Clinical Disorders and Clinical Manifestation of

Food Allergy
Food hypersensitivities develop in genetically predisposed individuals, presumably when oral tolerance fails to develop normally or breaks
down. IgE-mediated reactions develop when food-specific IgE antibodies residing on mast cells and basophils come in contact with and bind
circulating food allergens and activate the cells to release potent mediators and cytokines. As depicted in number of IgE-, cellular-, and mixed
IgE and cell-mediated food hypersensitivity disorders have been described. There is little evidence to implicate antigen-antibody complex
mediated hypersensitivity in food-related disorders.
In addressing possible food-induced allergic disease, the clinician must consider a variety of adverse reactions to foods that are not food allergies,
especially because more than 20% of adults and children alter their diets for perceived adverse reactions/allergies. Adverse reactions that are not
classified as food allergies include host-specific metabolic disorders (eg, lactose intolerance, galactosemia, and alcohol intolerance), a response to a
pharmacologically active component (eg, caffeine, tyramine in aged cheeses triggering migraine, and histaminic chemicals in spoiled dark-meat fish
resulting in scombroid poisoning masquerading as an allergic response), or toxins (eg, food poisoning). Additionally, psychologic (food aversion and
anorexia nervosa) or neurologic (eg, auriculotemporal syndrome manifested by a facial flush from tart foods or gustatory rhinitis manifested by
rhinorrhea from hot or spicy foods) responses can mimic food allergies
It is conceptually and diagnostically helpful to categorize food-induced allergic disorders based on immunopathology among those that are and are not
mediated by IgE antibodies. Disorders with an acute onset of symptoms after ingestion are typically mediated by IgE antibody. Food-specific IgE
antibodies arm tissue mast cells and blood basophils, a state termed sensitization. On re-exposure, the causal food proteins bind to the IgE antibodies
specific for them and trigger the release of mediators, such as histamine, that cause the symptoms. Another group of food hypersensitivity disorders are
subacute or chronic and are mediated primarily by T cells. A third group of chronic disorders attributed to food allergy are variably associated with
detectable IgE antibody (IgE-associated/cell-mediated disorders). The features of a spectrum of the most common food-induced allergic disorders
categorized by pathophysiology. The table does not include disorders such as recalcitrant childhood gastroesophageal reflux, constipation, and irritable
bowel syndrome, which are sometimes attributed to food allergy. Detection of IgG antibodies to foods is not considered diagnostic of food allergy.
However, Heiner syndrome, a rare infantile disorder characterized by pulmonary hemosiderosis triggered by milk protein, is associated with increased
milk-specific IgG antibodies. Celiac disease and the related skin disorder dermatitis herpetiformis can be considered food allergies because an immune
response to gluten in grains, such as wheat, rye, and barley, is responsible, but these disorders are not discussed further here. Dietary (food) protein
induced enteropathy is another malabsorption syndrome, but unlike celiac disease, it is usually caused by cows milk, is transient, is not associated with
malignancy or dermatitis, and, for unclear reasons, has been rarely described in the past decade. Although symptoms of mucous and bloody stools in
breast-fed infants have typically been attributed to dietary proctitis/proctocolitis caused by immune responses to maternal ingestants, such as cows milk,
studies have recently emphasized that alternative causes, such as infection or other inflammatory disorders, should be considered. Thus empiric maternal
dietary interventions should be undertaken with consideration that alternative explanations might exist, and retrials of the avoided allergen can be
considered shortly after resolution of symptoms if other signs of allergy are absent. Lastly, contact dermatitis has also been attributed to foods,
particularly with occupational exposure.
Food hypersensitivity disorders
IgE mediated

Gastrointestinal Oral allergy syndrome, gastrointestinal anaphylaxis
Cutaneous Urticaria, angioedema, morbilliform rashes and flushing
Respiratory Acute rhinoconjunctivitis, bronchospasm (wheezing)
Generalized Anaphylactic shock
Mixed IgE and cell mediated
Gastrointestinal Allergic eosinophilic esophagitis, allergic eosinophilic gastroenteritis
Cutaneous Atopic dermatitis
Respiratory Asthma
Cell mediated

