Clinic Rev Allerg Immunol

DOI 10.1007/s12016-012-8339-6

Clinical Spectrum of Food Allergies:

a Comprehensive Review
Marco H.-K. Ho & Wilfred H.-S. Wong & Christopher Chang

# 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 response. 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 nonIgE mediated (cellular, delayed type hypersensitivity). Recent advances in food allergy in early childhood have highlighted increasing recognition of a spectrum of delayedonset non-IgE-mediated manifestation of food allergy. Common presentations of food allergy in infancy including atopic 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 include milk, egg, soy, wheat, peanut, treenut, fish, and shellfish. Milk and egg allergies are usually outgrown, but
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

peanut and treenut allergy tends to persist. The prevalence

of food allergy in infancy is increasing and may affect up to
1520 % 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 avoidance. Whether it leads to subsequent medical consultation is dependent on several factors such as the severity
and persistence of the symptoms, the perceived usefulness of medical opinions, the accessibility and availability of the relevant health care, and the prevailing healthseeking 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 themselves or their children, food allergy can be ascertained in
only 68 % of children under five, and in 34 % of
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 reactions. There are many types of non-immunological adverse
reactions to ingestion of food, such as gastroesophageal
reflux, gastrointestinal anatomical or functional abnormalities, food poisoning, infection, etc.

Clinic Rev Allerg Immunol

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 reproducible reaction to a food or food ingredient which occurs even
in DBPCFC (examples include lactose intolerance and metabolic 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 differences 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 allergies is the variation of the prevalence with age, as a significant 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 [13]. Based on Isle of Wight
birth cohort studies, Grundy et al. [8] compared the prevalence of peanut allergy in two birth cohorts less than a
decade apart. They reported a significant increase in sensitization 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 sensitization. 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 hypersensitivity (based on food challenge). The reason of 3fold 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 sensitivity of food-specific IgE assays, should be considered. In
fact, with more consistent methodology incorporating oral
challenge and robust sampling methodology with high participation rates, a Montreal group found there was no increase 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 development 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 commonly occurs in infancy and childhood. It is largely attributed 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 prevalence. 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 46 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 (immediate 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 mechanisms. 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 potential for the progression of IgE-mediated reactions to
anaphylaxis and death. Until we have better understanding

Clinic Rev Allerg Immunol

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 clinicians or practicing immunologists and allergists alike for
application of diagnostic maneuvers, counseling on management, 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 IgEmediated reaction, non-IgE-mediated reaction, or a mixed
reaction to this particular food. For example, a child may
have an immediate reaction only to cows milk, or an immediate 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 nonIgE-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 develop 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
Fig. 1 The spectrum of food
allergy of different
immunopathophysiology

cells and the release of pre-formed granules containing

histamine and tryptase. Other mediators may also be released, including prostaglandins, leukotrienes, chemokines,
etc. These mediators have the ability to induce vasodilatation, 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 are
rapid in onset and can result in multi-system or systemic
manifestations. In general, IgE-mediated reactions are considered 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. Foodspecific IgE testing and placebo-controlled challenges confirm an association with food sensitivity in less than 10 %
of circumstances.

Clinic Rev Allerg Immunol

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- tumor necrosis factor alpha

Respiratory symptoms together with ocular symptoms

can occur in isolation or more commonly with other systemic reactions. Conjunctivitis (lacrimation, periorbital edema, 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, decreased exercise tolerance, wheezing, etc.) can be observed
during positive controlled challenge tests [13]. Vapors or
steam emitted from cooking certain foods may induce asthmatic 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 Bakers 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, malabsorption, weight loss, constipation, and failure to thrive are
usually not symptoms of IgE-mediated but rather of nonIgE-mediated food allergy.
Cardiovascular symptoms are the most severe manifestation of a systemic reaction and may include hypotension,
vascular collapse, arrhythmia, etc. Cardiovascular symptoms 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 departments in the USA [11, 14]. The overall rate of fatalities as a
result of food-induced anaphylaxis is probably much lower
because of the bodys 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-IgEmediated food allergy is poorly understood. Clinical symptoms are subacute or chronic in nature and usually present

Clinic Rev Allerg Immunol

Table 1 The frequency of food allergy among various specific allergic
disorders

Table 2 Examples of major class 1 food allergens

Cows milk

Food allergy prevalence in specific disorders

Disorder

Food allergy prevalence

Anaphylaxis
Oral allergy syndrome
Atopic dermatitis
Urticaria
Asthma
Chronic rhinitis

3555 %
2575 % in pollen allergic patients
35 % in children (rare in adults)
20 % in acute (rare in chronic)
56 % in asthmatic or food allergic children
Rare

with isolated gastrointestinal symptoms. Food proteininduced enterocolitis, proctitis, proctocolitis, celiac disease,
dermatitis herpetiformis, and food-induced pulmonary hemosiderosis 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 gastroenteritis. 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 classification 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 [1921].

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.

