Food Allergy

Allergy Course 4.0 – 8th IPACI Virtual Meeting 2022

July 30-31, 2022

Endah Citraresmi
Allergy Immunology Working Group – Indonesian Pediatric Society
Harapan Kita Women & Children Hospital, Jakarta, Indonesia
Pointers

Supporting
Epidemiology Manifestation Diagnosis Management
Test
Definition
• A food allergy is defined as an adverse health effect arising from a
specific immune response that occurs reproducibly on exposure to a
given food

“Guidelines for the Diagnosis and Management of Food Allergy in the United States: Report of
the NIAID-Sponsored Expert Panel.” Journal of Allergy and Clinical Immunology 126, no. 6
(December 2010): S1–58.
Epidemiology
• The prevalence of IgE-mediated
food allergy in the population varies
between 2% and 10%
• Food allergy is greater in the
pediatric population than in adults,
with estimates of 6% to 8% in
children under 5 years and 3% to
4% in adults
• Different methods: self-reported vs
sensitization vs confirmed by
DBPCFC
• Recently emerging as a ‘second
wave’ of the allergy epidemic
J Allergy Clin Immunol. 2014;134:1016-25.e43; JAMA. 2010;303:1848-56;
Nat Rev Dis Primers 2018;4:17098
Food Allergy: Mechanism

Gastroenterology
2015;148:1120–1131
 Food Allergy Classification
Based on the immunological mechanism involved
IgE-
mediated
Mediated by antibodies
belonging to the
Immunoglobulin E (IgE). The
best-characterized food allergy
reactions
<1 hour after ingestion
Skin: Urticaria, angioedema
GIT: Vomiting, diarrhea, colic
Respiratory manifestations
(asthma or allergic rhinitis):
infrequent, especially as
isolated symptoms
Most severe form: anaphylaxis
Mixed IgE
Cell mediated-
mediated When the cell component of
the immune system is
cell
responsible of the food allergy mediated
and mostly involve the
gastrointestinal tract
Hours – days after ingestion
Food protein induced When both IgE and immune
enteropathy (FPIE): diarrhea, cells are involved in the
mild to moderate steatorrhea reaction
(80% of cases) & poor weight EGIDS (Eosinophilic
gain Gastrointestinal Disorders):
Food protein-induced Allergic eosinophilic esophagitis,
Proctocolitis (FPIAP): rectal gastritis, gastroenteritis, colitis
bleeding, well & thriving Acute flare-up of atopic
infants eczema
Food protein-induced
enterocolitis syndrome
(FPIES): immediate-onset,
repeated vomiting episodes,
sometimes leading to
dehydration
IgE-mediated-food allergy

• Most IgE-mediated food allergies occur immediately on exposure to

the allergen
• Occasionally, the reaction may be delayed for up to an hour, but this
is an exception, and tends to occur only when the allergen has been
consumed in a fatty food, which may slow its release
• When evaluating older patients, certain complementary factors must
be considered, such as exercise, alcohol consumption, and use of
aspirin or nonsteroidal anti-inflammatory drugs (NSAIDs)

Journal of Allergy and Clinical Immunology 126, no. 6 (December 2010): S1–58.
Cutaneous Manifestations
Urticaria and/or angioedema
• IgE-mediated
• Need to be differentiated from acute urticaria
caused by other etiologies: infections,
drug/contact allergy, dermographism,
spontaneous
Atopic dermatitis
• Majority of atopic dermatitis: genetic &
environment factors
• Food-induced AD: worsening of AD in
exposure to a food allergen, usually develop 2
to 6 hours after the exposure to the food
• Allergy evaluation (specifically to milk, egg,
peanut, wheat, and soy) should be
considered in children younger than 5 years
with severe AD if the child has persistent AD
despite optimal management and topical
therapy
Gastrointestinal Manifestations

IgE-mediated
• Immediate gastrointestinal hypersensitivity (e.g. nausea, vomiting, diarrhea)
• Oral allergy syndrome

