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Clinical Spectrum of Food Allergies:
a Comprehensive Review
Marco H.-K. Ho & Wilfred H.-S. Wong & Christopher Chang
Published online: 16 November 2012# Springer Science+Business Media New York 2012
Abstract Food allergy is defined as an adverse immune
response towards food proteins or as a form of a food
intolerance associated with a hypersensitive immune re-sponse. It should also be reproducible by a double-blind
placebo-controlled food challenge. Many reported that food
reactions are not allergic but are intolerances. Food allergy
often presents to clinicians as a symptom complex. This
review focuses on the clinical spectrum and manifestations
of various forms of food allergies. According to clinical
presentations and allergy testing, there are three types of
food allergy: IgE mediated, mixed (IgE/Non-IgE), and non-
IgE mediated (cellular, delayed type hypersensitivity). Re-
cent advances in food allergy in early childhood have high-
lighted increasing recognition of a spectrum of delayed-
onset non-IgE-mediated manifestation of food allergy. Com-mon presentations of food allergy in infancy including atop-
ic eczema, infantile colic, and gastroesophageal reflux.
These clinical observations are frequently associated with
food hypersensitivity and respond to dietary elimination.
Non-IgE-mediated food allergy includes a wide range of
diseases, from atopic dermatitis to food protein-induced
enterocolitis and from eosinophilic esophagitis to celiac
disease. The most common food allergies in children in-
clude milk, egg, soy, wheat, peanut, treenut, fish, and shell-
fish. Milk and egg allergies are usually outgrown, but
peanut and treenut allergy tends to persist. The prevalence
of food allergy in infancy is increasing and may affect up to
15 –
20 % of infants. The alarming rate of increase calls for a public health approach in the prevention and treatment of
food allergy in children.
Keywords Food allergy . Food protein-induced enterocolitis .
Eosinophilic esophagitis . Oral allergy syndrome . Urticarial .
Anaphylaxis . Wheezing . Atopic dermatitis
Introduction
“Food allergy” is a common complaint from the general
public which often leads to self-imposed food avoid-
ance. Whether it leads to subsequent medical consulta-
tion is dependent on several factors such as the severity
and persistence of the symptoms, the perceived useful-
ness of medical opinions, the accessibility and availabil-
ity of the relevant health care, and the prevailing health-
seeking behaviors of the local community and culture.
Though patients, parents, caretakers, and families alike
generally believe themselves or their children have food
allergy; these usually represent cases of non-immunological
adverse food reactions or food intolerances instead. Of the
20 to 30 % of people who report food allergy in them-
selves or their children, food allergy can be ascertained in
only 6 – 8 % of children under five, and in 3 – 4 % o f
adults [1, 2].
Adverse food reaction should be used as a general term
for any untoward response to the ingestion of a food. It can
be cases of food allergy or other non-immunological reac-
tions. There are many types of non-immunological adverse
reactions to ingestion of food, such as gastroesophageal
reflux, gastrointestinal anatomical or functional abnormali-
ties, food poisoning, infection, etc.
M. H.-K. Ho (*):
W. H.-S. Wong
The Division of Immunology, Rheumatology and Allergy,
Department of Paediatrics and Adolescent Medicine,
Queen Mary Hospital, Li Ka Shing Faculty of Medicine,
The University of Hong Kong, Hong Kong, China
e-mail: marcoho@hku.hk
C. Chang (*)
Division of Allergy, and Immunology, Thomas Jefferson
University, Nemours Hospital for Children, 1600 Rockland Road,
Wilmington, DE 19803, USA
e-mail: c3chang@yahoo.com
Clinic Rev Allerg Immunol (2014) 46:225 – 240
DOI 10.1007/s12016-012-8339-6
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Food allergy is defined as an adverse immune response
toward food proteins, or as a form of food intolerance
associated with a hypersensitive immune response. It should
also be reproducible by a double-blind placebo-controlled
food challenge (DBPCFC). Food intolerance is a reproduc-
ible reaction to a food or food ingredient which occurs even
in DBPCFC (examples include lactose intolerance and met-
abolic diseases/enzymatic deficiencies); while aversion or phobia to food is a bodily reaction associated with a food
ingestion which cannot be reproduced by DBPCFC.
Food allergy often presents to clinicians with a symptom
complex which develops after ingestion of foods, with time
of onset ranging from minutes to days and occasionally
weeks, as in the case of atopic dermatitis (AD). This review
focuses on the clinical spectrum and manifestations of various
forms of food allergies.
Prevalence
It appears to be the general consensus that the prevalence of
food allergies and related atopic disorders is increasing in
industrialized countries [3, 4]. However, it has remained
unresolved to what extent this represents a true prevalence
increase or is attributable to an increasing awareness of the
clinical manifestations of food allergy [3]. The available
prevalence studies cannot easily be compared due to differ-
ences in epidemiological methodology. Some studies define
food allergy according to laboratory findings or objective
proof of sensitization, whereas other studies define food
allergy by clinical reactivity. Food-specific IgE antibodies
can be found in healthy individuals clearly tolerant to that
food and even without any history of clinical reaction.
Another difficulty in defining the prevalence of food aller-
gies is the variation of the prevalence with age, as a signif-
icant proportion of food allergic infants will develop
tolerance during early childhood. Finally, the prevalence of
food allergy and the spectrum of food allergens may vary
between countries due to differences in environmental and
genetic factors [4, 5].