Chicken egg
Peanut
Soybean
Shrimp
Fish
Fruits, vegetables

Caseins (a, b, k), -lactoalbumin, -lactoglobulin,

serum albumin
Ovomucoid, ovalbumin, ovotransferrin
Vicillin, conglutin, glycinin
Glycinin, profilin, trypsin inhibitor
Tropomyosin
Parvalbumins
Lipid transfer proteins (LTPs)

Class 2 food allergens are generally cross-reactive with

plant-derived proteins. 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 heatlabile food allergens.
Food allergens may be found in non-food items such as
medications, vaccines, cosmetics, childrens 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 3 Examples of class 2 food allergens
Pathogen-related protein 2 group
(glucanase)
Pathogen-related protein 3 group
(chitinase)
Pathogen-related protein 5
(thaumatin-like)
Birch Bet v1 homologues
(pathogen-related proteins 10)
Birch Bet v2 homologues
(celery-mugwort-spice
syndrome) profilin

Latex, avocado, banana, chestnut,

fig
Latex (Hev b6), avocado
Cherry, apple, kiwi
Apple, cherry, apricot, peach,
pear, carrot, celery, parsley,
hazelnut
Latex, celery, potato, pear, peanut,
soybean

Clinic Rev Allerg Immunol

products prepared on the same equipment. Dishwashing liquid 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 evaluating 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 individual. 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. Postingestion exercise is a pre-requisite trigger for the development 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

Fig. 3 The frequency of cross-reactions within the same food family

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 reaction, although there are few good clinical predictors of a
biphasic reaction. Hence, vigilant observation within an
appropriate setting for 24 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 reactions, 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

Clinic Rev Allerg Immunol

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 develop 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].
Cows Milk Allergy
Cow milk allergy can be regarded as a model of food allergy
as cows 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 cows milk
allergy (CMA) 1.92.8 %. Prevalence figures from Australia were similar [32]. In China, the newly assumed second
largest economy of the world, an increase in cows 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 diverse group of clinical symptoms and syndromes that could
Fig. 4 A schematic diagram
illustrating 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
(Peyers patch) involvement,
which then leads to IgE-, nonIgE-, or mixed type-mediated
food hypersensitivities. There is
a continuous interplay of cellular and humoral molecular
factors and signaling pathways.
Abbreviations: APC antigen
presenting cells, TNF- tumor
necrosis factor alpha, IL-5
interleukin 5

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
cows milk were also manifestations during challenge. Analysis 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 cows milk-specific IgE antibodies, detected either
in vitro by RAST or in vivo by SPT. The second, the intermediate 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 demonstrated that this group had greater levels of T cell sensitization 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 involve IgE- and non-IgE-mediated pathways.

Clinic Rev Allerg Immunol

Since Hill et al.s initial studies, the clinical spectrum of

CMA has been further expanded. First, Carrocio et al. [35]
described a group of children presenting with very delayed
reactions after challenge with cows milk protein. In his
cohort of 86 young children with CMA, 10 patients reacted
4 to 26 days after re-challenge with cows milk. Symptoms
included constipation, persistent wheeze, or atopic dermatitis exacerbations [35]. Whether CMA was a cause of these
symptoms is uncertain, as constipation is not a symptom of
immediate type 1 hypersensitivity reactions. In addition,
Caffarelli and Petrocciou [36] reported on a small group of
children with CMA who had apparent false-negative
immediate food challenges to cows milk; however, on
subsequent exposure on the day following their initial challenge they developed symptoms of immediate anaphylactic
hypersensitivity. A similar phenomenon was observed in a
small group of children in the MMAS [37].
CMA in infancy usually resolves around 12 to 24 months
of age [1]. Host and Halken demonstrated development of
tolerance to cows milk in 56 % of infants with CMA at
1 year, 77 % at 2 years and 87 % at 3 years [38]. However,
CMA may persist to adult life. Kokkonen et al. recently
described a group of school-aged children with CMA in
infancy in whom non-characteristic gastrointestinal symptoms persisted to 10 years of age, suggestive of residual
cows milk-sensitive enteropathy [39]. These patients may
often tolerate small amounts of cows milk protein but often
limit their intake of dairy products. There was evidence of
mucosa T cell activation on small bowel biopsy [40, 41].
One striking finding from the 5-year follow-up of the 100
infants with cows milk allergy in the MMAS was the
observation that up to 70 % of infants had hypersensitivity
to unrelated food proteins. This was particularly common in
infants with slowly evolving, late-onset reactions to cows
milk who were also suffering from colic, reflux esophagitis,
and eczema. In these infants, intolerance to cows milk
protein, soy protein, and extensively hydrolysed protein as
well as other common or less common foods was frequently
seen, i.e., they had multiple food allergies (MFA).
A couple of factors seem to affect the rate of resolution of
food allergies. In the Danish cohort of over 1,700 children
recruited from birth and followed up until age of 3, it was
found that non-IgE-mediated allergy appeared to be transient condition, which children outgrew faster than IgEmediated allergy. Almost all non-IgE resolved by age of
one while one in five of children with IgE-mediated CMA
persisted beyond age of three [38]. Development of allergy
to other foods, and progression of the atopic march towards
respiratory allergy later in childhood also unfavorably affected the rate of resolution [30]. The rate of decline of level
of IgE also seems to be able to predict the likelihood of
development of tolerance. Patients who develop tolerance
were more likely to have a faster rate in decline of IgE level