Non-IgE-mediated
• Allergic eosinophilic esophagitis, gastritis or gastroenterocolitis
• Food protein-induced enterocolitis syndrome (FPIES)
• Food protein-induced allergic proctocolitis (FPIAP)
• Food protein-induced enteropathy (FPE)
 Clinical characteristics of non-IgE-mediated
gastrointestinal food allergies
FPIES FPIAP FPE
Typical age of onset Days to 1 year Days to 6 months 2-24 months
Symptoms
Emesis Prominent No Intermittent
Diarrhea Severe No Moderate
Bloody stools Severe Moderate Rare
Edema Acute, severe No Moderate
Shock 15-20% No No
Failure to thrive Moderate No Moderate

Allergy Asthma Clin Immunol 2018, 14(Suppl 2):56. Pediatr Allergy Immunol 2017: 28: 6–17.
 Infections

Other
allergic
disorders

GI disorders

Others

Differential Diagnosis
Pediatr Allergy Immunol 2017: 28: 6–17.
Eosinophilic GI disorders (EGIDs)
• A group of inflammatory disorders primarily classified by the
presence of a high density of infiltrating eosinophils within the GI
mucosal epithelium, muscularis, and serosal layers
• Include eosinophilic esophagitis (EoE), eosinophilic gastroenteritis
(EG), and eosinophilic colitis (EC)

Postgrad Med J 2014;90:282–289

Pediatr Clin North Am. 2015;62:1393-408
Characteristic findings for the EGIDs
Disease Location Affected Symptoms Endoscopic Findings Histology/Lab Test
Eosinophilic Esophagus Adults: Dysphagia, food Ringed esophagus, ≧15 eosinophil per
esophagitis impaction strictures, linear high—powered field
Children: Irritability, furrows, narrow (eos/hpf) in middle
feeding difficulties, esophagus, vesicles esophagus,
vomiting, abdominal pain, on mucosal surface peripheral
malnutrition eosinophilia
Eosinophilic Stomach & Abdominal pain, nausea, Nodular gastric ≧30 eos/hpf (no
gastritis duodenum, but can vomiting, diarrhea, weight mucosa, erythema, consensus),
affect esophagus to loss, anemia, erosions abnormal D-xylose,
colon malabsorption, motility and increased fecal
issues (affecting muscle fat (in
layer), ascites (serosal malabsorption)
layer)
Eosinophilic Large intestine Abdominal pain, bloody Edema, patchy Eosinophilic
colitis stools, diarrhea granularity infiltration on
biopsy

Pediatr Clin North Am. 2015;62:1393-408

 Common Food Allergens

Cows'
milk
Hen's
eggs

Peanuts and other legumes such

as soybean, pea, and chickpea

Tree nuts (such as walnut, almond, hazelnut,

pecan, cashew, pistachio, and Brazil nuts)
Common Food Crustacean shellfish (such as
Allergens shrimp, crab, and lobster) and fish

Wheat
J Allergy Clin Immunol 2012;129:906-20
Oral allergy syndrome (or pollen-food
syndrome)

• Localized food allergy which may occur due to cross

reactivity between aeroallergens, such as birch
pollen, and fresh vegetables, fruits, and nuts
• As a result, pollen sensitized people mount an
IgE response to epitopes present in fruit and
vegetables on oral contact
• An epitope is a portion of a foreign protein, or
antigen, which can stimulate an immune
response by binding to a B-cell receptor.

