Mild, moderate to

severe food allergy:

what’s the difference
and implication?
Endah Citraresmi
UKK Alergi Imunologi IDAI
RSAB Harapan Kita, Jakarta, Indonesia
Pointers
• Food allergy: definition & epidemiology
• Food allergy severity
• Impact of food allergy severity
• Guideline on food allergy management
• When to use extensive and amino acid-based formula
Adverse Food
Reaction
A broad term
representing any
abnormal clinical
response
associated with
ingestion of a food

Allergology International. 2009;58:457-466

 Food Allergy: Definition
• Food allergy: adverse health effect arising from a specific immune
response that occurs reproducibly on exposure to a given food
• Allergy:
• not limited to IgE-mediated immunologic reactions
• used to connote the induction of clinical signs and symptoms
• Sensitivity: presence of IgE antibodies to a food, often in the absence
of clinical symptomatology

J Allergy Clin Immunol 2014;134:1016-25

 Food Allergy: Epidemiology
• Food allergy prevalence: > 1% and <10% of the population
• prevalence are highest when based on self-report (12% to 13%)
compared with estimates based on studies using tests, such as
OFCs (approximately 3%)
• >170 foods have been identified as triggers of food allergy
• Those causing most of the significant allergic reactions include
peanut, tree nuts, fish, shellfish, milk, egg, wheat, soy, and seeds

J Allergy Clin Immunol 2014;134:1016-25

 Food Allergy Classification
Based on the immunological mechanism involved

Mixed IgE
IgE- Cell mediated-
When the cell component of
mediated mediated the immune system is cell
Mediated by antibodies responsible of the food allergy
and mostly involve the
mediated
belonging to the
Immunoglobulin E (IgE). The gastrointestinal tract
best-characterized food allergy When both IgE and immune
Hours – days after ingestion
reactions cells are involved in the
Food protein induced reaction
<1 hour after ingestion enteropathy: diarrhea, mild to
EGIDS (Eosinophilic
Skin: Urticaria, angioedema moderate steatorrhea (80% of
Gastrointestinal Disorders):
cases) & poor weight gain
GIT: Vomiting, diarrhea, colic eosinophilic esophagitis,
Proctocolitis: rectal bleeding, gastritis, gastroenteritis, colitis
Respiratory manifestations well & thriving infants
(asthma or allergic rhinitis): Acute flare-up of atopic
infrequent, especially as Food protein-induced eczema
isolated symptoms enterocolitis syndrome
(FPIES): immediate-onset,
Most severe form: anaphylaxis repeated vomiting episodes,
sometimes leading to
dehydration
How to define food allergy severity
Severe food allergy: abnormal immune response to a certain food in a
susceptible host, causing life-threatening clinical syndromes to the
latter
• The definition differs
• Depends on the mechanism: IgE-mediated vs Non-IgE-mediated

J Pediatr (Rio J). 2017;93:53-9

Severity has different meanings to
different stakeholders with
patients and clinicians rating the
significance of particular symptoms
very differently

IgE

Allergy, 2018;73:1792–1800
Classification of severities according to clinical symptoms – Japan
IgE

M. Ebisawa et al. Allergology International,2020; 69:370-86

 Clinical and
Translational Allergy
2013, 3:23
Cow’s Milk Allergy - ESPGHAN
Mild-Moderate CMPA Severe CMPA Failure to thrive
• GI: frequent regurgitation, vomiting, diarrhea, • GI: failure to thrive due to chronic diarrhea,
constipation (with/without perianal rash), and/or regurgitation/vomiting and/or refusal
blood in stool, iron deficiency anemia to feed; iron deficiency anemia due to occult
or macroscopic blood loss; protein-losing
• Dermatological: atopic dermatitis, enteropathy (hypoalbuminemia);
angioedema, urticaria endoscopic/histologically confirmed
• Respiratory: runny nose, chronic cough, enteropathy or severe ulcerative colitis
wheezing (all unrelated to infection) • Dermatological: exudative or severe atopic
• General: persistent distress or colic (>=3 h per dermatitis with hypoalbuminemia-anemia or
day wailing/irritable) at least 3 days/week failure to thrive or iron deficiency anemia
over a period of >3 weeks • Respiratory: acute laryngoedema or bronchial
• Others (rare) obstruction with difficulty breathing
• Systemic reactions (anaphylactic shock –
needs immediate referral to hospital for
management)

Life threatening
Arch. Dis. Child. 2007;92;902-908
Impact of food allergy
Feeding difficulties in children with non-IgE-mediated food allergic
gastrointestinal disorders

Ann Allergy Asthma Immunol.2019; 122:603-9

Impact of food allergy
Faltering growth/failure to thrive

Differences in height between children on elimination diets and controls in

unadjusted and adjusted models, studied by multiple linear regression.

Despite consuming a balanced diet with sufficient

energy and protein, the children on milk
elimination diets grew slower than the control
children (p=0.009)

Acta Paediatr 2017;106:1142–9.

