Gastrointestinal manifestation of

food allergy in infants and children

Jeanette I.Ch. Manoppo

Department of Child Health
Prof. Dr. R.D. Kandou Hospital - Sam Ratulangi Faculty of Medicine
Manado
11
Disclosure of Conflict of Interest:

Nothing to declare
Definition
Food allergy :
An adverse health arising from a specific
immune response that occurs reproducibly on
exposure to a given food

Gastrointestinal food allergy :

A spectrum of GI disorders that result from
adverse immunologic responses to dietary
antigens
Boyce JA, et al. Guidelines for the Diagnosis and Management of Food Allergy in the United States. J Allergy Clin Immunol. 2010
December ; 126(6 0): S1–58 2 3
Clinical spectrum of food allergy

Food induced Gastrointestinal Cutaneous

anaphylaxis food allergies reactions

Respiratory
conditions

Boyce JA, et al. Guidelines for the Diagnosis and Management of Food Allergy in the United States. J Allergy Clin Immunol. 2010
December ; 126(6 0): S1–58 3 4
Classification of food allergy

Food allergies are

classified into 3
types depending
on the
involvement of
IgE in their patho-
genesis

Labrosse R, Graham F, Caubet JC. Non-IgE mediated gastrointestinal food allergies in children: An update. Nutrients 2020, 12, 2086;
doi:10.3390/nu12072086
4 5
Gastrointestinal food allergies manifestations
Disorders that primarily Disorders that affect Disorders that generally
affect infants both infants and children present outside infancy
• Food protein induced • Immediate GI • Oral allergy
proctocolitis (FPIP) hypersensitivity syndrome (Pollen-
• Eosinophilic food syndrome)
gastroenteropathy
• Food protein induced • Cow-milk allergy • Celiac disease
enterocolities (FPIES) induced
gastroesophageal
• Food protein reflux (CMA-GER)
enteropathy (FPE) • Constipation
• Infantile colic

Boyce JA, et al. Guidelines for the Diagnosis and Management of Food Allergy in the United States. J Allergy Clin Immunol. 2010
December ; 126(6 0): S1–58 5 6
Gastrointestinal
food allergies
manifestations

Morita H, et al. Gastrointestinal food allergy in infants. Allergology International 2013;62:297-2307 6 7

GI food allergy in infants and children : Clinical challenge

Gastrointestinal food allergies present during early childhood with

a diverse range of symptoms

There is a significant overlap between gastrointestinal food allergies

and common non-allergic disorders that occur during infancy, such
as GERD or carbohydrate malabsorption

Absence of clear diagnostic markers often delays the recognition

of non-IgE mediated gastrointestinal allergic manifestations and
may lead to adverse nutritional outcomes (protein energy
malnutrition, specific micronutrient or feeding disorders)

Heine RG. Gastrointestinal food allergies. Chem Immunol Allergy 2015;101:171-180

10/24/2020 8
Gastrointestinal food allergic disorders that
primarily affect infants

9 9
 Food protein induced proctocolitis

It was first reported by Lake et al ✓ Primary complaints by parents:

(1982) in a series of 6 infants who a visible specks or streaks of
developed bloody diarrhea in the blood mixed with mucus in the
stool
first month of life while being
exclusively breastfed → the ✓ Patients develop no systemic
symptom was improved after symptoms and seen to be well
being switched to hydrolyzed milk and healthy.
or soy-based formula
✓ No growth-delay or poor
• Lake AM. Food-induced eosinophilic proctocolitis. J Pediatr
Gastroenterol Nutr. 2000;30 Suppl:S58–60. weight gain
• Morita H, Nomura I, Matsuda A, Saito H, Matsumoto K.
Gastrointestinal food allergy in infants. Allergology International
2013;62:297-2307

10/24/2020 10
Food protein induced proctocolitis
• The most common cause of low-
• Main triggers : cow milks protein.
grade rectal bleeding in infants less
than 3 months of age
• Most often exclusively breastfed
infants – a results of maternally
• The disease is typically limited but
ingested protein excreted in breast
may be accompanied by colic or
milk (60%)
increased frequency of bowel
• Some of them were formula-fed
movements, and sometimes
infants
increased gas (up to 30% of
patients), intermittent emesis (up to
• Mechanism underlying this
27%), pain on defecation (22%), or
disorder is unknown (skin prick
abdominal pain (up to 20%) may be
test/IgE RAST always negative)
present
Sicherer SH. Clinical aspects of gastrointestinal food allergy in
childhood. Pediatrics 2003;111(6):1609-1610