on sequential testing [31]. The mechanisms leading to

persistent non-IgE CMA hypersensitivity are poorly understood. Jrvein et al. [42] have hypothesized that sensitization to specific epitopes of several cows milk proteins
may be associated with long-term persistence of CMA
[42, 43].
Egg Allergy
Egg allergy occurs in 1 to 2 % of children in the first few
years of life. In developed nations, it is one of the commonest of food allergies found in children. Most egg allergies are
IgE mediated [44]. Up to two thirds of the egg allergic
children become clinically tolerant by the age of 5 years.
The rate of decline in the IgE level predicts the likelihood of
development of tolerance, and is used as prognostic marker
and to define the timing of a food challenge and reintroduction of egg [45]. Recent evidence has shown that
egg, as well as milk, allergic children develop tolerance
earlier if they are exposed to baked egg products [4648].
While the consumption of baked egg product may have
favorable effects on the development of tolerance, patients
should not expose their egg allergic children to baked egg
products without first consulting their allergist or physician.
Egg allergy has been linked to several to 10-folds increase in
likelihood of developing future asthma compared with the
background population risk [49].
Peanut and Tree Nut Allergy
Peanut allergy children may have a 3040 % chance of
having tree nut allergy which can be due to either crossreactivity or co-morbidity. Nut allergy is the leading cause
of fatal and near fatal anaphylaxis in North America and
UK. Peanut and tree nut allergy were originally believed to
be permanent, but recent studies have found that 20 to 25 %
of children can outgrow their nut allergy [50, 51]. Peanutand tree nut-specific IgE levels also appear to be able to
predict the rate of resolution of peanut and tree nut allergy
[5055], similar to the experience with cows milk and egg
allergy. Children who outgrow peanut allergy were more
likely to outgrow tree nut allergy, though development of
tolerance to peanut did not predict the development tolerance to tree nut in all children. The severity of initial
reaction, history of having outgrown other foods and the
presence of other atopic diseases did not predict the resolution or if and when tolerance was achieved. Children
who outgrow peanut allergy can re-acquire their peanut
allergy. This occurs more commonly in those who continuously avoid peanut in their diet following a successful
challenge [54]. For this reason, we recommend that children continue to ingest peanut once a week following a
successful food challenge.

Clinic Rev Allerg Immunol

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, placebocontrolled 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.

negative IgE testing should alert the clinician to the possibility 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 seafood. Ciguatera, caused by Gambierdiscus toxicus toxins
including ciguatoxin, maitotoxin, scaritoxin, and palytoxin,
can cause gastrointestinal symptoms such as vomiting, nausea, and diarrhea, as well as neurological symptoms including dyspareunia and allodynia. Scombroid fish poisoning
can also mimic type 1 hypersensitivity reactions because of
the production of histamine from histidine occurring naturally in spoiled fish.

Seafood Allergy
Oral Allergy Syndrome
Seafood allergy includes both fish and shellfish allergy.
Seafood allergy often develops in young children but is
increasingly 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 generalized reactions or isolated gastrointestinal or extragastrointestinal 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 geographic region, which affects the pattern of consumption
and exposure. Parvalbumin in fish and tropomyosin in
shellfish are the key seafood allergens. They are different
proteins so there is not a great deal of clinical crossreactivity between fish and seafood, although food contamination 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 diminishes 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 experience 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

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 ingestion 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 history 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 extensively for coloring, sweetening, as preservatives or thickeners or
antioxidants, etc. Industrialized countries in general have
tight regulations on the quantity limit of individual known

Clinic Rev Allerg Immunol

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 research 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 anecdotal or reflect poorly designed studies [66]. For example,
Chinese restaurant syndrome refers to a symptom complex 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.
Nonetheless, a recent randomized double-blind controlled 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 illustrates that a certain skeptism or vigilance is necessary when
presented with studies that introduce data before a confirmatory 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 hypersensitivity to dietary antigens in the induction and maintenance
of this chronic inflammatory response is controversial [68].
An expert panel of American paediatric dermatologists recently concluded that food allergy affects only a minority
of atopic dermatitis patients [69]. Hanifin [70, 71] estimated 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 [7274].
The latest findings suggest that allergen-specific IgE antibodies bound to Langerhans cells play a unique role as nontraditional receptors. Double-blind, placebo-controlled food

challenges generally provoke a markedly pruritic, erythematous, 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 (cows milk, egg, and
peanut) and AE was investigated [77]. IgF FA was compared between MACS children with AE (MACS AE+) and
without AE (MACS AE) in a group of consecutively
referred infants of similar age with severe AE. The calculated 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 eczema 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. Management of infantile atopic eczema at both the individual
and community level should incorporate appropriate diagnostic 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 esophagitis (AEE) can occur in children [7981] and adults. A
yearly incidence was estimated to be 23/100,000 population
in Switzerland. In children, symptoms similar to gastroesophageal reflux [80], and in adults, dysphagia and impaction, 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 infiltration 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 hyperplasia, 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].

Clinic Rev Allerg Immunol

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 proteinlosing enteropathy [86]. Vomiting and post-prandial diarrhea are also common symptoms. Chronic occult blood loss
in the gastrointestinal tract may cause iron deficiency anemia. 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 sometimes 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-IgEmediated food hypersensitivity disorder. It occurs in infants
prior to 812 months of age, but may be delayed in breastfed babies. Cows milk- or soy protein-based formulas are
implicated [17, 90]. Symptoms may include irritability, protracted vomiting 13 h after feeding, bloody diarrhea, dehydration, anemia, abdominal distension, and failure to
Table 4 A clinical comparison
of different presentations of
FPIES

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 protracted 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 respond well to an exclusion diet and quickly relapse upon
re-introduction or re-challenge. A significant proportion
resolves by 23 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, cows 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 prognosis with the majority having resolution by 12 months
of life [60, 91].
Celiac Disease
This is the classical form of a cellular immune based mechanism. In celiac disease, the immune response is against

