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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: [email protected]

C. Chang (*)

Division of Allergy, and Immunology, Thomas Jefferson

University, Nemours Hospital for Children, 1600 Rockland Road,

Wilmington, DE 19803, USA

e-mail: [email protected]

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

Clinic Rev Allerg Immunol (2014) 46:225 – 240 227


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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



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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



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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


12/16

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



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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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