A telephone survey in Americans revealed a self-reported
prevalence of peanut allergy of 1.1 % [6]. The prevalence
doubled from 1997 to 2002 [6, 7]. However, reliance on
self-reporting may be prone to overestimation of the true
prevalence of food allergy [1 – 3]. Based on Isle of Wight
birth cohort studies, Grundy et al. [8] compared the preva-
lence of peanut allergy in two birth cohorts less than a
decade apart. They reported a significant increase in sensi-
tization to peanut, from 1.1 % in 1989 to 3.3 % in 1994 –
1996. Only a small proportion reacted upon challenge and
there was a high clinical tolerance rate despite the sensitiza-
tion. Furthermore, the overall recruitment rate was less than
50 %. This highlights the importance of differentiating
between IgE food sensitization (based on skin prick testing
(SPT) or radioallergosorbent test (RAST)) and clinical hy-
persensitivity (based on food challenge). The reason of 3-
fold increase in sensitization [8, 9] is unclear; apart from a
real prevalence increase, differences in methodology, such
as an increased potency of SPT extracts or diagnostic sensi-
tivity of food-specific IgE assays, should be considered. In
fact, with more consistent methodology incorporating oralchallenge and robust sampling methodology with high par-
ticipation rates, a Montreal group found there was no in-
crease in prevalence of peanut allergy among school
children from 2005 to 2010 [10]. On the other hand, the
baseline peanut allergic rate was already slightly above 1 %
and thus it may represent the plateau scenario in countries
with high prevalence. Nonetheless, food allergy is one of the
most common causes of anaphylaxis presenting to accident
and emergency departments in the USA [11].
Though food allergy is not traditionally considered one of
the atopic diathesis, the most predictive risk factor for de-
velopment of food allergy is a strong family history of atopic diseases, e.g., hay fever, asthma, eczema, etc. The
risk increases as the number of parents and siblings having
atopic diseases increases. The onset of food allergy com-
monly occurs in infancy and childhood. It is largely attrib-
uted to the so-called “immature or leaky” gut barrier. The
practice of avoidance or delayed introduction of highly
allergic foods during weaning period has been common in
Western countries the last 10 to 15 years, but it is now
believed that this had little impact on the “rising” preva-
lence. The pendulum has now shifted to an emphasis on
early or the “right timing” of introduction of semi-solid or
solid foods to be around 4 – 6 months for better development
of immune tolerance. The discussion of these prevention
strategies is beyond the scope of this review.
Clinical Manifestations of Food Allergy
Food allergy is broadly divided into IgE-mediated (imme-
diate type, type I hypersensitivity) or non-IgE mediated
(delayed type, cellular, type IV hypersensitivity) based on
their clinical features, food-specific IgE measurements,
results of food challenge, and other auxiliary tests such as
patch test and endoscopic examination. There is also an
intermediate group or so-called mixed type which involves
eosinophilic and other cellular components and often shows
clinical features of the overlap of the above two mecha-
nisms. Such categorizations may sometimes be criticized as
being an over-simplistic way to account for the underlying
complex immune pathophysiology. However, the distinction
between various mechanisms is crucial in view of the po-
tential for the progression of IgE-mediated reactions to
anaphylaxis and death. Until we have better understanding
226 Clinic Rev Allerg Immunol (2014) 46:225 – 240
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of the immunological, molecular, genetic, and epigenetic
aspects of food allergy, it remains the most accepted way
of classification and is currently widely adopted by clini-
cians or practicing immunologists and allergists alike for
application of diagnostic maneuvers, counseling on man-
agement, natural history, and prognostication.
Some patients present with a history of a food allergy to a
single food. For these patients, they can have either an IgE-mediated reaction, non-IgE-mediated reaction, or a mixed
reaction to this particular food. For example, a child may
have an immediate reaction only to cow’s milk, or an im-
mediate reaction followed by an eczema flare-up, or he or
she may only have gastrointestinal symptoms such as colitis.
Other patients may have multiple food allergies. For them, it
can be all IgE mediated, mixed type, or rarely, all non-IgE
mediated. It is also possible to have IgE-, mixed-, or non-
IgE-mediated food allergy existing independently within the
same individual with regard to different foods. (Fig. 1)
IgE-Mediated Food Allergy
Type I hypersensitivity reactions occur when patients devel-
op IgE antibodies as a result of food proteins or peptides
penetrating through skin, gut, or respiratory lining. The
antigen is then processed by an antigen presenting cell
which presents the antigen in a MHC-restricted manner to
T cells. Activation of the T cell receptor leads to cross-talk
between T and B cells leading to the production of specific
IgE antibodies. The IgE antibodies circulate and bind to the
IgE receptors on the surfaces of mast cells and basophils.
Upon reexposure of allergen, a much quicker and stronger
response ensues, leading to the degranulation of effectors
cells and the release of pre-formed granules containing
histamine and tryptase. Other mediators may also be re-
leased, including prostaglandins, leukotrienes, chemokines,
etc. These mediators have the ability to induce vasodilata-
tion, mucous secretion, smooth muscle contraction, and
influx of other inflammatory cells, all characteristics of a
classical inflammatory response.
The stereotypic symptoms of IgE-mediated reactions arerapid in onset and can result in multi-system or systemic
manifestations. In general, IgE-mediated reactions are con-
sidered to be acute reactions, although they are frequently
associated with chronic symptoms through the late-phase
reaction and recurrent exposures associated with the influx
of inflammatory cells. Patient with atopic dermatitis and
food-specific IgE-mediated reactions frequently develop
chronic complaints. (Fig. 2)
The cutaneous manifestations, including urticaria and
angioedema, are the most prevalent symptoms. The lifetime
prevalence of significant urticaria is estimated to be 10 –
20 % in some populations. Some of these cases are a result of variety of triggers such as infection, insect bites, food, or
drug allergy. Food allergy may account for 20 % of cases
[12]. The majority of cases of chronic hives are idiopathic.
Acute urticaria developing after skin contact with food is not
infrequently seen, but whether this is an IgE-mediated type I
reaction is unclear.
Despite patients’ perception about food allergy, in cases
of chronic urticaria and angioedema lasting longer than
6 weeks, food allergy usually is not the culprit. Food-
specific IgE testing and placebo-controlled challenges con-
firm an association with food sensitivity in less than 10 %
of circumstances.