10/24/2020 11
Food protein induced proctocolitis
• Diagnosis exclusively relies
on the clinical history ,
with rectal bleeding
disappearing following
elimination diet (either in
the mother or child),
within usually 72-96 hours
(sometimes much later at
least 2-4 weeks)

• Exclusion of other causes

of rectal bleeding is
important (Table)
Dupont C. Food protein induced enterocolitis syndrome and
proctocolitis. Ann Nutr Metab 2018;73(suppl 4):8–16
10/24/2020 12
Food protein induced enterocolitis syndrome
✓ Age of onset of typical FPIES is
• First report by Gryboski
less than 9 months
(1967) in a series of 21
children with vomiting and/or
✓ FPIES may be mild-moderate
diarrhea after ingestion of
and also classic, with no
milk.
detectable food specific IgE, or
atypical when food spesific IgE
• Powell (1986) coined the
are present
term: food protein induced
entercolities of infancy
✓ Consists of : acute and chronic
Dupont C. Food protein induced enterocolitis syndrome and
form
proctocolitis. Ann Nutr Metab 2018;73(suppl 4):8–16

10/24/2020 13
Food protein induced enterocolitis syndrome
✓ Main symptoms : severe vomiting and
• The most common causal foods of
diarrhea with dehydration, lethargy
FPIES are cow’s milk and soy-
and acidosis. Infants may seem septic
based formulas.
with high polymorphonuclear
leukocyte counts.
• Other foods : rice, oats, eggs,
barley, chicken, banana, lamb corn
✓ Acute form : when the offending
are also reported
foods are ingested accidentally
• The syndrome may develop up to
✓ Chronic form: when the offending
1 year of age. When starting
food is consumed regularly
during infancy, FPIES has a good
prognosis and disappearing grossly
at 2 years of age Sicherer SH. Clinical aspects of gastrointestinal food allergy in
childhood. Pediatrics 2003;111(6):1609-1610

10/24/2020 14
 FPIES: Offending foods
• study by Yilmaz, et al in
children diagnosed with
FPIES or with FPIAP in an
outpatient pediatric clinic
in Turkey

Yilmaz EA, Soyer O, Cavkaytar O, Karaatmaca B, Buyukyityaki

B, Sahiner UM, et al. Characteristics of children with food
protein-induced enterocolitis and allergic proctocolitis.
Allergy and Asthma Proceedings.
10/24/2020 15
FPIES : Chronic form
In infants : the first period of disease is marked by the chronic form, related
with the permanent consumption of offending foods (cow’s milk protein)

Intermittent emesis and chronic, sometimes bloody diarrhea occurs

without a specific temporal relationship with ingestion of offending foods

✓ Other symptoms : abdominal distension, dehydration, weight loss and

lethargy
✓ Lab : anemia, leukocytosis with eosinophilia
✓ Abdominal radiograph: intramural gas suggesting necrotizing
enterocolitis
✓ The condition may be mistaken for gastroenteritis, sepsis or even bowel
obstruction
Dupont C. Food protein induced enterocolitis syndrome and
proctocolitis. Ann Nutr Metab 2018;73(suppl 4):8–16
10/24/2020 16
FPIES : Acute form
Acute form : following a period of avoidance, the accidental or
deliberate (during a food challenge) exposition to offending foods
(cow’s milk protein, egg) induce acute symptoms

✓ These occurs within 1-4 hours, mainly emesis, usually projectile and
repetitive (sometimes up to more 10 times)
✓ Child appears pale and lethargic
✓ Diarrhea occurs from 5 to 10 h after food ingestion, sometimes bloody
and containing mucus
✓ In extreme cases, abdominal distension is severe enough to suggest
ileus, wrongly leading to an exploratory laparotomy
✓ Hypotension is possible and may lead to hypovolemic shock
Dupont C. Food protein induced enterocolitis syndrome and
proctocolitis. Ann Nutr Metab 2018;73(suppl 4):8–16
1717
FPIES : Classification

Labrosse R, Graham F, Caubet JC. Non-IgE

mediated gastrointestinal food allergies in
children: An update. Nutrients 2020, 12,
2086; doi:10.3390/nu12072086 18
Food protein induced enterocolitis syndrome : Diagnosis