Dermatitis 2015;26:78-88; J Allergy Clin Immunol 2010;126:S1-S58

Risk factors for the development of food
allergy
• Known food allergy — the presence of a confirmed food allergy increases
the likelihood of additional food allergies
• Known atopic eczema — the development of early-onset atopic eczema
before 6 months of age, and severe eczema below the age of one year, are
associated with the development of egg, milk, and peanut allergy
• Peanut allergy may develop through skin sensitization in children with an impaired
skin barrier function
• Family history of food allergy — confirmed food allergy in a parent or
sibling increases the risk of food allergy
• Family history of atopy — particularly affecting parents and/or siblings
RCPCH, 2011; Allergy 2014;69:62-75; J Allergy Clin Immunol 2012;129:906-20
The possible complications of food allergy
Severe and life-
threatening reactions
• Food allergy is the most
common trigger of anaphylaxis
• The risk of anaphylaxis
depends on the specific food
allergy — allergy to peanuts,
tree nuts, fish, and shellfish are
associated with a higher risk of
anaphylaxis
Clin Exp Allergy 2013;43:1333-1341; J Allergy Clin Immunol 2010;126:S1-S58; Allergy 2014;69:1046-1057; Pediatr Allergy Immunol 2018; 29:689-704
Stress and anxiety
• This may be associated with
the need for constant vigilance
over food choices, and risk of
accidental food exposure and
severe reactions
Restricted diet and
Reduced quality of life
malnutrition
• Dietary restrictions • The risk of inadequate
affecting food shopping and nutritional intake and faltering
family meal provision, which growth in children, if food
may be stressful and time- allergens that contribute
consuming essential nutrients are
• The impact on social eliminated
interactions, such as eating
out, playing at friends' houses,
attending birthday parties, and
participating in school meals
• The impact of peer pressure,
stigma, and embarrassment
about food allergy on the
person
• Potential social exclusion, such
as not being invited to friends'
houses, trips, and activities
Prognosis
• The prognosis of food allergy depends on the person's age, co-morbidities, and
specific causal food allergen.
• Most children outgrow their food allergy over time: cow’s milk, egg, wheat, soy
• Certain food allergies are most likely to persist, such as peanuts, tree nuts, fish,
and shellfish
• Factors which may increase the likelihood of severe food allergy and/or
anaphylaxis include:
• A history of asthma, especially if it is poorly controlled
• A history of other atopic disease, such as atopic eczema or allergic rhinitis.
• A history of previous systemic allergic reaction.
• Allergy to the food classes of peanut, tree nut, fish, or shellfish

J Allergy Clin Immunol 2010;126:S1-S58; Lancet 2013;382:1656-1664;

J Allergy Clin Immunol 2007; 120:1413-1417; Ann Allergy Asthma Immunol 2009; 102:410-415.
Diagnosis of Food Allergy
Ask about: Examine the person for:
• The possible causal food or foods
• The symptoms, frequency, speed of onset, duration, and the timing of the
• Nutritional status, including weight, length/height,
reaction in relation to the suspected allergen exposure. A food and symptom and calculation of body mass index (BMI).
diary may be helpful. • Any signs of a clinical reaction
• The form in which the food has been eaten (raw, semi-cooked, cooked, or • Any signs of co-morbid conditions such as asthma,
baked), and quantity of food ingested
• Any uneventful exposures to the suspected allergen before or after the atopic eczema, and/or allergic rhinitis
reaction
• The setting of reactions (such as school or home)
• The reproducibility of symptoms on repeated food exposure
• The age when symptoms started, the person's feeding history (age of
complementary feeding [weaning], breast- or formula-fed), weight gain, and Arrange for skin prick testing and/or serum-specific
nutritional status IgE allergy testing to the suspected food allergens and
• Any co-factors which may increase the likelihood of a clinical reaction: age likely cross-reactive foods, depending on local referral
(teenager and young adults), exercise, menstruation, stress,
infection; ingestion of aspirin, nonsteroidal anti-inflammatory drugs pathways and availability
(NSAIDs), or alcohol
• Any co-morbid atopic conditions such as asthma, eczema, or allergic rhinitis Allergy testing should only be offered if appropriate,
• Any family history of food allergy or atopic conditions, particularly in parents
after an allergy-focused history has been taken.
and siblings.
• Any symptom response to dietary restrictions or reintroduction of
foods, and/or medications tried, such as oral antihistamines
Allergy testing
• Skin prick testing or measuring serum-specific immunoglobulin (Ig)E levels
to different food allergens
• Should be undertaken by healthcare professionals with the appropriate facilities,
expertise, and training to select and perform tests, and interpret results