Fig. 1 The spectrum of food
allergy of different
immunopathophysiology
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Respiratory symptoms together with ocular symptoms
can occur in isolation or more commonly with other sys-
temic reactions. Conjunctivitis (lacrimation, periorbital ede-
ma, redness and itchiness of eyes), rhinitis (sneezing, runny
nose, nasal obstruction, itchy of nose, cough, voice changes,
etc.) and asthma attacks (cough, shortness of breath, de-
creased exercise tolerance, wheezing, etc.) can be observed
during positive controlled challenge tests [13]. Vapors or
steam emitted from cooking certain foods may induce asth-
matic reactions. Food-induced asthmatic symptoms should
be suspected in patients with refractory asthma and history
of atopic dermatitis, gastroesophageal reflux, food allergy,
feeding problems as an infant, or history of positive skin
tests or clinical reactions to food.
Asthma, by itself, is an uncommon manifestation of food
allergy. An exception is occupational asthma occurs in adult,
such as Baker ’s asthma. The patients may not react to the
food upon ingestion, but to inhalation of a food allergen, for
example, wheat flour, or to a “contaminant ” or by product of
the food, such as fungal spores in mushrooms or storage
mites in grain. Hypersenstivity pneumonitis can also occur
as a result of contamination of food storage facilities by
various biological agents or products.
Gastrointestinal symptoms such as throat discomfort, mouth
and tongue itchiness, nausea, vomiting, abdominal cramps,
and diarrhea may be clinical manifestations in patients with
IgE-mediated food allergy. The onset can range from
minutes to 2 h for upper gastrointestinal symptoms or
occasionally over 2 h for lower gastrointestinal symptoms.
Gastrointestinal symptoms such as bloody stools, malab-
sorption, weight loss, constipation, and failure to thrive are
usually not symptoms of IgE-mediated but rather of non-
IgE-mediated food allergy.
Cardiovascular symptoms are the most severe manifesta-
tion of a systemic reaction and may include hypotension,
vascular collapse, arrhythmia, etc. Cardiovascular symp-
toms seldom occur alone without the involvement of other
organ systems. Fatality is associated with up to half of the
cases of anaphylaxis seen in accident and emergency depart-
ments in the USA [11, 14]. The overall rate of fatalities as a
result of food-induced anaphylaxis is probably much lower
because of the body’s ability to compensate. The relative
frequency of food allergy in different clinical disorders is
shown in Table 1.
Non-IgE-Mediated Food Allergy
The exact underlying immunopathophysiology of non-IgE-
mediated food allergy is poorly understood. Clinical symp-
toms are subacute or chronic in nature and usually present
Fig. 2 A schematic diagram illustrating the time sequence and key
factors precipitating the early- and late-phase reactions of food allergy
or anaphylaxis (biphastic reactions). Abbreviations: CysLT cysteinyl
leukotriene, ECP eosinophilic cationic protein, GM-CSF granulocyte
macrophage colony-stimulating factor, IL interleukin, MBP major basic
protein, PAF platelet-activating factor, TNF-α tumor necrosis factor alpha
228 Clinic Rev Allerg Immunol (2014) 46:225 – 240
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with isolated gastrointestinal symptoms. Food protein-
induced enterocolitis, proctitis, proctocolitis, celiac disease,
dermatitis herpetiformis, and food-induced pulmonary hemo-
siderosis are forms of food allergy with a non-IgE-mediated
immunological basis.
Food allergy with abnormal eosinophilic infiltration of the intestinal tract is another form of food allergy. Examples
include eosinophilic esophagitis and eosinophilic gastroen-
teritis. The only region of the gastrointestinal system where
eosinophils are not normally found is the esophagus. The
underlying pathophysiology of eosinophilic gastrointestinal
diseases and its relationship to food allergy have yet to be
clearly defined. Studies have demonstrated food sensitivity
in some of the patients and food elimination can be
helpful in both the diagnosis and therapy of eosinophilic
esophagitis [15, 16]. Endoscopy and biopsy are often needed
for definitive diagnosis.
International agreement has been reached on a classifica-
tion of gastrointestinal disorders due to adverse immune
reaction to foods [17, 18] based on clinical observations.
Figure 1 summarizes the spectrum of food allergy with
regard to the different immunopathophysiology.
Many patients and even some healthcare professionals
believe that certain foods might be a trigger or aggravating
factors to certain chronic conditions such as migraines;
behavioral/developmental disorder such as autism, arthritis,
seizures, and inflammatory bowel disease. It should be
emphasized that there has never been any solid scientific
evidence for any of these associations [19 – 21].
Food Allergens
There are two types of food allergens [22]. Class 1 food
allergens are the primary sensitizers. Sensitization may occur
through the gastrointestinal tract. These are water-soluble
glycoproteins of molecular weights ranging from 10 to
70 kD. They are stable to heat, acid, and proteases. Table 2
illustrates some examples of the class 1 food allergens.
Class 2 food allergens are generally cross-reactive with
plant-derived prote ins. The cross -reactivity commonly
results in oral allergy syndrome or latex-fruit syndrome.
They are highly heat labile and difficult to isolate. There
are no good, standardized commercial extracts available
for diagnostic purposes. Often, clinicians need to resort
to raw materials and perform skin prick (epicutaneous)
testing. Examples of class 2 food allergens are shown in
Table 3.
A particular food allergen can cause reactions in raw
form but not when it is well cooked. Food processing can
alter the allergenic state (epitope) of the food. This is why
some patients are able to tolerate food products when they
are heated well but not when they are either unheated or
heated to a low degree, for example, in the case of egg
allergy. This also forms a pathophysiological basis for using
heated allergens to induce tolerance to native allergens.
Taking anti-ulcer therapy concomitantly with eating can
alter the gastric acidity, and thereby alter the protection that
the gastric environment normally offers to unstable heat-
labile food allergens.
Food allergens may be found in non-food items such as
medications, vaccines, cosmetics, children’s crafts, or in
the body fluid of others who have recently ingested food
allergens [23].