Nowak-Węgrzyn A, et al. International consensus guidelines for the diagnosis and management of food protein-induced enterocolitis
syndrome: Executive summary-Workgroup Report of the Adverse Reactions to Foods Committee, American Academy of Allergy,
Asthma & Immunology. J Allergy Clin Immunol. 2017 Apr; 139(4): 1111–1126.e4.
10/24/2020 19
Food protein induced enterocolitis syndrome : Differential diagnosis

Nowak-Węgrzyn A, et al. International consensus guidelines for the diagnosis and management of food protein-induced enterocolitis
syndrome: Executive summary-Workgroup Report of the Adverse Reactions to Foods Committee, American Academy of Allergy,
Asthma & Immunology. J Allergy Clin Immunol. 2017 Apr; 139(4): 1111–1126.e4.
10/24/2020 20
Food protein induced enterocolitis syndrome : Diagnostic Challenge

History taking is the key for diagnosis of FPIES

Analyzing the clinical features, excluding other etiologies and
preparing the food challenge. Very frequently, FPIES is not
recognized, whether in its chronic form or acute form → lack of
knowledge of this “emerging syndrome”

✓ Diagnostic standard is oral food challenge (but it’s not

mandatory when the clinical history shows repeated severe
reactions which disappear when suspected food has been
eliminated)

✓ Specific IgE test for cow’s milk only positive in 1/3 patients
Heine RG. Gastrointestinal food allergies. Chem Immunol Allergy 2015;101:171-180
10/24/2020 21
Food protein-induced enteropathy (FPE)

FPE presents with protracted diarrhea in the first 9

months, typically the first 1 to 2 months, within weeks
after the introduction of food

The syndrome of FPE usually resembling that of celiac

disease
In most cases, symptoms develop in infants shortly after
the introduction of cow’s milk in the diet, with chronic
diarrhea and features of malabsorption such as
steatorrhea and failure to thrive (FTT)
Nowak-Wegryzn A, Katz Y, Mehr SS, Koletzko S. Non IgE-mediated gastrointestinal food allergy. J Allergy Clin Immunol 2015;136(5):1-11
10/24/2020 22
Food protein-induced enteropathy (FPE)
✓ >50% infants have FTT
• Offending foods: infantile FPE
is usually caused by cow’s
✓ Extra-digestive symptoms
milk formula
seen in celiac disease, such as
dermatitis herpetiformis are
• Soybean, wheat and egg have
absent
also been confirmed as
frequent triggers in children
✓ Some presents with abdominal
with allergy to multiple food
distension, early satiety and
malabsorption → secondary
carbohydrate intolerance
Labrosse R, Graham F, Caubet JC. Non-IgE mediated gastrointestinal food allergies in children: An update. Nutrients 2020, 12, 2086;
doi:10.3390/nu12072086
10/24/2020 23
Comparison between FPIAP, FPIES and FPE :
Epidemiology, Anatomy and Severity

Nutrients 2020, 12,

2086;doi:10.3390/nu1
2072086

2424
Comparison
between FPIAP,
FPIES and FPE :
Clinical and
laboratory features

Nutrients 2020, 12,

2086;doi:10.3390/nu1
2072086
25
25
Gastrointestinal food allergic disorders that
affect infants and children

2626
IgE-mediated food allergy (Immediate hypersensitivity)

IgE-mediated food reactions are

✓ The symptoms are usually rapid
type I hypersensitivity which
in onset and cause death
occur when patient have
developed IgE antibodies agains ✓ The symptoms can involve
the offending food protein almost every organ system
followed by an exposure to that (skin, respiratory,
cardiovascular, and also
protein
gastrointestinal)
✓ Anaphylaxis : a severe form of
an IgE-mediated allergic
• Anvari S, Miller J, Yeh CH, Davis CM. IgE-mediated food allergy.
Clinical Reviews in Allergy and Immunology 2019;57:244-260
reaction

10/24/2020 27
 IgE-mediated food allergy (Immediate hypersensitivity)

• Anvari S, Miller J, Yeh CH, Davis CM. IgE-mediated food allergy. Clinical Reviews in Allergy and Immunology 2019;57:244-260
10/24/2020 28
 IgE-mediated food allergy (Immediate hypersensitivity)
Gastrointestinal involvement includes subjective and
objective symptoms