Skin prick testing Serum-specific IgE testing

• Epicutaneous introduction of allergen extracts • Widely available, but results are not
with a lancet, typically to the volar aspect of immediate and may take days to weeks to
the forearm process
• The site is inspected after 15 minutes and
compared with positive and negative controls
(observer dependent), to detect sensitization
to allergens

[RCPCH, 2011; Burks, 2012; Longo, 2013; Steele, 2014; Turnbull, 2015; Stiefel, 2017; NICE, 2018]
Allergy testing: sensitization vs true allergy
Allergy testing cannot distinguish between sensitization and true allergy, so test results must be
interpreted in the context of the clinical history

• Some people have positive test results but do not develop symptoms of clinical allergy on exposure to the
relevant food allergen (food sensitization only and a false positive result)
• Due to the poor specificity of tests, indiscriminately testing for large panels of food allergens is not
recommended as there is a high false positive rate.
• Some people may have a strong clinical history of IgE-mediated food allergy but negative allergy test
results (false negative result)

Increased size of the skin prick wheal or concentrations of serum-specific IgE are associated with
an increased likelihood of food allergy, but they do not predict symptom severity

• Ideally raw foods should be used in skin prick testing for the assessment of suspected oral allergy
syndrome
 Predictive Value of Food Specific IgE
Allergen Decision Point Rechallenge Value
(kUA/L) (kUA/L)
Egg ≥ 7.0 ≤ 1.5
≤2 years old ≥ 2.0
Milk ≥ 15.0 ≤ 7.0
≤2 years old ≥ 5.0
Peanut ≥ 14.0 ≤ 5.0
Fish ≥ 20.0
Tree nuts ≥ 15.0 <2
J Allergy Clin Immunol. 2001; 107: 891–896
Assessing tolerance
• Allergy testing may also be used to assess whether tolerance has
developed in a person with a confirmed food allergy. The optimal
interval for follow-up testing is not known, and partly depends on the
specific food allergen:
• For egg, soybean, or wheat allergy, testing every 12–18 months up to the age
of 5 years, and every 2–3 years following this, may be recommended.
• For peanut, tree nut, fish, and shellfish allergy, testing every 2–4 years may be
recommended.

[RCPCH, 2011; Burks, 2012; Longo, 2013; Steele, 2014; Turnbull, 2015; Stiefel, 2017; NICE, 2018]
Oral Food Challenge
• If the results of allergy testing do not correspond with the clinical
history, an oral food challenge may be needed to confirm the
diagnosis
• Oral food challenge is the gold standard for diagnosis of
food allergy, and is an accurate and sensitive test
• It involves the administration of increasing quantities of the
food allergen under medical supervision, starting with direct
mucosal exposure (allergen contact with the lips) and then
titrated oral ingestion as tolerated
• If symptoms are not provoked, the test is negative and
clinical allergy can be excluded
• If there has been a previous severe reaction to a known
food, a repeat challenge is not usually arranged for at least
two years
https://www.foodallergy.org/resources/oral-food-challenge
Oral Food Challenge
• Types of oral food challenge:
• Double-Blind Placebo-Controlled Food Challenge
• Single-Blind Placebo-Controlled Food Challenge
• Open Oral Food Challenge → objective symptoms, infants
• Location of food challenge:
• Clinical settings
• Home challenge → mild/moderate reactions, not life threatening, non-IgE-
mediated
Investigational studies
• Atopy patch testing - identify allergens that cause reactions through
delayed contact hypersensitivity where T-cells play a major role. Allergenic
extract is occluded against intact skin for 48 hours; it is available for
investigational use only
• Patch testing is well validated for contact dermatitis but not food allergy in general
• Purified or recombinant allergens - identify specific IgE sensitisation to
proteins within an individual food allergen in component-resolved
diagnostics
• Some studies have shown an increased ability to predict the likelihood of having a
severe allergic reaction to foods like peanut, soy, or hazelnut; however, geographical
pollen sensitisation patterns may affect results, and further studies are needed to
generalise interpretability
Allergen Components