An allergic reaction can occur with the ingestion of minute
amounts of food allergen, or by ingestion of food which is
cross-contaminated, as in the case of peanut and tree nut
Table 1 The frequency of food allergy among various specific allergic
disorders
Food allergy prevalence in specific disorders
Disorder Food allergy prevalence
Anaphylaxis 35 – 55 %
Oral allergy syndrome 25 – 75 % in pollen allergic patients
Atopic dermatitis 35 % in children (rare in adults)
Urticaria 20 % in acute (rare in chronic)
Asthma 5 – 6 % in asthmatic or food allergic children
Chronic rhinitis Rare
Table 2 Examples of major class 1 food allergens
Cow’s milk Caseins (a, b, k), α-lactoalbumin, β-lactoglobulin,
serum albumin
Chicken egg Ovomucoid, ovalbumin, ovotransferrin
Peanut Vicillin, conglutin, glycinin
Soybean Glycinin, profilin, trypsin inhibitor
Shrimp Tropomyosin
Fish Parvalbumins
Fruits, vegetables Lipid transfer proteins (LTPs)
Table 3 Examples of class 2 food allergens
Pathogen-related protein 2 group
(glucanase)
Latex, avocado, banana, chestnut,
fig
Pathogen-related protein 3 group
(chitinase)
Latex (Hev b6), avocado
Pathogen-related protein 5
(thaumatin-like)
Cherry, apple, kiwi
Birch Bet v1 homologues
(pathogen-related proteins 10)
Apple, cherry, apricot, peach,
pear, carrot, celery, parsley,
hazelnut
Birch Bet v2 homologues
(celery-mugwort-spice
syndrome) profilin
Latex, celery, potato, pear, peanut,
soybean
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products prepared on the same equipment. Dishwashing liq-
uid has been shown to be inadequate in the removal of food
allergens from contaminated dishware [24].
Clinical implications of cross-reactions of different foods
include an assessment of cross-reacting foods when evalu-
ating a patient for food allergies (Fig. 3).
IgE-Mediated Systemic Reaction/Anaphylaxis/
Anaphylaxis Syndrome
Food-induced anaphylaxis has a very rapid-onset and
multi-organ system involvement. It is potentially fatal. It
can be caused by virtually any food but certain common
foods (peanut, nut, seafood, milk, egg) seem to convey a
higher risk. Peanut allergy is of particular high risk and
over 90 % of food-induced anaphylaxis-related fatalities
are a result of exposure to peanut in a sensitized individ-
ual. Food-dependent exercise-induced anaphylaxis is a
special condition which can either be associated with a particular food (e.g., wheat) or with eating any food. Post-
ingestion exercise is a pre-requisite trigger for the develop-
ment of anaphylaxis in this disorder.
Fatal Food Anaphylaxis
It is estimated that fatal food anaphylaxis causes a toll of
about 100 deaths per year in the USA [14]. Analysis of the
risk factors among the death cases found that most of them
had known allergy to the food, had underlying asthma,
experienced a delay in administration of epinephrine or
had a previous history of severe reactions [14]. In some
cases, the patient denied or trivialized their food allergic
symptoms. In others, the onset of reaction was associated
with a lack of easily recognizable cutaneous symptoms,
thereby delaying the proper use of adrenaline.
Another risk factor was the presence of a biphasic reac-
tion, although there are few good clinical predictors of a
biphasic reaction. Hence, vigilant observation within anappropriate setting for 2 – 4 h post-early-phase reactions is
pivotal to ensure patients’ safety.
To predict who is at higher risk is highly relevant in
clinical counseling. It has been shown that serum platelet
activating factor acetylhydrolase activity is a promising
biomarker. It was significantly lower in patients with fatal
peanut anaphylaxis than in control patients [25]. Whether or
not this test will become a useful marker for anaphylaxis is
not clear at this time.
Common Food Allergy
A relatively small number of foods, which we term the
“major ” food allergens, account for the majority of food
allergic reactions [1, 4, 5]. These include milk, egg,
peanut, tree nut, seafood, shellfish, soy, and wheat. While
these foods are globally accepted to some degree to be
associated with immediate type 1 hypersensitivity reac-
tions, there may be local or regional variations in the
relative importance of these allergens, as well as possible
allergens that are unique to a particular region of the
world. Likelihood of development of allergy increases
Fig. 3 The frequency of cross-reactions within the same food family
230 Clinic Rev Allerg Immunol (2014) 46:225 – 240
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with exposure, so the variability may depend on the particular
cuisine in different parts of the world.
In adults, the allergen spectrum is quite different as a
significant proportion of children with food allergies devel-
op tolerance to some of these allergens. Adults may also
develop new food allergies which affect the distribution.
The main food allergens in adults in many developed
countries are peanut, tree nuts, fish, and shellfish [2, 7,11]. New plant-origin food allergens derived from seeds
(mustard, sesame, and sunflower), chickpea, buckwheat,
mushroom [26] as well as those associated with fruit-latex
and Prunoideae groups, have recently been reviewed and
are a topic of allergies to lipid transfer proteins, another
article in this issue, reflecting an increased awareness of
food hypersensitivity [27].
Cow’s Milk Allergy
Cow milk allergy can be regarded as a model of food allergy
as cow’s milk is usually one of the first food proteins that infants are exposed to in the Western Hemisphere [14, 28].
Prevalence studies from Sweden [29], Denmark [30] and the
Netherlands [31] demonstrated a prevalence of cow’s milk
allergy (CMA) 1.9 – 2.8 %. Prevalence figures from Aus-
tralia were similar [32]. In China, the newly assumed second
largest economy of the world, an increase in cow’s milk
allergy has been associated with rapid urbanization, with a
latest estimation of CMA of 2.3 % in a major city [33]. The
Melbourne Milk Allergy Study (MMAS) described a di-
verse group of clinical symptoms and syndromes that could
be demonstrated by dietary challenge [28]. These ranged
from anaphylaxis and urticaria occurring within minutes of
challenge to distress, vomiting, and diarrhea within hours.