Gastrointestinal
Food proteininduced enterocolitis, food proteininduced proctocolitis, food
proteininduced enteropathy syndromes, celiac disease
Cutaneous Contact dermatitis, dermatitis herpetiformis
Respiratory Food-induced pulmonary hemosiderosis (Heiner syndrome)
Gastrointestinal food hypersensitivity reactions
The number of gastrointestinal food hypersensitivities have been described. As indicated above, the pollen-food allergy syndrome (oral allergy syndrome)
is elicited by a variety of plant proteins that cross-react with airborne allergens, especially birch, ragweed, and mugwort pollens.
32
Patients with ragweed
allergy might react to fresh melons and bananas, patients with grass pollen allergy might have symptoms when ingesting raw tomatoes, and patients with
birch pollen allergy might have symptoms after the ingestion of raw potatoes, carrots, celery, apples, pears, hazelnuts, and kiwi. Because the allergens
responsible for these reactions are easily broken down by heat or gastric enzymes, most patients only experience allergic symptoms in the oral and
pharyngeal mucosa. Gastrointestinal anaphylaxis typically presents as acute nausea, colicky abdominal pain, and vomiting and generally occurs with
allergic manifestations in other target organs.
1

Gastrointestinal food hypersensitivities
DISORDER MECHANISM SYMPTOMS DIAGNOSIS
Pollen-food allergy
syndrome (oral
allergy syndrome) IgE mediated
Mild pruritus, tingling,
and/or angioedema of the
lips, palate, tongue, or
oropharynx; occasional
sensation of tightness in
the throat and rarely
systemic symptoms
Clinical history and
positive SPT responses
to relevant food proteins
{prick-plus-prick
method}; oral
challengepositive with
fresh food, negative with
cooked food
Gastrointestinal
anaphylaxis IgE mediated
Rapid onset of nausea,
abdominal pain, cramps,
vomiting, and/or
diarrhea; other target
organ responses (ie, skin,
respiratory tract) often
involved
Clinical history and
positive SPT responses
or RAST results;oral
challenge
Allergic
eosinophilic
esophagitis
IgE mediated
and/or cell
mediated
Gastroesophageal reflux
or excessive spitting-up or
emesis, dysphagia,
intermittent abdominal
pain, irritability, sleep
disturbance, failure to
respond to conventional
reflux medications
Clinical history, SPTs,
endoscopy and biopsy,
elimination diet and
challenge
Allergic
eosinophilic
gastroenteritis
IgE mediated
and/or cell
mediated
Recurrent abdominal
pain, irritability, early
satiety, intermittent
vomiting, FTT, and/or
weight loss
Clinical history, SPTs,
endoscopy and biopsy,
elimination diet and
challenge
Food protein
induced
Cell mediated Gross or occult blood in
stool; typically thriving;
usually presents in first
SPT responses negative;
elimination of food
protein clearing of
most bleeding in 72 h;
DISORDER MECHANISM SYMPTOMS DIAGNOSIS
proctocolitis few months of life endoscopy and biopsy;
challenge induces
bleeding within 72 h
Food protein
induced
enterocolitis Cell mediated
Protracted vomiting and
diarrhea (bloody) not
infrequently with
dehydration; abdominal
distention, FTT; vomiting
typically delayed 1-3 h
after feeding
SPT responses negative;
elimination of food
protein clearing of
symptoms in 24-72 h,
challenge recurrent
vomiting within 1-2 h,
15% have hypotension
Food protein
induced
enteropathy, celiac
disease (gluten-
sensitive
enteropathy) Cell mediated
Diarrhea or steatorrhea,
abdominal distention and
flatulence, weight loss or
FTT, nausea and
vomiting, oral ulcers
Endoscopy and biopsy
IgA; elimination diet
with resolution of
symptoms and food
challenge; celiac: IgA
anti-gliadin and anti-
transglutaminase
antibodies
source: J Allergy Clin Immunol.2003;111(suppl):S540-7.
Cutaneous food hypersensitivity reactions
IgE, cellular, and mixed IgE and cellular reactions to foods can induce a variety of cutaneous hypersensitivity disorders. Acute urticaria and angioedema
are among the most common symptoms of food-induced allergic reactions, although the exact prevalence of these reactions is unknown. Acute contact