Non-IgE mediated: FPIES (non-IgE mediated) protein-induced syndromes

Age of onset
Times from onset to remission
Clinical features

Enterocolitis

Enteropathy

Proctocolitis

Infant
1224 months
Failure to thrive
Shock
Lethargy

Infant/toddler
? 1224 months
Malabsorption syndrome
Villous atrophy on biopsy
Chronic diarrhea

Newborn
<12 months
Bloody stools
Usually well baby
Eosinophil in
peripheral blood

Chronic diarrhea

Clinic Rev Allerg Immunol

Special Considerations in 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 lowallergen foods including rice, several vegetables, fruits,
chicken, and lamb were reported. On average, adverse reactions 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 identified 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 cows milk allergy demonstrated efficacy of AAF when compared to EHF in children, with
MFA manifesting as severe atopic eczema, reflux oesphagitis, and any of the food-induced gastro-entero-colitisproctitis syndromes with failure to thrive [101].

Multiple Food Allergy of Infancy

Infantile Colic

In the Melbourne Food Allergy Study, 60 infants allergic to

cows 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 Intolerance of Infancy (MPPI) [96, 97]. It was later renamed
Multiple Food Allergy (MFA) to be consistent with international nomenclature. These infants need to be distinguished 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 hydrolyzed 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 exclusively breast-fed. The remission of symptoms occurred
within 2 weeks of commencing an amino acid-based formula (AAF). DBPCFC showed 12 infants were intolerant to
EHCF (n 04), EHWF (n02) or soy (n06). Two infants

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 prospectively 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

gliadin peptides (wheat, rye, and barley) resulting in extensive enteropathy leading to malabsorption syndrome
[92]. Host factor plays an important role. Celiac disease
is highly associated with HLA-DQ2 (1*0501, 1*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 families [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 glutencontaining foods.
Non-IgE-Mediated Syndromes Affecting the Skin and Lung
Dermatitis herpetiformis is a form of dermatitis characterized by a vesicular, pruritic eruption which occurs in glutensensitive subjects and tends to be associated with celiac
disease. Heiners syndrome is a rare form of infantile pulmonary hemosideroisis resulted in anemia and failure to
thrive. It is widely believed to be cows milk associated
and infants may develop precipitating antibodies to cows
milk protein.

Clinic Rev Allerg Immunol

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, failure to thrive, or respiratory symptoms. GER has traditionally been considered a primary motility disorder but several
studies suggest a causal relationship between CMA and
GER in infancy [105108]. In a study of 204 infants with
GER and esophagitis, more than 40 % of patients had
evidence of cows milk allergy and improved symptomatically on changing to extensively hydrolyzed formula.[106]
Electrophysiological studies in infants with CMA have
demonstrated a gastric motility disturbance following ingestion of cows 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 presentations and allergen testing profiles. Food allergies can be
simplistically categorized into three main types: IgE- mediated, 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-IgEmediated allergy [109112].
History and clinical examination are of paramount importance in clinical practice to differentiate the different
forms of food allergy. Despite the improvement in diagnostic 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 tolerance, 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 delayedonset, 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 spectrum of food allergy in infancy and may affect up to 15
20 % of infants. The increasing prevalence and the broadening 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 parents
about the spectrum of food allergic disorders in infants and
children will facilitate early diagnosis and appropriate management and may provide significant cost savings to the
health care budget.

References
1. Bock SA (1987) Prospective appraisal of complaints of adverse
reactions to foods in children during the first 3 years of life.
Pediatrics 79:683688
2. Jansen JJ, Kardinaal AF, Huijbers G, Vlieg-Boerstra BJ,
Martens BP, Ockhuizen T (1994) Prevalence of food allergy
and intolerance in the adult Dutch population. J Allergy Clin
Immunol 93:446456
3. Kay AB (2001) Allergy and allergic diseases. First of two parts.
N Engl J Med 344:3037
4. Hill DJ, Hosking CS, Heine RG (1999) Clinical spectrum of food
allergy in children in Australia and South-East Asia: identification and targets for treatment. Ann Med 31:272281
5. Shek LP, Lee BW (1999) Food allergy in childrenthe Singapore story. Asian Pac J Allergy Immunol 17:203206
6. Sicherer SH, Munoz-Furlong A, Sampson HA (2003) Prevalence
of peanut and tree nut allergy in the United States determined by
means of a random digit dial telephone survey: a 5-year follow-up
study. J Allergy Clin Immunol 112:12031207
7. Sicherer SH, Munoz-Furlong A, Burks AW, Sampson HA (1999)
Prevalence of peanut and tree nut allergy in the US determined by
a random digit dial telephone survey. J Allergy Clin Immunol
103:559562
8. Grundy J, Matthews S, Bateman B, Dean T, Arshad SH (2002)
Rising prevalence of allergy to peanut in children: data from 2
sequential cohorts. J Allergy Clin Immunol 110:784789
9. Tariq SM, Stevens M, Matthews S, Ridout S, Twiselton R, Hide
DW (1996) Cohort study of peanut and tree nut sensitisation by
age of 4 years. BMJ 313:514517
10. Ben-Shoshan M, Kagan RS, Alizadehfar R, Joseph L, Turnbull E,
St Pierre Y et al (2009) Is the prevalence of peanut allergy
increasing? A 5-year follow-up study in children in Montreal. J
Allergy Clin Immunol 123:783788
11. Yocum MW, Butterfield JH, Klein JS, Volcheck GW, Schroeder
DR, Silverstein MD (1999) Epidemiology of anaphylaxis in
Olmsted county: a population-based study. J Allergy Clin Immunol 104:452456
12. Champion RH, Roberts SO, Carpenter RG, Roger JH (1969)
Urticaria and angio-oedema. A review of 554 patients. Br J Dermatol 81:588597
13. Bock SA, Atkins FM (1990) Patterns of food hypersensitivity
during sixteen years of double-blind, placebo-controlled food
challenges. J Pediatr 117:561567
14. Sampson HA, Mendelson L, Rosen JP (1992) Fatal and near-fatal
anaphylactic reactions to food in children and adolescents. N
Engl J Med 327:380384