Exacerbations of atopic dermatitis as well as gastrointestinal
or respiratory symptoms occurring after 24 h of ingesting
cow’s milk were also manifestations during challenge. Anal-
ysis of these data using a K means algorithm identified three
clinical groups with different immunological profiles, and a subsequent step-wise discriminant analysis confirmed the
validity of this classification
The first group, the immediate reactors, developed acute
skin rashes, including peri-oral erythema, facial angioedema,
urticaria, and pruritus at eczema sites, with or without signs of
anaphylaxis. Patients in this group typically had had high
levels of cow’s milk-specific IgE antibodies, detected either
in vitro by RASTor in vivo by SPT. The second, the interme-
diate group, had reactions occurring from 1 to 24 h after
ingestion of milk; they had predominantly gastrointestinal
symptoms, including vomiting and diarrhea. As a group, these
patients did not exhibit features of IgE sensitization. The third,the late-reacting group, developed symptoms from 24 h to
5 days after the commencement of the challenge procedures;
these patients presented with exacerbations of AD, cough,
wheeze and/or diarrhea. Varying degrees of IgE sensitization
were seen in those with AD. Subsequent studies have dem-
onstrated that this group had greater levels of Tcell sensitiza-
tion to milk than the immediate or intermediate reactors or
control children [34]. Figure 4 illustrates the mechanisms in
play in the gastrointestinal-immune system interface that in-
volve IgE- and non-IgE-mediated pathways.
Fig. 4 A schematic diagramillustrating the hypothetical
gastrointestinal and immune
interface. The digestive
processes and absorption of
food are dependent on gastric
acidity, enzymatic digestion,
and tight junctions, which is
followed by antigen processing
via local mucosal lymphoid
(Peyer ’s patch) involvement,
which then leads to IgE-, non-
IgE-, or mixed type-mediated
food hypersensitivities. There is
a continuous interplay of cellu-
lar and humoral molecular factors and signaling pathways.
Abbreviations: APC antigen
presenting cells, TNF-α tumor
necrosis factor alpha, IL-5
interleukin 5
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Thermal processing such as roasting, may play a part in
enhancing the allergenic properties of peanuts [56]. It
appears that the methods of frying and boiling peanuts, as
practiced in China, might actually reduce the allergenicity of
peanuts compared with the method of dry roasting practiced
widely in the USA.
The minimum dose of food protein to which subjects
with food allergy have reacted in double-blind, placebo-controlled food challenges (DBPCFC) is between 50 and
100 mg [57, 58]. However, subjects with peanut allergy
often report severe reactions after ingesting minimal
quantities of peanuts. Studies have not yet had the power
to investigate whether peanut allergy is more commonly
associated with much lower doses than seen in allergy to
other foods.
Seafood Allergy
Seafood allergy includes both fish and shellfish allergy.
Seafood allergy often develops in young children but isincreasingly prevalent in teens and adults, as less than 5 %
of initially allergic subjects develop tolerance over time.
IgE-mediated reactions accounts for the majority of allergic
reactions to seafood. Clinical presentation may include gen-
eralized reactions or isolated gastrointestinal or extra-
gastrointestinal reactions. The severity varies, ranging from
mild to severe or even fatal. Seafood allergy tends to recur
for some of the subjects showing initial resolution [59].
The specific type of fish or shellfish perhaps depends on
the availability of the type of seafood in a particular geo-
graphic region, which affects the pattern of consumption
and exposure. Parvalbumin in fish and tropomyosin in
shellfish are the key seafood allergens. They are different
prot eins so there is not a great deal of clinica l cros s-
reactivity between fish and seafood, although food contam-
ination may play a role. Within the group, however, there is
homology of protein structure across various types of fish or
shellfish and hence cross-reactivity is highly possible. The
negative predictive value of skin prick test by commercial
food extracts is relatively high and a negative test dimin-
ishes the possibility of a food allergy. If the history is
suggestive while the skin prick test or specific IgE level
are negative, a controlled food challenge with the implicated
seafood prepared in a manner similar to the exposure that
caused the reaction should be performed.
Non-IgE-mediated mechanisms are much less recognized
with regard to seafood allergy. If this type of reaction is the
predominant mechanism, clinically, the patient may experi-
ence food protein-induced enterocolitis resulting in nausea,
diarrhea, and abdominal pain after a few minutes to several
hours post-ingestion [60]. Contact dermatitis to seafood in
occupational and household exposure to seafood has been
reported [61]. Clinically apparent, seafood allergy with
negative IgE testing should alert the clinician to the possi-
bility of fish parasite Anisakis simplex allergy. The Anisakis
allergy is an interesting entity and researchers believed that
the parasite must be alive and be able to penetrate through
gastric mucosa in order to elicit the cascade of events.
Neither the skin prick test with parasite extract nor oral
challenge reproduces the symptoms [62]. It should also be
noted that other diseases can mimic a food allergy to sea-food. Ciguatera, caused by Gambierdiscus toxicus toxins
including ciguatoxin, maitotoxin, scaritoxin, and palytoxin,
can cause gastrointestinal symptoms such as vomiting, nau-
sea, and diarrhea, as well as neurological symptoms includ-
ing dyspareunia and allodynia. Scombroid fish poisoning
can also mimic type 1 hypersensitivity reactions because of
the production of histamine from histidine occurring natu-
rally in spoiled fish.
Oral Allergy Syndrome
Oral allergy syndrome is a very common but mild type of food allergy. It is an IgE-mediated allergic reaction and
tends to be limited to the oropharynx. It occurs after inges-
tion of certain fresh fruits or vegetables in pollen-sensitized
individuals [63]. The allergens in fruits, nuts, and vegetables
share homology to pollen allergens. The patients are initially
sensitized from exposure to pollen allergens, and subsequent
presentation of the homologous allergen upon ingestion of
raw fruits, nuts, or vegetables results in pruritus, tingling,
erythema, and swelling of the lip, oral mucosa, palate, and
throat during or soon after contact. The implicated allergens
are type 2 allergens and are sensitive to heat, acid, and
digestive enzymes, in contrast to isolated fruit/nut/vegetable
allergy. Clinical reactions normally occur upon ingestion of
raw, uncooked food. One caution is that though infrequent,
one in 10 patients may experience systemic reactions and
1.7 % had anaphylactic shock in a review analyzed over
1,300 subjects [64]. Another commonly employed term is
“Pollen food hypersensitivity syndrome”. This is considered
to be the commonest form of food allergy in adults, and
in certain regions the estimated prevalence rate is about
5 % of the general population [65]. Sensitization to birch
pollens and multiple sensitizations to pollens with a his-
tory of clinical allergy to these pollens are risk factors for
development of oral allergy syndrome. Immunotherapy to
treat the pollen-induced rhinitis may reduce or eliminate
oral allergy symptoms.