urticaria caused by food (eg, meats, vegetables, and fruits) also is common. Food allergy is infrequently the cause of chronic urticaria and angioedema
(symptoms lasting >6 weeks).
Cutaneous food hypersensitivities
DISORDER MECHANISM SYMPTOMS DIAGNOSIS
Acute urticaria IgE mediated Pruritus, hives, and/or Clinical history; SPTs or
DISORDER MECHANISM SYMPTOMS DIAGNOSIS
and
angioedema
swelling RAST; challenge
Chronic
urticaria and
angioedema IgE mediated
Pruritus, hives, and/or
swelling of >6 wk
duration
Clinical history; SPTs or
RAST; elimination diet;
challenge
Atopic
dermatitis
IgE and cell
mediated
Marked pruritus;
eczematous rash in
classic distribution
Clinical history; SPTs;
CAP-System FEIA (ie,
quantitative IgE);
elimination diet and food
challenges
Contact
dermatitis Cell mediated
Marked pruritus;
eczematous rash Clinical history; patch test
Dermatitis
herpetiformis Cell mediated
Marked pruritus;
papulovesicular rash
over extensor surfaces
and buttocks
Skin biopsy (IgA
deposition); IgA anti-
gliadin and anti-
transglutaminase
antibodies; endoscopy
source: J Allergy Clin Immunol.2003;111(suppl):S540-7.
Respiratory food hypersensitivity reactions
Food allergy can induce a number of disorders in the respiratory tract, as depicted in Table V. Acute respiratory symptoms caused by food allergy
generally represent isolated IgE-mediated reactions, whereas chronic respiratory symptoms represent a mix of IgE- and cell-mediated reactions. Isolated
rhinoconjunctivitis is rarely the result of a food-induced allergic reaction, although it frequently occurs in association with other food allergy symptoms.
Asthma is an uncommon manifestation of food allergy, although acute bronchospasm is usually seen with other food-induced symptoms.
70
However,
airway hyperreactivity and worsening of asthma also can be induced in the absence of marked bronchospasm after the ingestion of small amounts of food
allergens in sensitized subjects.
71
Interestingly, food allergy recently was found to be a major risk factor for severe life-threatening asthma. Roberts
reported that about one half of asthmatic children requiring intubation for severe asthma had food allergy compared with about 10% of asthmatic patients
seen at the same hospital. Vapors or steam containing proteins emitted from cooking food (eg, fish) can induce asthmatic reactions and even anaphylaxis.
It has been estimated that about 1% of asthma in adults might involve reactions to inhalational exposures to food, especially in the workplace. Similarly,
particulate matter, such as peanut dust in airplanes, can induce allergic reactions, whereas the smell of peanut butter, primarily organic solvents, is not
likely to induce allergic symptoms. Food-induced asthmatic symptoms should be suspected in patients with refractory asthma and a history of atopic
dermatitis, gastroesophageal reflux, food allergy, or feeding problems as an infant or a history of positive skin test responses or reactions to a food.
Heiners syndrome is a rare form of food-induced pulmonary hemosiderosis typically caused by cows milk.
Respiratory food hypersensitivities
DISORDER MECHANISM SYMPTOMS DIAGNOSIS
Allergic
rhinoconjunctivitis IgE mediated
Periocular pruritus,
tearing, and
conjunctival
erythema, nasal
congestion,
rhinorrhea, sneezing
Clinical history, SPTs,
elimination diet, food
challenge
Asthma
IgE and cell
mediated
Cough, dyspnea,
wheezing
Clinical history, SPTs,
elimination diet, food
challenge
Heiners syndrome ?
Recurrent pneumonia,
pulmonary infiltrates,
hemosiderosis, iron-
deficiency anemia,
FTT
Clinical history,
peripheral
eosinophilia, milk
precipitins (if caused
by milk), lung
biopsy, elimination
diet
source J Allergy Clin Immunol.2003;111(suppl):S540-7.
Food-induced allergic disorders
IMMUNOPATHOLOGY DISORDER
KEY
FEATURES
ADDITIONAL
IMMUNOPATHOLOGY
TYPICAL
AGE
MOST
COMMON
CAUSAL
FOODS
NATURAL
COURSE
IgE antibody dependent