Clinic Rev Allerg Immunol

15. Henderson CJ, Abonia JP, King EC, Putnam PE, Collins MH,
Franciosi JP et al (2012) Comparative dietary therapy effectiveness in remission of pediatric eosinophilic esophagitis. J Allergy
Clin Immunol 129:15701578
16. Kagalwalla AF, Amsden K, Shah A, Ritz S, Manuel-Rubio M,
Dunne K et al (2012) Cows milk elimination: a novel dietary
approach to treat eosinophilic esophagitis. J Pediatr Gastroenterol
Nutr (in press)
17. Sampson HA, Anderson JA (2000) Summary and recommendations: classification of gastrointestinal manifestations due to immunologic reactions to foods in infants and young children. J
Pediatr Gastroenterol Nutr 30(Suppl):S87S94
18. Sampson HA, Sicherer SH, Birnbaum AH (2001) AGA technical
review on the evaluation of food allergy in gastrointestinal disorders. Gastroenterology 120:10261040
19. Buie T, Campbell DB, Fuchs GJ 3rd, Furuta GT, Levy J, Vandewater
J et al (2010) Evaluation, diagnosis, and treatment of gastrointestinal
disorders in individuals with ASDs: a consensus report. Pediatrics
125(Suppl 1):S1S18
20. Charleston L, Holland S, Silberstein SD, Freitag F, Dodick DW,
Argoff C (2012) Evidence-based guideline update: NSAIDs and
other complementary treatments for episodic migraine prevention
in adults: report of the quality standards subcommittee of the
American Academy of Neurology and the American Headache
Society. Neurology 79:13011302
21. Liden M, Kristjansson G, Valtysdottir S, Venge P, Hallgren R
(2010) Self-reported food intolerance and mucosal reactivity after
rectal food protein challenge in patients with rheumatoid arthritis.
Scand J Rheumatol 39:292298
22. Burks W (2004) Food allergens. J Allergy Clin Immunol 18:319337
23. Maloney JM, Chapman MD, Sicherer SH (2006) Peanut allergen
exposure through saliva: assessment and interventions to reduce
exposure. J Allergy Clin Immunol 118:719724
24. Perry TT, Conover-Walker MK, Pomes A, Chapman MD, Wood
RA (2004) Distribution of peanut allergen in the environment. J
Allergy Clin Immunol 113:973976
25. Vadas P, Gold M, Perelman B, Liss GM, Lack G, Blyth T et al
(2008) Platelet-activating factor, PAF acetylhydrolase, and severe
anaphylaxis. N Engl J Med 358:2835
26. Ho MH, Hill DJ (2006) White button mushroom food hypersensitivity in a child. J Paediatr Child Health 42:555556
27. Pastorello EA, Pravettoni V, Calamari AM, Banfi E, Robino AM
(2002) New plant-origin food allergens. Allergy 57(Suppl 72):106
110
28. Hill DJ, Firer MA, Shelton MJ, Hosking CS (1986) Manifestations of milk allergy in infancy: clinical and immunologic findings. J Pediatr 109:270276
29. Jakobsson I, Lindberg T (1979) A prospective study of cows
milk protein intolerance in Swedish infants. Acta Paediatr Scand
68:853859
30. Host A (2002) Frequency of cows milk allergy in childhood.
Ann Allergy Asthma Immunol 89:3337
31. Schrander JJ, van den Bogart JP, Forget PP, Schrander-Stumpel
CT, Kuijten RH, Kester AD (1993) Cows milk protein intolerance in infants under 1 year of age: a prospective epidemiological
study. Eur J Pediatr 152:640644
32. Hill DJ, Hosking CS, Zhie CY, Leung R, Baratwidjaja K, Iikura
Y et al (1997) The frequency of food allergy in Australia and
Asia. Environ Toxicol Pharmacol 4:101110
33. Chen J, Hu Y, Allen KJ, Ho MH, Li H (2011) The prevalence of
food allergy in infants in Chongqing, China. Pediatr Allergy
Immunol 22:356360
34. Abernathy-Carver KJ, Sampson HA, Picker LJ, Leung DY
(1995) Milk-induced eczema is associated with the expansion
of T cells expressing cutaneous lymphocyte antigen. J Clin Invest
95:913918