Current Allergy & Clinical Immunology;2015;28:104-11

Current Allergy & Clinical Immunology;2015;28:104-11
Current Allergy & Clinical Immunology;2015;28:104-11
Basophil Activation Test
• Flow cytometric assay that detects the functional ability of IgE to activate
basophils which are stimulated due to allergen exposure
• The BAT measures the expression of activation markers (mainly CD63 or CD203c)
on the basophil cell membrane following cross-linking of IgE antibodies caused
by an allergen

Journal of Asthma and Allergy 14 (November 2, 2021): 1335–48

Not recommended diagnostic tools
• Serum-specific immunoglobulin (Ig)G testing.
• Trial food elimination diet (although this may be helpful in the diagnosis of
non-IgE-mediated food allergy, under dietetic supervision)
• Vega testing (electroacupuncture devices)
• Applied kinesiology (muscle strength testing)
• Hair analysis (assessing mineral content)
Management
Acute reactions: Anaphylaxis
• Airway, oxygen
• Epinephrine
• Recumbent position, fluid replacement, other measures as indicated
Milder acute reactions
• Oral antihistamines – rhinoconjunctivitis, localized urticaria/pruritus
• Bronchodilator - wheezing
• H2 antagonist – cutaneous symptoms
Arrange referral to an allergy specialist

Arrange referral to a pediatric dietitian or dietitian

Avoidance of food allergens
• Patients should be educated regarding strict avoidance of the causative
food allergen
• Involvement of a dietician in this process is often very helpful, as poorly
prepared elimination diets may lead to malnutrition
• Successful avoidance relies on:
• Specific identification of the causative food allergen in the patient;
• Recognition of cross-reacting foods;
• Education of the patient and/or carer about avoidance measures, with emphasis on
hidden food allergens or additives;
• Willingness of the educated patient and/or carer to read labels carefully and give
particular attention to hidden ingredients when eating at restaurants in order to
prevent accidental exposures
Cow’s Milk Protein

Hypoallergenic Formula
Tolerated by 90% of children with
CMPA
• Extensively hydrolyzed formula
(EHF), which contains short
peptides (most below 1500 Da)
• Amino acid formula (AAF), which
provides protein in the form of
amino acids
Arch Dis Child 1999;81:80-4
J Allergy Clin Immunol Pract 2018;6:383-99
 Pediatric Formula Recommendations
Based on DRACMA Guidelines
Food Allergy Symptom or Disorder 1st Choice 2nd Choice 3rd Choice
IgE-mediated allergy eHF AAF SF
Low risk anaphylaxis
IgE-mediated allergy AAF eHF SF
High risk anaphylaxis
FPIES AAF eHF -
Eosinophilic esophagitis AAF - -
Heiner syndrome AAF SF eHF
Other Non-IgE-mediated: GERD, eHF AAF
enteropathy, constipation, colic,
gastroenteritis & proctocolitis, atopic
dermatitis

eHF: extensively hydrolyzed formula; AAF: amino acid formula; SF: soy formula

World Allergy Organization Journal.2016;9:35

Food processing (high temperature,
low pH, and enzymatic digestion)
may alter (destroy) conformational
epitopes that are dependent on
protein folding but generally do not
affect sequential epitopes

Curr Opin Allergy Clin Immunol 9:234–237

 Milk Ladder

https://gpifn.files.wordpress.com/2019/10/imap
_final_ladder-may_2017_original.pdf
Egg Ladder

https://www.ifan.ie/egg/egg-classification-ladder/
Education

Signs &
School & Importance symptoms of
Reading food
eating out of avoidance food allergy,
label
preparation adherence emergency &
management
Reading food
label
Reading Food Label
Eating out:
Avoid cross-contamination
Food Allergy Reactions & How to Manage
Growth Monitoring
• Growth disorders can occur:
• Due to an allergic reaction that has
occurred: gastrointestinal symptoms
(vomiting, diarrhea, refusal to
breastfeed), severe atopic dermatitis
• Consequences of avoiding cow's milk
from the diet: difficult to choose
food
• It is important to monitor growth
to prevent growth disorders →
involve nutritionist
Follow Up: Tolerance Evaluation

