General Pediatrics 8 (Licari) 15.11.

19
Sbob: Araki
Topics covered: Rev: Kaloudi
• IgE-mediated reactions
• Anaphylaxis
• Non-Ig-mediated reactions
• Non immunologic reactions
• Psychological reactions
• Evaluation of food allergy

FOOD ALLERGY

Definition
Food allergy is defined as an adverse health effect arising from a specific immune response that occurs
reproducibly on exposure to a given food. These immune responses may be IgE-mediated, non-IgE-mediated,
or an apparent mixture of multiple mechanisms.
The term food intolerance is used to designate a nonimmune-mediated reaction that may include metabolic,
pharmacologic, or toxic mechanisms. The most important food intolerances are celiac disease and lactose
intolerance. For example, in lactose intolerance there is a metabolic reaction due to lack of the enzyme that
digests lactose. Therefore, food allergy is defined as a reaction with an underlying immune mechanism, which
is different from food intolerance in which there is not an underlying immune mechanism.
Another important term is sensitization, which indicates that individuals may have demonstrable IgE or other
antibodies or antigen-reactive cells in the absence of clinical symptoms.

An immune-mediated food allergy requires both the presence of sensitization and clinical responsiveness when
the food is ingested. In other words, allergy shows both sensitization and clinical symptoms.

Prevalence
Proven food allergy (which relies on oral food challenge test) is found in up to 10% of the general population
and the prevalence is increasing in children. Food allergy is recognized as a global substantial health problem
like asthma and other allergic pathologies.

Food Hypersensitivity (Allergic) Disorders by Predominant Organ Affected

Table 1 shows different disorders (IgE-mediated, predominantly non-IgE-mediated, and non-IgE-mediated
disorders) that can affect different organs in the body:
• Skin: urticaria and angioedema are the most important cutaneous manifestations of food allergy, they
are IgE-mediated and are immediate reactions (several minutes to 4 hours). There are also non-IgE-
mediated diseases with skin manifestations, such as atopic dermatitis, which actually has a mixed
pathogenesis.
• Lungs: IgE-mediated disorders that cause an immediate reaction of the respiratory system include
allergic rhinoconjunctivitis and acute bronchospasm (as may occur with an acute asthma attack). A non-
IgE-mediated disorder that may affect the lungs is called Heiner syndrome1, which is a pulmonary
hemosiderosis caused by cow’s milk allergy.
• Gastrointestinal tract: predominantly non-IgE-mediated disorders affecting the GI tract are the various
eosinophilic GI disorders, such as eosinophilic esophagitis or eosinophilic gastritis. There are also non-
IgE-mediated disorders, such as food protein-induced enterocolitis or proctocolitis syndrome. In case
of an IgE-mediated disorders, there can be an acute gastrointestinal spasm, or an oral allergy

1
Heiner syndrome, also called cow’s milk hypersensitivity, is a food-induced pulmonary hypersensitizing syndrome that
affects primarily infants and that is characterized by pulmonary hemosiderosis, digestive bleeding, anemia and poor
growing, improving with elimination of cow’s milk from the diet. Source: https://www.orpha.net/consor/cgi-
bin/OC_Exp.php?lng=en&Expert=99932

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 syndrome2, the latter is a rather new entity in Allergology, and is a syndrome that includes symptoms
limited to the oral cavity (e.g. pruritus in the oral cavity and the upper pharynx).
• Cardiovascular system: there can be immediate, IgE-mediated reactions involving the cardiovascular
system, which are generally under the umbrella of anaphylaxis, e.g. hypotension, dizziness and/or
fainting, and are always IgE-mediated.
• Others: some IgE-mediated disorders that are not so common in children, but rather in adults, are
uterine cramping and contractions, or food-associated exercise-induced anaphylaxis.

Table 1: food hypersensitivity disorders by the predominant organ affected

Remember the abovementioned classification of different food hypersensitivity disorders according to the
pathological mechanism (the most common of which is an IgE-mediated disorder as a cause of food allergy).