IMMUNOPATHOLOGY DISORDER
KEY
FEATURES
ADDITIONAL
IMMUNOPATHOLOGY
TYPICAL
AGE
MOST
COMMON
CAUSAL
FOODS
NATURAL
COURSE
(acute onset)

Urticaria/angioedema
Triggered by
ingestion or
direct skin
contact
(contact
urticaria);
food
commonly
causes acute
(20%) but
rarely chronic
(2%) urticaria

Children >
adults
Primarily
major allergens
Depending
on food

Oral allergy
syndrome (pollen
food related)
Pruritus, mild
edema
confined to
oral cavity
Uncommonly
progresses
beyond mouth
(7%) or
anaphylaxis
(1% to 2%)
Might increase
after pollen
season
Sensitization to pollen
proteins by the respiratory
route results in IgE that binds
certain homologous, typically
labile food proteins (in
certain fruits/vegetables (eg,
apple Mal d 1 and birch bet v
1)
Onset after
pollen allergy
established
(adult > young
child)
Raw
fruit/vegetables
Cooked forms
tolerated
Examples of
relationships:
birch (apple,
peach, pear,
carrot),
ragweed
(melons)
Might be
long-lived
and vary
with seasons

Rhinitis, asthma
Symptoms
might
accompany a
food-induced

Infant/child >
adult, except
for
occupational
General: major
allergens
Occupational:
wheat, egg, and
Depending
on food
IMMUNOPATHOLOGY DISORDER
KEY
FEATURES
ADDITIONAL
IMMUNOPATHOLOGY
TYPICAL
AGE
MOST
COMMON
CAUSAL
FOODS
NATURAL
COURSE
allergic
reaction but
rarely an
isolated or
chronic
symptom
Symptoms
might also be
triggered by
inhalation of
aerosolized
food protein
disease (eg,
bakers asthma)
seafood, for
example

Anaphylaxis
Rapidly
progressive,
multiple organ
system
reaction can
include
cardiovascular
collapse
Massive release of mediators,
such as histamine, although
mast cell tryptase levels not
always increased Key role of
platelet-activating factor Any
Any but more
commonly
peanut, tree
nuts, shellfish,
fish, milk, and
egg
Depending
on food

Food-associated,
exercise-induced
anaphylaxis
Food triggers
anaphylaxis
only if
ingestion
followed
temporally by
exercise
Exercise is presumed to alter
gut absorption, allergen
digestion, or both
Onset more
commonly later
childhood/adult
Wheat,
shellfish, and
celery are most
described
Presumed
persistent
IgE antibody associated/cell-
mediated (delayed

IMMUNOPATHOLOGY DISORDER
KEY
FEATURES
ADDITIONAL
IMMUNOPATHOLOGY
TYPICAL
AGE
MOST
COMMON
CAUSAL
FOODS
NATURAL
COURSE
onset/chronic)

Atopic dermatitis
Associated
with food in
35% of
children with
moderate-to-
severe rash
Might relate to homing of
food-responsive T cells to the
skin
Infant > child >
adult
Major
allergens,
particularly egg
and milk
Typically
resolves

Eosinophilic
gastroenteropathies
Symptoms
vary on
site(s)/degree
of eosinophilic
inflammation
Esophageal:
dysphagia and
pain
Generalized:
ascites, weight
loss, edema,
and
obstruction
Mediators that home and
activate eosinophils play a
role, such as eotaxin and IL-5 Any Multiple
Likely
persistent
Cell-mediated (delayed
onset/chronic)