✓ Subjective symptoms: itching of the mouth or throat, Symptoms such as

nausea or abdominal pain failure to thrive, bloody
diarrhea and
✓ Objective symptoms : vomiting, intermittent or constipation, emesis
persistent diarrhea after 4 h of food
✓ The onset of GI symptoms is usually immediate, often ingestion are not
within minutes and not more than 2-4 h typically IgE-mediated

• Anvari S, Miller J, Yeh CH, Davis CM. IgE-mediated food allergy. Clinical Reviews in Allergy and Immunology 2019;57:244-260
10/24/2020 29
Food protein induced gastrointestinal motility
disorder

✓ GERD and constipation are among Gastrointestinal food allergy

the most common disorders that should therefore be considered
occur during infancy and early in the differential diagnosis of
childhood infants presenting with
✓ In a subset of infants with these
persistent regurgitation or
functional disorders, improvement constipation,
after dietary elimination of specific particularly if conventional
food proteins has been treatment has not been
demonstrated beneficial
Iacono G, Carroccio A, Cavataio F, Montalto G, Kazmierska I, Lorello D, Soresi M, Notarbartolo A: Gastroesophageal reflux and cow’s
milk allergy in infants: a prospective study. J Allergy Clin Immunol 1996; 97: 822–827
10/24/2020 30
Food protein induced gastrointestinal motility disorder : GERD

• GASTROESOPHAGEAL REFLUX • GERD

(GER) If GER associated with clinical
an involuntary and passive complications (reflux
regurgitation of gastric contents esophagitis aspiration or
into the esophagus and occurs in failure to thrive)
about 20-25% healthy young
infants
✓ Infants with cow’s milk induced GORD
present with frequent regurgitation.
• In the vast majority of cases,
infantile GER doesn’t require
✓ Feeding refusal is a common problem
treatment and resolves at around
and may lead to poor weight gain
12-18 months of age
Sicherer SH. Clinical aspects of gastrointestinal food allergy in
childhood. Pediatrics 2003;111(6):1609-1610

10/24/2020 31
Food protein induced gastrointestinal motility disorder : GERD

Several studies have linked reflux esophagitis during infancy to

non-IgE mediated cow’s milk allergy

❑ In a study of infants with biopsy-proven esophagitis, 42%

improved after treatment with extensively hydrolyzed formula
and relapse with subsequent blinded cow’s milk challenge

❑ To differentiate this with eosinophilic esophagitis, the number

of mucosal eosinophils is not increased (<5 / high power filed)
on biopsy
Iacono G, Carroccio A, Cavataio F, Montalto G, Kazmierska I, Lorello D, Soresi M, Notarbartolo A: Gastroesophageal reflux and cow’s
milk allergy in infants: a prospective study. J Allergy Clin Immunol 1996; 97: 822–827
10/24/2020 32
Food protein induced gastrointestinal motility disorder : GERD

If symptoms improve significantly following the initiation of a

hypoallergenic diet
→ a diagnosis of cow’s milk protein induced GERD is
assumed.

This diagnosis should be confirmed by

cautious cow’s milk challenge to avoid
unnecessary elimination diet

Heine RG. Gastrointestinal food allergies. Chem Immunol Allergy 2015;101:171-180

33
Food protein induced gastrointestinal motility disorder :
Constipation

Constipation : A patient must

experienced less than 3 bowel
movements per week

Northern American Society of

Gastroenterology, Hepatology
and Nutrition (NASPGHAN) :
A delay or difficulty in the
defecation for two weeks or more
• Benninga M, et al. The Paris Consensus on Childhood Constipation Terminology (PACCT) Group. J Pediatr Gastroenterol Nutr. 2005;
40: 273-275.
• Xinnias I. Constipation in childhodd: An update. Hippokratia. 2015;19(1):11-19
3434
Food protein induced gastrointestinal motility disorder :
Causes of constipation

• Xinnias I. Constipation in childhodd: An update. Hippokratia. 2015;19(1):11-19

3535
Food protein induced gastrointestinal motility disorder :
Constipation and Food Allergy
Food protein-induced
constipation is a poorly defined
clinical entity
Only a small proportion of
constipation in children <2 years
of age is due to food allergies,
and the vast majorities of cases
are functional in nature.
10/24/2020
NOTES :
❑ Minor non-allergic
constipation commonly
occurs at the transition from
breast to formula feeding
❑ Cow’s milk formula with a
high casein:whey ratio and
high levels of palmitic acid
has been shown to negatively
affect stool consistency
36
Food protein induced gastrointestinal motility disorder :
Constipation and Food Allergy
Infants with cow’s milk allergy constipation typically present
with infrequent bowel movements from the first week of life or
after the dietary introduction of cow’s milk based product