 Height z-score in patients with
• Cross-sectional study
IgE-CMA versus controls.
• Patients diagnosed with IgE-CMA who
Individual height z-scores of
were at least 2 years
patients with CMA (n=87) and
• postpubertal, as classified by Tanner’s
controls (n=36). The middle line
Stage 5, were included.
in each group represents the
• The minimum age for females was
mean value (A). Distribution of
15.0 years, and for males 16.5 years
height z-scores among CMA and
control patients (B).

Young adults who have CMA from infancy

are at risk of not reaching their growth
potential

J Allergy Clin Immunol Pract 2019;7:509-15

 • Schools and • Meals &
bullying nutrition
• Social Activities/
Impact of Dining Out

food allergy
Social & Economic Social Daily
Impact Activities Activities

Mental Economic
Health impact
• Parental • Direct cost
emotions • Opportunity
• Child's lost
emotions

JAMA Pediatr. 2013;167:1026-31. Pediatr Clin N Am. 2015; 62:1453–61

JAMA Pediatr. 2013;167:1026-31
 Impact of
food allergy
Quality of life

Severity: Sampson’s Score

Grade 1: itching in mouth, itching lips, itchy eyes, itchy
skin
Grade 2: hives, swelling of the skin, nausea, stomach
cramps, stuffy nose, sneeze, red rash, red eyes,
worsening eczema
Grade 3: throat tightness, itching throat, itching ears,
runny nose, shortness of breath, vomiting,
palpitations, tears
Grade 4: difficulty swallowing, hoarseness, difficulty
breathing, wheezing, diarrhoea, cough, light-
headedness, inability to stand.
Grade 5: loss of consciousness

Clinical & Experimental Allergy. 2016;47:530–9

Impact of food allergy

• Discomfort • Life threatening

• Failure to
thrive,
malnutrition
Mild-
Severe
moderate

Decrease QoL Social & economic impact

Guideline on Food Allergy Management
2010 2010

2012

2010

2014

2014
 SUSPECT COW’S MILK ALLERGY

Clinical Examination
- Clinical Findings
- Atopic Family (Risk factor)

MILD TO MODERATE CMA SEVERE CMA

One/more of these symptoms: One/more of the following symptoms:
- recurrent regurgitation, vomiting, - Failure to thrive
Skin Prick
diarrhea, constipation, bloody stool, Test,
- iron deficiency anemia due to blood loss
- iron deficiency anemia Serum - Protein losing enteropathy (hypoalbuminemia),
- atopic dermatitis, angioedema, urticaria Specific IgE chronic ulserative colitis proven by endoscopy/
Any doubt
- colds, chronic cough, wheezing consult to histology
- persistent colic (>3 hrs/wk of >3 wks) allergy- - severe atopic dermatitis
immunology
experts
- Acute laryngioedema, difficulty of breathing
Continue breastfeeding - Anaphylactic shock
Diet elimination of the mother 2-4 weeks
Calcium supplementation
Continue breastfeeding with diet elimination of
(+) Improvement the mother, refer to pediatric allergologist

Reintroduce cow’s No Improvement

milk protein
Continue breastfeeding
Symptoms recur Symptoms not recur Resume regular diet of the mother
Diet elimination of the mother x 6 months Regular diet of the Consider other allergic diagnosis
Ca supplementation breastfed mother

Extensively hydrolyzed formula* * In the state of any financial constrain, taste,

Solid food free of cow’s milk protein up to 9– unavailability of product, give soy formula with
12 months old or at least 6 months duration education of allergy possibility to soy formula
 SUSPECT COW’S MILK ALLERGY

Clinical Examination
- Clinical Findings
- Atopic Family (Risk factor)

MILD TO MODERATE CMA SEVERE CMA

One/more of these symptoms: One/more of the following symptoms:
- recurrent regurgitation, vomiting, Skin Prick - Failure to thrive
Test,
diarrhea, constipation, bloody stool, Serum - iron deficiency anemia due to blood loss
- iron deficiency anemia Specific IgE - Protein losing enteropathy (hypoalbuminemia),
- atopic dermatitis, angioedema, urticaria Any doubt, chronic ulserative colitis proven by endoscopy/
consult to
- colds, chronic cough, wheezing Allergy- histology
- persistent colic (>3 hrs/wk of >3 wks) Immunology - severe atopic dermatitis
experts
- Acute laryngioedema, difficulty of breathing
Extensively Hydrolyzed formula 2–4 weeks* - Anaphylactic shock

(+) Improvement No Improvement Amino acid formula with diet elimination of

cow’s milk protein for at least 2–4 weeks*, refer
to pediatric allergologist
Open challenge with regular milk
formula under clinical observation
(+) Improvement No Improvement
Symptoms recur Symptoms not recur
Free cow’s milk protein diet/ Regular milk formula Consider other diagnosis
Open challenge test
formula up to 9–12 months old or under observation
at least 6 months duration
* In the state of any financial constrain, taste,
Repeat open challenge test unavailability of product, give soy formula with
education of allergy possibility to soy formula
 Food allergy management - summary
Anamnesis & Physical Examinations Supporting Tests Oral food challenges

Is if food allergy? IgE-mediated: Food elimination diets

• Exclude infections & other adverse food • SPT, specific IgE serum 2-4 weeks
reactions (poisoning, metabolic) Non-IgE-mediated: Oral food challenges:
• IgE vs Non-IgE mediated? • Biopsy, endoscopy, feces • DBPCFC
• Previous reactions to the same food analysis • Single blind or
open-food
Which is the culprit food? challenges
• Which allergens are involved?