IgE-mediated Food Allergy

• Although the symptoms are mild to moderate, when provocation is carried out, severe
symptoms can occur
• Provocation is carried out and supervised at the hospital to anticipate severe reactions

Severe Non-IgE-mediated Food Allergy (FPIES)

• Provocation is monitored in hospital, anticipate severe reactions (severe dehydration,
shock)
Mild-Moderate Non-IgE-mediated Food Allergy
• Home reintroduction
Home reintroduction – Cow’s Milk
Day Volume (ml) Hypoallergenic formula Standar Formula
(measuring spoon) (measuring spoon)

1 210 mL 6 in 1st bottle 1 in 1st bottle

2 210 mL 5 in 1st bottle 2 in 1st bottle
3 210 mL 4 in 1st bottle 3 in 1st bottle
4 210 mL 3 in 1st bottle 4 in 1st bottle
5 210 mL 2 in 1st bottle 5 in 1st bottle
6 210 mL 1 in 1st bottle 6 in 1st bottle
7 210 mL 0 7 in 1st bottle

Clin Transl Allergy, 2017;7:26

 Emerging treatments •Gradual oral exposure to native food proteins induces
regulatory T cells early in treatment and results in
immune deviation towards non-allergic Th1 responses
later in therapy
• A number of oral immunotherapy (OIT) trials have •Studies investigating the utility of SLIT for food allergy
focused on treatment of peanut allergy and have are ongoing and its use is still considered
shown that the majority of children with peanut Sublingual
immunotherapy investigational
allergy can be desensitised using OIT
• Peanut (Arachis hypogaea) allergen powder has
been approved by FDA, aged 4 to 17 years, with a
confirmed diagnosis of peanut allergy Oral
immunotherapy
• OIT to other foods, such as milk and egg, has also
shown promise •Epicutaneous immunotherapy (EPIT) involves
prolonged exposure to an allergen to the skin via an
Epicutaneous epicutaneous patch
immunotherapy •Ongoing trials are investigating the efficacy of milk
EPIT in milk-allergic children and peanut EPIT in
peanut-allergic children 1 to 3 years of age
Anti-IgE
•Omalizumab administered during the build-up and monoclonal
antibody
maintenance phase of milk oral immunotherapy has
been shown to improve safety, but not efficacy
Allergy Prevention – Dual Allergen Hypothesis

Toit, George du, Teresa Tsakok, Simon Lack, and Gideon Lack. “Prevention of Food Allergy.” Journal of Allergy and Clinical Immunology 137, no. 4 (April 2016): 998–1010.
 Early Introduction of Allergenic Foods
• RCTs: early introduction of allergenic foods (peanut/egg) to high-risk
infants with severe AD or pre-existing food sensitization may reduce the
risk of developing peanut or egg allergies
The Prevention of Egg allergy with Tiny amount
Learning Early About Peanut Allergy (LEAP) study
InTake (PETIT) study
• Highrisk infants aged 4-11 months with severe AD • Investigated the effects of early introduction of
and/or egg allergy and peanut skin prick test (SPT) heated egg powder to high-risk Japanese infants
responses of 1-4 mm with AD on the development of egg allergy
• Infants randomized to consume 6 grams of peanut • The intervention group which received 50 mg of
protein at least 3 times a week or 2 grams 3 times heated whole egg powder between 6-9 months of
a week had an 81.4% lower risk of developing age, then 250 mg between 9-12 months of age,
challenge-proven peanut allergy by age 5 years, had 30% lower risk of developing challenge-
compared to those who completely avoided proven hen's egg allergy at 12 months of age,
peanut products compared to the placebo group
Natsume O, Kabashima S, Nakazato J, Yamamoto-Hanada K, Narita M, Kondo M, et al. Two-step egg
Du Toit G, Roberts G, Sayre PH, Bahnson HT, Radulovic S, Santos AF, et al. Randomized trial of
introduction for prevention of egg allergy in high-risk infants with eczema (PETIT): a randomised,
peanut consumption in infants at risk for peanut allergy. N Engl J Med 2015;372:803-13
double-blind, placebo-controlled trial. Lancet 2017;389:276-86.