Dietary protein
enterocolitis
Primarily
affects infants
Chronic
exposure:
emesis,
Increased TNF- response,
decreased response to TGF- Infancy
Cows milk,
soy, rice and
Usually
resolves
IMMUNOPATHOLOGY DISORDER
KEY
FEATURES
ADDITIONAL
IMMUNOPATHOLOGY
TYPICAL
AGE
MOST
COMMON
CAUSAL
FOODS
NATURAL
COURSE
diarrhea, poor
growth, and
lethargy Re-
exposure after
restriction:
emesis,
diarrhea, and
hypotension
(15%) 2 hours
after ingestion
oat

Dietary protein
proctitis
Mucus-laden,
bloody stools
in infants Eosinophilic inflammation Infancy
Milk (through
breast-feeding)
Usually
resolves
Reference :
Sicherer SH, Sampson HA. Food allergy. J Allergy Clin Immunol. Feb 2010;125(2 Suppl 2):S116-25.
Scott H. Sichererand Hugh A. Sampson. Food Allergy: Recent Advances in Pathophysiology and Treatment. Annual Review of Medicine Vol.
60: 261-277 (Volume publication date February 2009)
Sampson H. Update on food allergy. J Allergy Clin Immunol 2004 113 (5): 805819.
Julie Wang and Hugh A Sampson. Food allergy: recent advances in pathophysiology and treatment. Allergy Asthma Immunol Res. 2009
October; 1(1): 1929.
Lemon-Mule H, Sampson HA, Sicherer SH, Shreffler WG, Noone S, Nowak-Wegrzyn A. Immunologic changes in children with egg allergy
ingesting extensively heated egg. J Allergy Clin Immunol. 2008;122:977983
Shreffler WG, Castro RR, Kucuk ZY, Charlop-Powers Z, Grishina G, Yoo S, et al. The major glycoprotein allergen from Arachis hypogaea, Ara
h 1, is a ligand of dendritic cell-specific ICAM-grabbing nonintegrin and acts as a Th2 adjuvant in vitro. J Immunol. 2006;177:36773685
Meyer S, van Liempt E, Imberty A, van Kooyk Y, Geyer H, Geyer R, et al. DC-SIGN mediates binding of dendritic cells to authentic pseudo-
LewisY glycolipids ofSchistosoma mansoni cercariae, the first parasite-specific ligand of DC-SIGN. J Biol Chem. 2005;280:3734937359
Commins SP, Satinover SM, Hosen J, Mozena J, Borish L, Lewis BD, et al. Delayed anaphylaxis, angioedema, or urticaria after consumption of
red meat in patients with IgE antibodies specific for galactose-alpha-1,3-galactose. J Allergy Clin Immunol. 2009;123:426433
Anna Nowak-Wgrzyn, Hugh A. Sampson. Future therapies for food allergies. Journal of Allergy and Clinical Immunology March 2011 Vol.
127, Issue 3, Pages 558-573
Scott H. Sicherer, Hugh A. Sampson. Journal of Allergy and Clinical Immunology February 2010 Vol. 125, Issue 2, Supplement 2, Pages S116-
S125
Stephan Steckelbroeck, Barbara K. Ballmer-Weber, Stefan Vieths. Potential, pitfalls, and prospects of food allergy diagnostics with recombinant
allergens or synthetic sequential epitopes. Journal of Allergy and Clinical Immunology June 2008 Vol. 121, Issue 6, Pages 1323-1330
A. Wesley Burks, Mimi Tang, Scott Sicherer, Antonella Muraro, et al. ICON: Food allergy. Journal of Allergy and Clinical Immunology 24
February 2012
Report of the NIAID-Sponsored Expert Panel, NIAID-Sponsored Expert Panel. Guidelines for the Diagnosis and Management of Food Allergy
in the United States: Practice guideline. December 2010. Journal of Allergy and Clinical Immunology Vol. 126, Issue 6, Supplement, Pages S1-
S58