Food Additives Allergy
The modern food industry utilizes food additives extensive-
ly for coloring, sweetening, as preservatives or thickeners or
antioxidants, etc. Industrialized countries in general have
tight regulations on the quantity limit of individual known
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additives, but the regulations do not adequately address the
situation of multiple additives. Moreover, enforcing such
regulations is not an easy task amid the intense globalization
of economies and human activities. The medical community
has reacted “inappropriately” slow in initiating good re-
search on the potential health impact of regular human
consumptions of such additives.
At the current writing, it is generally believed that most food additives are safe and only a small number of them
have been postulated to be a culprit with an immunological
basis. Reports on allergy to food additives is usually anec-
dotal or reflect poorly designed studies [66]. For example,
“Chinese restaurant syndrome” refers to a symptom com-
plex that includes nausea, myalgia, neck pain, backache,
sweating, flushing, and chest tightness, and presumably
occurs after ingestion of monosodium glutamate (MSG).
MSG is a meat flavor enhancer which is often found in
Chinese and Asian food. It has been difficult to reproduce
the syndrome with controlled oral challenge tests.
Nonethel ess, a rece nt rand omized double-blin d con-trolled trial indicated that artificial coloring or a sodium
benzoate preservative (or both) in the diet may result in
increased hyperactivity in 3-year-old and 8 to 9-year-old
children in the UK [67]. It is uncertain whether this is
reproducible on individuals by DBPCFC. The mechanism
for this unproven observation is unknown. This study illus-
trates that a certain skeptism or vigilance is necessary when
presented with studies that introduce data before a confir-
matory study can be performed. If unproven conclusions are
accepted without question, this may impact public health
mandates that may consume a great deal of health care
resources to legislate a wrong recommendation.
Mixed IgE/Non-IgE Mediated
Atopic Eczema
Atopic dermatitis generally begins in early infancy. It is
characterized by a typical distribution, extreme pruritus,
and a chronically relapsing course. The role of hypersensi-
tivity to dietary antigens in the induction and maintenance
of this chronic inflammatory response is controversial [68].
An expert panel of American paediatric dermatologists re-
cently concluded that “food allergy affects only a minority
of atopic dermatitis patients” [69]. Hanifin [70, 71] estimat-
ed that only 10 % of children with atopic eczema (AE) have
food allergy contributing to their disease. Food allergy plays
a pathogenic role in about 35 % of moderate-to-severe
childhood atopic dermatitis in the USA [72 – 74].
The latest findings suggest that allergen-specific IgE anti-
bodies bound to Langerhans cells play a unique role as “non-
traditional” receptors. Double-blind, placebo-controlled food
challenges generally provoke a markedly pruritic, erythema-
tous, morbilliform rash [75, 76].
In the Melbourne Atopy Cohort Study (MACS) birth
cohort of 620 Australian children with a positive family
history of atopy, the association between IgE food allergy
(IgEFA) to common food allergen (cow’s milk, egg, and
peanut) and AE was investigated [77]. IgF FA was com-
pared between MACS children with AE (MACS AE+) andwithout AE (MACS AE−) in a group of consecutively
referred infants of similar age with severe AE. The calcu-
lated attributable risk percent for IgEFA as a cause of AE
was 65 and 62 %, at 6 and 12 months of age, respectively. In
the separate group of infants with severe AE, the equivalent
degree of IgE food allergy was 83 % at 6 months and 65 %
at 12 months. A critique of the study was that the patients
were selected from an allergy clinic and this introduced a
selection bias. The authors thus extended the study to in
infants with eczema attending a Dermatology Department in
the same Children Hospital. Their clinical history and ecze-
ma severity were documented. The results showed 90% of the infants had IgEFA to milk, egg and/or peanut. The
findings highlighted the strong association between IgEFA
and eczema in infants attending a dermatology clinic. Man-
agement of infantile atopic eczema at both the individual
and community level should incorporate appropriate diag-
nostic and dietary strategies [78].
Allergic Eosinophilic Disorders
These conditions are gaining medical attention and are
perhaps on a rising trend in industrialized countries. They
are considered mixed IgE/non-IgE-mediated gastrointestinal
manifestations of food allergy. Allergic eosinophilic esoph-
agitis (AEE) can occur in children [79 – 81] and adults. A
yearly incidence was estimated to be 23/100,000 population
in Switzerland. In children, symptoms similar to gastro-
esophageal reflux [80], and in adults, dysphagia and impac-
tion, are common. Patients with AEE often have a poor
response to anti-reflux drugs [79, 80]. Almost 50 % of
patients have other atopic diseases [82, 83].
Diagnosis is based on endoscopic findings and biopsy [79].
In AEE, endoscopic findings show characteristic rings and
white plagues which correspond to underlying mucosal infil-
tration of eosinophils. Furrowing can also be seen in advanced
cases. Histological findings of allergic eosinophilic disorders
are characterized by infiltration of the esophagus, stomach
and/or intestinal walls with eosinophils, basal zone hyperpla-
sia, papillary elongation, absence of vasculitis, and peripheral
eosinophilia in about 50 % of patients. Normally, a cut off of
>15 eosinophils per high-power field is required for diagnosis
of AEE [84]. Eotaxin-3 tissue expression has been found to
correlate with eosinophilia and likely plays a crucial role in the
pathogenesis of this disorder [85].