FOOD ALLERGY DIAGNOSIS

 Food allergy management - summary
Pharmacological Management Food Avoidance Follow up

Mild to moderate IgE-mediated reactions: • Food substitution • Periodic re-

antihistamines o Breastfed infants: diet challenges to
Anaphylaxis: adrenaline elimination of the mother monitor tolerance
Adjunctive therapies o Cow’s milk protein allergy (every 6-12 months)
in formula fed infants: • sIgE level: declining
Oral Immunotherapy hypoallergenic formulas levels of sIgE
• Food label correlate well with
• Growth monitoring the development of
tolerance
Hypoallergenic formulas
• 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

World Allergy Organization Journal.2016;9:35

When Should Infants with Cow’s Milk Protein
Allergy Use an Amino Acid Formula?
(1) symptoms not fully resolved on an EHF

(2) faltering growth/failure to thrive

symptoms not fully
resolved on an EHF
(3) multiple food eliminations

(4) severe complex gastrointestinal food allergies

faltering growth/
(5) eosinophilic esophagitis (EoE)
failure to thrive
(6) food protein-induced enterocolitis syndrome (FPIES)

(7) severe eczema

severe reactions/ life
(8) symptoms while breast-feeding threatening
(9) anaphylaxis

J Allergy Clin Immunol Pract. 2018;6:383-99

Case #1: A, 4-month-old
male infant
• Exclusively breastfed infant. Develop
atopic dermatitis at 4 months of age.
• Give emollient and topical corticosteroid
• Should we suggest mother to avoid food
from her diet? Which one?
Case #1: A, 4-month-old • Exclusively breastfed infant. Develop
atopic dermatitis at 4 months of age.
male infant
When to think food allergy in atopic dermatitis?
• Atopic dermatitis → increased risk of food allergy (typically after starting solid food or
CM
• Severe AD >90%
• Moderate AD 30%
• Mild AD <5%
• Food allergen – can be a trigger for exacerbation of atopic dermatitis

Clue:
• Moderate-severe AD nonresponsive to topical treatment
• Exacerbation of AD after exposure to certain food
Case #1: A, 4-month-old
male infant
• Exclusively breastfed infant. Develop
atopic dermatitis at 4 months of age.
• Give emollient and topical corticosteroid
• Should we suggest mother to avoid food
from her diet? Which one?

Mild atopic dermatitis

Continue breastfeeding without

any food avoidance
• His eczema was kept under
control with emollients and
topical steroids.
• When his mother decided to
go back to work at 6 months
of age, his grandmother fed
him with his first CM formula
meal. After 30 minutes, his
grandmother reported
urticaria and an AD flare-up
after 1 hour for a duration of
12 hours
• The infant presented to his
pediatrician with suspected
CMA
 Case - continued
• Specific IgE for cow’s milk: 8 kuA/L (<0.35 kuA/L)
• Should we perform oral food challenge to confirm the diagnosis?
 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
 Case - continued
• Specific IgE for cow’s milk: 8 kuA/L (<0.35 kuA/L)
• Should we perform oral food challenge to confirm the diagnosis?

Advice the mother to strictly avoid cow’s milk in her diet and
stop the cow’s milk formula
 Case - continued
• The mother decided to continue to give her child formula because
she feels her breastmilk is not sufficient since she started to work.
What is your choice?

IgE-mediated, low risk of anaphylaxis

Extensively hydrolyzed formula

 1 feeding with a CM- • ED evaluation: rule out infections
Case #2 based formula →
Approximately 90
• She received IV fluid resuscitation & antibiotics and
was observed in the hospital for 3 days
minutes after the • She tolerated an extensively hydrolyzed formula and
A full-term female feeding, she developed was discharged after 3 days when cultures were
infant initially repetitive vomiting and negative.
breast-fed became lethargic
1 mo 4 mo 5 mo

BIrth 3 mo
A CM-based formula was used to
Her weight percentile was decrease (P50 → P15) instead of
supplement breast-feeding and over a
improvement of symptoms, weight for length ↓to > -2SD
2-week period, the patient developed
frequent episodes of vomiting, poor • Change to amino acid formula
weight gain, and small specks of blood
in her stools
• Weight for length ↑ to >-1SD
Soy-based formula was substituted but
was discontinued in 2 days because of • Plan to solid food (avoid cow’s milk & soy)
continued vomiting. • Re-challenge after 6-9 months of avoidance
Exclusively breast-fed