35. Carroccio A, Montalto G, Custro N, Notarbartolo A, Cavataio F,

DAmico D et al (2000) Evidence of very delayed clinical reactions to cows milk in cows milk-intolerant patients. Allergy
55:574579
36. Caffarelli C, Petroccione T (2001) False-negative food challenges
in children with suspected food allergy. Lancet 358:18711872
37. Firer MA, Hoskings CS, Hill DJ (1987) Humoral immune response to cows milk in children with cows milk allergy. Relationship to the time of clinical response to cows milk challenge.
Int Arch Allergy Immunol 84:173177
38. Host A, Halken S (1990) A prospective study of cow milk allergy
in Danish infants during the first 3 years of life. Clinical course in
relation to clinical and immunological type of hypersensitivity
reaction. Allergy 45:587596
39. Kokkonen J, Tikkanen S, Savilahti E (2001) Residual intestinal
disease after milk allergy in infancy. J Pediatr Gastroenterol Nutr
32:156161
40. Caffarelli C, Romanini E, Caruana P, Street ME, de Angelis G
(1998) Clinical food hypersensitivity: the relevance of duodenal
immunoglobulin E-positive cells. Pediatr Res 44:485490
41. Chung HL, Hwang JB, Kwon YD, Park MH, Shin WJ, Park JB
(1999) Deposition of eosinophil-granule major basic protein and
expression of intercellular adhesion molecule-1 and vascular cell
adhesion molecule-1 in the mucosa of the small intestine in
infants with cows milk-sensitive enteropathy. J Allergy Clin
Immunol 103:11951201
42. Jarvinen KM, Chatchatee P, Bardina L, Beyer K, Sampson HA
(2001) IgE and IgG binding epitopes on alpha-lactalbumin and
beta-lactoglobulin in cows milk allergy. Int Arch Allergy Immunol 126:111118
43. Vila L, Beyer K, Jarvinen KM, Chatchatee P, Bardina L, Sampson
HA (2001) Role of conformational and linear epitopes in the
achievement of tolerance in cows milk allergy. Clin Exp Allergy
31:15991606
44. Eggesbo M, Botten G, Halvorsen R, Magnus P (2001) The
prevalence of allergy to egg: a population-based study in young
children. Allergy 56:403411
45. Shek LP, Soderstrom L, Ahlstedt S, Beyer K, Sampson HA
(2004) Determination of food specific IgE levels over time can
predict the development of tolerance in cows milk and hens egg
allergy. J Allergy Clin Immunol 114:387391
46. Koplin JJ, Osborne NJ, Wake M, Martin PE, Gurrin LC,
Robinson MN et al (2010) Can early introduction of egg prevent
egg allergy in infants? A population-based study. J Allergy Clin
Immunol 126:807813
47. Clark A, Islam S, King Y, Deighton J, Szun S, Anagnostou K et al
(2011) A longitudinal study of resolution of allergy to wellcooked and uncooked egg. Clin Exp Allergy 41:706712
48. Lieberman JA, Huang FR, Sampson HA, Nowak-Wegrzyn A
(2012) Outcomes of 100 consecutive open, baked-egg oral food
challenges in the allergy office. J Allergy Clin Immunol
129:16821684
49. Rhodes HL, Sporik R, Thomas P, Holgate ST, Cogswell JJ (2001)
Early life risk factors for adult asthma: a birth cohort study of
subjects at risk. J Allergy Clin Immunol 108:720725
50. Skolnick HS, Conover-Walker MK, Koerner CB, Sampson HA,
Burks W, Wood RA (2001) The natural history of peanut allergy.
J Allergy Clin Immunol 107:367374
51. Ho MH, Wong WH, Heine RG, Hosking CS, Hill DJ, Allen KJ
(2008) Early clinical predictors of remission of peanut allergy in
children. J Allergy Clin Immunol 121:731736
52. Hourihane JO, Roberts SA, Warner JO (1998) Resolution of
peanut allergy: casecontrol study. BMJ 316:12711275
53. Fleischer DM, Conover-Walker MK, Matsui EC, Wood RA
(2005) The natural history of tree nut allergy. J Allergy Clin
Immunol 116:10871093