✓ This symptom may be associated with abdominal distension

and should be distinguished from Hirschsprung’s disease

✓ In some cases, eosinophilic proctocolitis can be demonstrated

→ anal sphincter tone may be increased in infants with
eosinophilic proctocolitis and predispose to faecal retention
Iacono G, et al. Food intolerance and chronic constipation: manometry and histology study. Eur J Gastroenterol
Hepatol 2006; 18: 143–150.
10/24/2020 37
Infantile Colic (IC)
• Infantile colics presents with
episodes of persistent and
inconsolable crying during the first
week of life → in vast majority of
infants with colic, no organic cause
is found
• Despite decades of research, the
cause of IC remains partly
unknown.
✓ Food allergy (FA) have been
advocated as a possible cause of IC
✓ The possible relationship between
FAs and IC derives from two lines of
evidence: the presence of
dysmotility with visceral neuronal
hypersensitivity and dysbiosis
demonstrated in both conditions
and the clinical response to dietary
interventions

Nocerino R, et al. The controversial role of food allergy in

infalntile colic: evidence and clincial management .Nutrients
2015, 7, 2015-2025;
10/24/2020 38
Infantile Colic (IC)

According to Rome III criteria, IC is an episodes of irritability,

fussing or crying that begin and end for no apparent reason
and last ≥3 h per day, ≥3 days per week for ≥1 week

❑ It’s a common condition in the first 3 months of life (affecting

up to 25% infants)

❑ It’s a frequent cause of medical consultation and is associated

with high level of parental stress and anxiety

Nocerino R, et al. The controversial role of food allergy in infalntile colic: evidence and clincial management .Nutrients 2015, 7, 2015-
2025;
10/24/2020 39
 Infantile Colic (IC) and hypoallergenic diet
A high quality RCT reported an absolute risk reduction in infant’s
cry/fuss duration when mother changed from a control diet to
hypoallergenic diet (eliminating dairy food, eggs, peanuts, tree nuts,
wheat, soy and fish)
Iacono et al, in a long term prospective study have
demonstrated there was a remission of symptoms in
subjects with severe IC, when cow’s milk proteins were
eliminated form diet

In study mentioned above, after 18 month follow

up period, 44% of subjects developed food allergy
• Nocerino R, et al. The controversial role of food allergy in infalntile colic: evidence and clincial management .Nutrients 2015, 7,
2015-2025;
• Iacono, G.; Carroccio, A.; Montalto, G.; Cavataio, F.; Bragion, E.; Lorello, D.; Balsamo, V.; Notarbartolo, A. Severe infantile colic and
food intolerance: A long-term prospective study. J. Pediatr. Gastroenterol. Nutr. 1991, 12, 332–335.
40
Infantile Colic (IC)
History and physical exam
• Concomitant presence of a
positive atopic family history
and other symptoms (vomiting,
diarrhea, and extra-intestinal
symptoms such as eczema or
wheezing) strongly suggests
the presence of food allergy in
infantile colic
10/24/2020
Laboratory workup
• FA screening test (skin prick,
atopy patch test or specific IgE)
could be useful, but no
mandatory
• DD: infections, functional
constipation, GERD, hernia,
intussusception
Nocerino R, et al. The controversial role of
food allergy in infalntile colic: evidence
and clincial management .Nutrients 2015,
7, 2015-2025; 41
Infantile Colic (IC): Diagnostic Approach

Nocerino R, et al. The controversial role of

food allergy in infalntile colic: evidence
and clincial management .Nutrients 2015,
7, 2015-2025; 42
10/24/2020
 CONCLUSION

Gastrointestinal food allergies present during early childhood with a diverse

range of symptoms

There is a significant overlap between gastrointestinal food allergies and

common non-allergic disorders that occur during infancy
In the current situation, awareness must be created among family physicians
and paediatricians so as to facilitate early diagnosis and minimize morbidity and
unnecessary therapy

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THANK YOU

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