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Allergic Eosinophilic Gastroenteritis
Allergic eosinophilic gastroenteritis (AEG) may present as a
subacute weight loss in older children or failure to thrive in
younger children, and is occasionally associated with pitting
edema due to hypoalbuminaemia as a result of a protein-
losing enteropathy [86]. Vomiting and post-prandial diar-
rhea are also common symptoms. Chronic occult blood lossin the gastrointestinal tract may cause iron deficiency ane-
mia. Researchers found an increased Th2 profile in the
peripheral circulation and mucosa by biopsy [84]. Mast cells
and eosinophils are also prominent in intestinal mucosa with
elevated eotaxin-3 tissue expression [85]. The prognosis for
AEG is not favorable.
Food antigens have been implicated as one of the main
etiologies. Skin prick test and atopy patch tests can some-
times be useful for diagnosing a role of food allergies
[87]. Elimination diets or even amino acid formulas can
be instituted on the basis of allergy testing, clinical history,
biopsy, and treatment response. Pharmacologic treatment mainly constitutes of oral steroids [88] and/or swallowed
aerosolized fluticasone. Response to a novel treatment
using antibodies to IL-5 [89] seems promising but its
clinical indication has yet to be defined. Many patients
with AEG have persistent food hypersensitivity at 5-years
follow-up [86].
Non-IgE-Mediated Gastrointestinal Disorders
Food Protein-Induced Enterocolitis Syndrome
Food protein-induced enterocolitis syndrome (FPIES) is an
under-recognized and frequently misdiagnosed non-IgE-
mediated food hypersensitivity disorder. It occurs in infants
prior to 8 – 12 months of age, but may be delayed in breast-
fed babies. Cow’s milk- or soy protein-based formulas are
implicated [17, 90]. Symptoms may include irritability, pro-
tracted vomiting 1 – 3 h after feeding, bloody diarrhea, de-
hydration, anemia, abdominal distension, and failure to
thrive. In adults and older children, fish, shellfish, and cereal
hypersensitivity may provoke a similar syndrome with
delayed onset of severe nausea, abdominal cramps, and pro-
tracted vomiting. Longitudinal follow-up found 50 % resolved
at 18 months and about 90 % at 3 years of age.
Food Protein-Induced Enteropathy (Excluding Celiac
Disease)
Food protein-induced enteropathy can present between 0
and 24 months of age, but usually within the first few
months of life. The common presentation is diarrhea and
about 80 % are associated with mild to moderate steatorrhea
[17, 90]. Failure to thrive is also common. Foods implicated
include milk, cereals, egg, and fish. Definitive diagnosis
requires a mucosal biopsy, which would show patchy
villous atrophy with a prominent mononuclear round cell
infiltrate but with few eosinophils. Patients typically re-
spond well to an exclusion diet and quickly relapse upon
re-introduction or re-challenge. A significant proportionresolves by 2 – 3 years of age. Table 4 shows a clinical
comparison of the three entities: enteritis, enteropathy, and
protocolitis
Food protein-induced enteropathy is thought to be due
to food proteins passed to the infant in maternal breast
milk, cow’s milk-based formula, or soy-based formula.
Rectal bleeding is common [17, 90]. Diagnosis relies on
endoscopy and colonic biopsy and the typical histology
shows eosinophils in the intestinal tract epithelium and
lamina propria. Infants usually have a good response to
extensively hydrolyzed formulas. If breast feeding, the
mother should avoid consumption of dairy products.
Food protein-induced enteropathy carries very good prog-
nosis with the majority having resolution by 12 months
of life [60, 91].
Celiac Disease
This is the classical form of a cellular immune based mech-
anism. In celiac disease, the immune response is against
Table 4 A clinical comparison
of different presentations of FPIES
Non-IgE mediated: FPIES (non-IgE mediated) protein-induced syndromes
Enterocolitis Enteropathy Proctocolitis
Age of onset Infant Infant/toddler Newborn
Times from onset to remission 12 – 24 months ? 12 – 24 months
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gliadin peptides (wheat, rye, and barley) resulting in ex-
tensive enteropathy leading to malabsorption syndrome
[92]. Host factor plays an important role. Celiac disease
is highly associated with HLA-DQ2 (α 1*0501, β1*0201)
[91, 93, 94]. Positive serology tests of anti-transglutaminase
IgA and anti-gliadin IgA are often supportive criteria for
diagnosis, and quite useful in screening high-risk fami-
lies [60, 95]. Even among asymptomatic individuals, it is not an uncommonly seen positive serology. Hence,
clinicians have to interpret antibody testing results in the
context of clinical symptomatology, physical findings,
and response to elimination diets. Treatment for confirmed
celiac disease is essentially a complete elimination of gluten-
containing foods.
Non-IgE-Mediated Syndromes Affecting the Skin and Lung
Dermatitis herpetiformis is a form of dermatitis character-
ized by a vesicular, pruritic eruption which occurs in gluten-
sensitive subjects and tends to be associated with celiacdisease. Heiner ’s syndrome is a rare form of infantile pul-
monary hemosideroisis resulted in anemia and failure to
thrive. It is widely believed to be cow’s milk associated
and infants may develop precipitating antibodies to cow’s
milk protein.
Special Considerations in Infants
Multiple Food Allergy of Infancy
In the Melbourne Food Allergy Study, 60 infants allergic to
cow’s milk, soy, and extensively hydrolyzed formula, as
well as several other major food allergens including egg,
wheat, peanut, and fish were studied over a 10-year period.
The syndrome was called “The Multiple Food Protein In-
tolerance of Infancy (MPPI)” [96, 97]. It was later renamed
“Multiple Food Allergy (MFA)” to be consistent with inter-
national nomenclature. These infants need to be distin-
guished from those with “oligo-food hypersensitivity” who
are intolerant to only a few common food, such as milk, egg,
peanut, and nuts, but who tolerate soy or extensively hydro-
lyzed formulae.