Clinic Rev Allerg Immunol

54. Fleischer DM, Conover-Walker MK, Christie L, Burks AW,
Wood RA (2004) Peanut allergy: recurrence and its management.
J Allergy Clin Immunol 114:11951201
55. Ho MH, Heine RG, Wong W, Hill DJ (2006) Diagnostic accuracy
of skin prick testing in children with tree nut allergy. J Allergy
Clin Immunol 117:15061508
56. Maleki SJ, Hurlburt BK (2004) Structural and functional alterations in major peanut allergens caused by thermal processing. J
AOAC Int 87:14751479
57. Eller E, Hansen TK, Bindslev-Jensen C (2012) Clinical thresholds to egg, hazelnut, milk and peanut: results from a singlecenter study using standardized challenges. Ann Allergy Asthma
Immunol 108:332336
58. Taylor SL, Hefle SL, Bindslev-Jensen C, Atkins FM, Andre C,
Bruijnzeel-Koomen C et al (2004) A consensus protocol for the
determination of the threshold doses for allergenic foods: how
much is too much? Clin Exp Allergy 34:689695
59. Sicherer SH, Munoz-Furlong A, Sampson HA (2004) Prevalence
of seafood allergy in the United States determined by a random
telephone survey. J Allergy Clin Immunol 114:159165
60. Zapatero Remon L, Alonso Lebrero E, Martin Fernandez E,
Martinez Molero MI (2005) Food-protein-induced enterocolitis
syndrome caused by fish. Allergol Immunopathol (Madr)
33:312316
61. Jeebhay MF, Robins TG, Lehrer SB, Lopata AL (2001) Occupational seafood allergy: a review. Occup Environ Med 58:553562
62. Daschner A, Pascual CY (2005) Anisakis simplex: sensitization
and clinical allergy. Curr Opin Allergy Clin Immunol 5:281285
63. Kazemi-Shirazi L, Pauli G, Purohit A, Spitzauer S, Froschl R,
Hoffmann-Sommergruber K et al (2000) Quantitative IgE inhibition experiments with purified recombinant allergens indicate
pollen-derived allergens as the sensitizing agents responsible for
many forms of plant food allergy. J Allergy Clin Immunol
105:116125
64. Ortolani C, Pastorello EA, Farioli L, Ispano M, Pravettoni V,
Berti C et al (1993) IgE-mediated allergy from vegetable allergens. Ann Allergy 71:470476
65. Kleine-Tebbe J, Herold DA (2003) Cross-reactive allergen clusters in pollen-associated food allergy. Hautarzt 54:130137
66. Smith JM (1991) Adverse reactions to food and drug additives.
Eur J Clin Nutr 45(Suppl 1):1721
67. McCann D, Barrett A, Cooper A, Crumpler D, Dalen L,
Grimshaw K et al (2007) Food additives and hyperactive
behaviour in 3-year-old and 8/9-year-old children in the community: a randomised, double-blinded, placebo-controlled trial. Lancet
370:15601567
68. Leung DY, Bieber T (2003) Atopic dermatitis. Lancet 361:151
160
69. Halbert AR, Weston WL, Morelli JG (1995) Atopic dermatitis: is
it an allergic disease? J Am Acad Dermatol 33:10081018
70. Hanifin JM (1991) Atopic dermatitis in infants and children.
Pediatr Clin North Am 38:763789
71. Hanifin JM (1997) Critical evaluation of food and mite allergy in
the management of atopic dermatitis. J Dermatol 24:495503
72. Sicherer SH, Sampson HA (1999) Food hypersensitivity and
atopic dermatitis: pathophysiology, epidemiology, diagnosis,
and management. J Allergy Clin Immunol 104:S114S122
73. Sampson HA, McCaskill CC (1985) Food hypersensitivity and
atopic dermatitis: evaluation of 113 patients. J Pediatr 107:669
675
74. Ellman LK, Chatchatee P, Sicherer SH, Sampson HA (2002)
Food hypersensitivity in two groups of children and young adults
with atopic dermatitis evaluated a decade apart. Pediatr Allergy
Immunol 13:295298
75. Burks AW, Sampson HA (1992) Diagnostic approaches to the
patient with suspected food allergies. J Pediatr 121:S64S71

76. Sampson HA (1997) Food sensitivity and the pathogenesis of

atopic dermatitis. J R Soc Med 90(Suppl 30):28
77. Hill DJ, Hosking CS (2004) Food allergy and atopic dermatitis in
infancy: an epidemiologic study. Pediatr Allergy Immunol
15:421427
78. Hill DJ, Sporik R, Thorburn J, Hosking CS (2000) The association of atopic dermatitis in infancy with immunoglobulin E food
sensitization. J Pediatr 137:475479
79. Heine RG, Cameron DJ, Chow CW, Hill DJ, Catto-Smith AG
(2002) Esophagitis in distressed infants: poor diagnostic agreement between esophageal pH monitoring and histopathologic
findings. J Pediatr 140:1419
80. Kelly KJ, Lazenby AJ, Rowe PC, Yardley JH, Perman JA, Sampson
HA (1995) Eosinophilic esophagitis attributed to gastroesophageal
reflux: improvement with an amino acid-based formula. Gastroenterology 109:15031512
81. Liacouras CA, Wenner WJ, Brown K, Ruchelli E (1998) Primary
eosinophilic esophagitis in children: successful treatment with
oral corticosteroids. J Pediatr Gastroenterol Nutr 26:380385
82. Butt AM, Murch SH, Ng CL, Kitching P, Montgomery SM,
Phillips AD et al (2002) Upregulated eotaxin expression and T
cell infiltration in the basal and papillary epithelium in cows
milk associated reflux oesophagitis. Arch Dis Child 87:124130
83. Straumann A, Bauer M, Fischer B, Blaser K, Simon HU (2001)
Idiopathic eosinophilic esophagitis is associated with a T(H)2type allergic inflammatory response. J Allergy Clin Immunol
108:954961
84. Blanchard C, Wang N, Rothenberg ME (2006) Eosinophilic
esophagitis: pathogenesis, genetics, and therapy. J Allergy Clin
Immunol 118:10541059
85. Bullock JZ, Villanueva JM, Blanchard C, Filipovich AH, Putnam
PE, Collins MH et al (2007) Interplay of adaptive th2 immunity
with eotaxin-3/c-C chemokine receptor 3 in eosinophilic esophagitis. J Pediatr Gastroenterol Nutr 45:2231
86. Chehade M, Magid MS, Mofidi S, Nowak-Wegrzyn A, Sampson
HA, Sicherer SH (2006) Allergic eosinophilic gastroenteritis with
protein-losing enteropathy: intestinal pathology, clinical course,
and long-term follow-up. J Pediatr Gastroenterol Nutr 42:516
521
87. Spergel JM, Beausoleil JL, Mascarenhas M, Liacouras CA (2002)
The use of skin prick tests and patch tests to identify causative
foods in eosinophilic esophagitis. J Allergy Clin Immunol
109:363368
88. Schaefer ET, Fitzgerald JF, Molleston JP, Croffie JM, Pfefferkorn
MD, Corkins MR et al (2008) Comparison of oral prednisone and
topical fluticasone in the treatment of eosinophilic esophagitis: a
randomized trial in children. Clin Gastroenterol Hepatol 6:165
173
89. Stein ML, Collins MH, Villanueva JM, Kushner JP, Putnam PE,
Buckmeier BK et al (2006) Anti-IL-5 (mepolizumab) therapy for
eosinophilic esophagitis. J Allergy Clin Immunol 118:13121319
90. Sampson HA (2004) Update on food allergy. J Allergy Clin
Immunol 113:805819, quiz 20
91. Nowak-Wegrzyn A, Sampson HA, Wood RA, Sicherer SH
(2003) Food protein-induced enterocolitis syndrome caused by
solid food proteins. Pediatrics 111:829835
92. Selmi C (2012) Cutting-edge issues in autoimmunity and allergy
of the digestive system. Clin Rev Allergy Immunol 42:265268
93. Sollid LM, Markussen G, Ek J, Gjerde H, Vartdal F, Thorsby E
(1989) Evidence for a primary association of celiac disease to a
particular HLA-DQ alpha/beta heterodimer. J Exp Med 169:345
350
94. van der Windt DA, Jellema P, Mulder CJ, Kneepkens CM, van
der Horst HE (2010) Diagnostic testing for celiac disease among
patients with abdominal symptoms: a systematic review. JAMA
303:17381746

