
Prevention of food allergy / allergic disease
• Identify patients at risk (difficult)
– There is no reliable or genetic immunological
marker
– Atopic background in parents, siblings
• Dietary restriction (milk, egg, fish, nut)
– In pregnancy: No benefit
– Adverse effects on maternal-fetus nutrition
– Hydrolyzed formula (HF): Variable effect (Cochrane
Database Syst Rev. 2006 Oct 18); GINI Study, JACI
Mar 2007; extensively HF & partially HF reduce
incidence of AD, but not that of asthma
– Delayed introduction of solid food: Variable effect
(Ann Allergy Asthma Immunol. 2006;97:10-20)
• Prolonged breast feeding?
• Probiotics??
Probiotics and Food
Hypersensitivity
• LGG was evaluated in children with milk or
• egg sensitivity and atopic dermatitis
• IL-4 production increased in absence of
LGG
• TNF levels significantly increased in milk
antigen stimulated cultures which
significantly decreases with LGG
Frieri M et.al. Ann Allergy Asthma Immunol
92:134,P47a;2004.Soc. Mucosal Immunol, Oct.
2005
Future immunomodulatory therapies
• Humanized anti-IgE monoclonal antibody therapy
• “Engineered (mutated) allergen protein
immunotherapy
• Antigen-immunostimulatory sequence (CpG)modulated immunotherapy
• Peptide immunotherapy
• Plasmid-DNA immunotherapy
• Cytokine-modulated immunotherapy
• Induction of tolerance or oral immunotherapy (milk,
egg, hazelnut)
Huang YC, Leyko BT, Frieri M. Effects of omalizumab and budesonide on
markers of inflammation in human bronchial epithelial cells. Ann Allergy
Asthma Immunol 95;443-451,2005.
Summary
• IgE & non-IgE mediated food allergy
conditions exist
• History and examination paramount
• Diagnosis is by elimination and
challenge testing
• Avoidance / education / preparation
for emergencies are current therapies
• Periodic re-challenge to monitor
tolerance as indicated by history,
allergen, and level of food specific-IgE