In Hill et al.’s initial study which defined MFA, 19
infants with irritability (colic), vomiting and distress (reflux
esophagitis), AE, and growth failure which persisted despite
trials of soy, extensively hydrolysed casein-based (EHCF),
or extensively hydrolysed whey-based (EHWF) formulae
were studied. In 16, symptoms developed while being ex-
clusively breast-fed. The remission of symptoms occurred
within 2 weeks of commencing an amino acid-based formu-
la (AAF). DBPCFC showed 12 infants were intolerant to
EHCF (n04), EHWF (n02) or soy (n06). Two infants
developed anaphylactic hypersensitivity reactions to soy,
to which they were previously tolerant even in the face of
severe AE. The remaining 10 developed slowly evolving
reactions over 4 to 7 days [96, 97].
A high frequency of reported adverse reactions to low-
allergen foods including rice, several vegetables, fruits,
chicken, and lamb were reported. On average, adverse reac-
tions to six or 10 low-allergen foods were documented for each patient. Follow-up showed that most of the patients
tolerated these low-allergen foods by 2 years of age, and by
the age of 3 years only three required ongoing nutritional
support with AAF [97]. Vanderhoof et al. [98] and De
Boissieu et al. [99] have reported similar data for infants
with this disorder. Latcham et al. [100] in their study of a
large British cohort of infants with MFA frequently identi-
fied lymphocytic or eosinophilic esophagitis and subtle
enteropathy on endoscopy, as well as a consistent pattern
of delayed immune maturation with low IgA, IgG2, IgG4,
CD8+, and natural killer cells.
A prominent feature of MFA infants is their frequent onset of symptoms while being exclusively breast-fed, their
intolerance to soy and extensively hydrolyzed formulae and
a good response to AAF. A recent systematic review of
clinical trials of treatment of cow’s milk allergy demonstrat-
ed efficacy of AAF when compared to EHF in children, with
MFA manifesting as severe atopic eczema, reflux oesphagi-
tis, and any of the food-induced gastro-entero-colitis – proc-
titis syndromes with failure to thrive [101].
Infantile Colic
Infantile colic refers to a syndrome of paroxysmal fussiness
characterized by inconsolable, agonized crying. It generally
develops in the first 2 to 4 weeks of life and persists through
the third to fourth months of age, affecting between 15 and
40 % of infants. The role of dietary factors on colic is
controversial. In Hill et al.’s initial study of bottle-fed and
breast-fed “colicky” infants, bottle-fed infants who received
extensively hydrolyzed casein formula (EHCF) and those
infants whose mothers commenced a low-allergen diet
(milk, egg, wheat, peanut, nut, and soy-free) experience a
reduction in distressed behavior by >25 % more frequently
than those who received the control diet [102, 103]. The
treatment effect was greatest in breast-fed infants less than
6 weeks of age. These findings were subsequently prospec-
tively tested in a randomized trial that compared lactating
mothers on low-allergen diets (excluding milk, egg, peanut,
tree nuts, wheat, soy, and fish) with lactating mothers on a
control diet, and found an absolute reduction in colicky
behaviors of their infants by 37 %. The mean difference
in cry/fuss duration between the two groups at the end of
1 week was nearly 3 h per 48 h [ 104]. For infants on
formula, the clinical diagnosis can be established by the
236 Clinic Rev Allerg Immunol (2014) 46:225 – 240
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implementation of several brief trials of hypoallergenic
formula [90].
Gastroesophageal Reflux and Esophagitis in Infants
Gastroesophageal reflux (GER) is common during infancy
and is considered pathological if it causes esophagitis, fail-
ure to thrive, or respiratory symptoms. GER has tradition-ally been considered a primary motility disorder but several
studies suggest a causal relationship between CMA and
GER in infancy [105 – 108]. In a study of 204 infants with
GER and esophagitis, more than 40 % of patients had
evidence of cow’s milk allergy and improved symptomati-
cally on changing to extensively hydrolyzed formula.[106]
Electrophysiological studies in infants with CMA have
demonstrated a gastric motility disturbance following inges-
tion of cow’s milk, [107] making an association of food
allergies and GER plausible. Studies have suggested that
esophagitis, gastritis, and duodenitis are common in infants
with food intolerances [108].
Conclusion
Allergic reactions to foods are classified by clinical presen-
tations and allergen testing profiles. Food allergies can be
simplistically categorized into three main types: IgE- medi-
ated, mixed (IgE/non-IgE), and non-IgE-mediated (cellular,
delayed type). Patients can be allergic to only a single food,
but may also be allergic to multiple foods. The delayed type
food allergy may be mediated by antigen-specific activated
T-helper cells. There is evidence that T cells play a role in
IgE-mediated food allergy as well. Researchers have yet to
define the exact pathophysiologic mechanisms behind many
types of food allergies, especially mixed and non-IgE-
mediated allergy [109 – 112].
History and clinical examination are of paramount im-
portance in clinical practice to differentiate the different
forms of food allergy. Despite the improvement in diagnos-
tic methodology using wheal size diameters in allergen skin
testing or levels of food-specific IgE by ELISA testing
(CAP-FEIA), a conclusive diagnosis is still dependent on
elimination and challenge testing. To demonstrate the toler-
ance, natural resolution or the persistence of food allergy,
periodic re-challenge remains the cornerstone of practice.
Monitoring for the development of tolerance by clinical
history upon inadvertent exposure, in vivo skin testing,
and the level of food-specific IgE may also provide useful
information regarding a time to conduct a food challenge.
Recent advances in food allergy in early childhood have
highlighted increasing recognition of a spectrum of delayed-
onset, non-IgE-mediated manifestations of food allergy.
Common presentations in infancy including atopic eczema,
infantile colic, and gastroesophageal reflux are associated
with food hypersensitivity and often respond to dietary
elimination. These manifestations form the expanded spec-
trum of food allergy in infancy and may affect up to 15 –
20 % of infants. The increasing prevalence and the broad-
ening spectrum of food allergy calls for a public health
approach in the prevention and treatment of food allergy in
children. Education of health professionals and parentsabout the spectrum of food allergic disorders in infants and
children will facilitate early diagnosis and appropriate man-
agement and may provide significant cost savings to the
health care budget.
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