Clinic Rev Allerg Immunol

95. Rozenberg O, Lerner A, Pacht A, Grinberg M, Reginashvili D,
Henig C et al (2012) A novel algorithm for the diagnosis of celiac
disease and a comprehensive review of celiac disease diagnostics.
Clin Rev Allergy Immunol 42:331341
96. Hill DJ, Cameron DJ, Francis DE, Gonzalez-Andaya AM,
Hosking CS (1995) Challenge confirmation of late-onset
reactions to extensively hydrolyzed formulas in infants with
multiple food protein intolerance. J Allergy Clin Immunol
96:386394
97. Hill DJ, Heine RG, Cameron DJ, Francis DE, Bines JE (1999)
The natural history of intolerance to soy and extensively hydrolyzed formula in infants with multiple food protein intolerance. J
Pediatr 135:118121
98. Vanderhoof JA, Murray ND, Kaufman SS, Mack DR, Antonson
DL, Corkins MR et al (1997) Intolerance to protein hydrolysate
infant formulas: an underrecognized cause of gastrointestinal
symptoms in infants. J Pediatr 131:741744
99. de Boissieu D, Matarazzo P, Dupont C (1997) Allergy to extensively hydrolyzed cow milk proteins in infants: identification and
treatment with an amino acid-based formula. J Pediatr 131:744
747
100. Latcham F, Merino F, Lang A, Garvey J, Thomson MA,
Walker-Smith JA et al (2003) A consistent pattern of minor immunodeficiency and subtle enteropathy in children with multiple food
allergy. J Pediatr 143:3947
101. Hill DJ, Murch SH, Rafferty K, Wallis P, Green CJ (2007) The
efficacy of amino acid-based formulas in relieving the symptoms
of cows milk allergy: a systematic review. Clin Exp Allergy
37:808822
102. Hill DJ, Hudson IL, Sheffield LJ, Shelton MJ, Menahem S,
Hosking CS (1995) A low allergen diet is a significant intervention in infantile colic: results of a community-based study. J
Allergy Clin Immunol 96:886892

103. Hill DJ, Menahem S, Hudson I, Sheffield L, Shelton M, Oberklaid F

et al (1992) Charting infant distress: an aid to defining colic. J
Pediatr 121:755758
104. Hill DJ, Hosking CS (2000) Infantile colic and food hypersensitivity. J Pediatr Gastroenterol Nutr 30(Suppl):S67S76
105. Salvatore S, Vandenplas Y (2002) Gastroesophageal reflux and
cow milk allergy: is there a link? Pediatrics 110:972984
106. Iacono G, Carroccio A, Cavataio F, Montalto G, Kazmierska I,
Lorello D et al (1996) Gastroesophageal reflux and cows milk
allergy in infants: a prospective study. J Allergy Clin Immunol
97:822827
107. Ravelli AM, Tobanelli P, Volpi S, Ugazio AG (2001) Vomiting
and gastric motility in infants with cows milk allergy. J Pediatr
Gastroenterol Nutr 32:5964
108. Hill DJ, Heine RG, Cameron DJ, Catto-Smith AG, Chow CW,
Francis DE et al (2000) Role of food protein intolerance in infants
with persistent distress attributed to reflux esophagitis. J Pediatr
136:641647
109. Bellanti JA, Zeligs BJ, Malka-Rais J, Sabra A (2003) Abnormalities of Th1 function in non-IgE food allergy, celiac disease, and
ileal lymphonodular hyperplasia: a new relationship? Ann Allergy Asthma Immunol 90:8489
110. Noh J, Noh G (2012) Allergen-specific responses of CD19(high)and CD19(low)B cells in non-IgE Mediated food allergy of late
eczematous reactions in atopic dermatitis: presence of IL-17- and
IL-32-producing regulatory B cells (Br17 & Br32). Inflamm
Allergy Drug Targets 11:320329
111. Wang J, Sampson HA (2009) Food allergy: recent advances in
pathophysiology and treatment. Allergy Asthma Immunol Res
1:1929
112. Lied GA, Lillestol K, Valeur J, Berstad A (2010) Intestinal B cellactivating factor: an indicator of non-IgE-mediated hypersensitivity reactions to food? Aliment Pharmacol Ther 32:6673