IgE-Mediated Reactions to Food Allergens

Fig. 1 shows the pathological mechanism of an IgE-mediated immune reaction to a food allergy: there is an
ingestion of an allergen that then passes through the intestinal epithelium. With a variety of mechanisms, the
allergens usually encounter their specific, high affinity IgE receptors found on mast cells and other immune
cells. After the cross-linking with the high affinity IgE receptor and its allergen, the mast cells release their
preformed mediators, such as histamine and leukotrienes. There is also the production of other mediators,
usually leukotrienes, from arachidonic acid. These mediators act on the vascular endothelial tissue, causing
vasodilation and increase in the vascular permeability of the vessels, as well as induction of smooth muscle
contraction. When the mediators act on blood vessels, there are systemic reactions that may affect different
body systems, including the cardiovascular system, the skin, the respiratory system, the central and/or
peripheral nervous system, etc.
The most common symptoms are gastrointestinal symptoms: abdominal pain (a subjective initial symptom),
vomiting and diarrhea.

2
Oral allergy syndrome, also known as pollen-food allergy syndrome, is caused by cross-reacting allergens found in both
pollen and raw fruits, vegetables, or some tree nuts. The immune system recognizes the pollen and similar proteins in
the food and directs an allergic response to it. People affected by oral allergy syndrome can usually eat the same fruits
or vegetables in cooked form because the proteins are distorted during the heating process, and the immune system no
longer recognizes the food. Source: https://acaai.org/allergies/types/food-allergies/types-food-allergy/oral-allergy-
syndrome
2
 Figure 1: pathophysiology of an IgE-mediated reaction to a food allergen

IgE-Mediated Symptoms
Cutaneous Symptoms
• Urticaria: urticaria typically begins right after the ingestion of a known or an unknown food allergen. It
is usually diagnosed early. The parents usually tell that the child ate peanuts, for example, and then
suddenly developed urticaria. Therefore, the clinical history is very helpful, and by knowing it the doctor
can determine the cause of the allergy.
There could be a chronic urticaria, though it is not so simple to induce it from a food allergy. Usually,
children with a chronic urticaria have another reason for the chronic urticaria. For example, there could
by an underlying viral infection, or it could be the manifestation of an autoimmune disease in
adolescents, such as a particular autoimmune thyroiditis, or other hematological conditions that may
present as a chronic urticaria among other symptoms, or due to a parasitosis.
• Atopic dermatitis: food allergy may trigger up to 30-40% of cases of an eczematous rash. There might
be a moderate to severe atopic dermatitis when there is an underlying food allergy. Usually atopic
dermatitis improves when one starts with the elimination diet of the culprit food. The improvement of
atopic dermatitis is usually immediate after the elimination of the food allergen.

Respiratory Symptoms
• Upper: sneezing, nasal pruritus, rhinorrhea and congestion, and periocular pruritus and tearing. These
symptoms are similar to the symptoms of allergic rhinitis.
There might also be an involvement of the epiglottis and glottic area, in particular when there is an
involvement of the upper airways. It may cause a glottic edema.
• Lower: stridor, hoarse voice, cough, dyspnea and wheezing (dyspnea and wheezing are also seen in an
asthma attack).
The involvement of the respiratory tract is not so common but has a negative prognostic value – it is usually not
isolated and is generally associated with other symptoms and is, many times, seen in the context of an
anaphylactic reaction.

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Food allergy in individuals with asthma may predispose them to more severe episodes and may be a risk factor
for more severe and fatal asthma. Asthma is a negative prognostic value and a risk factor, especially when the
asthma is not controlled. When there is a child with both diseases, i.e. asthma and food allergy, it is very
important to be sure that the asthma is under control, because it might be dangerous for the child to have a
food allergy reaction together with an asthma attack.

It is important to remember that when there is food allergy, the most common clinical symptoms involve the
gastrointestinal tract and the skin. When there is an involvement of two systems (skin + GI / skin + respiratory
/ GI + respiratory, etc.), it usually has the picture of anaphylaxis (explained later).

Gastrointestinal Symptoms
• Immediate-onset symptoms: nausea, abdominal pain and cramps3, vomiting4 and diarrhea.
Rapid resolution of gastrointestinal symptoms and return of appetite are frequently noted after a
gastrointestinal food reaction. Diarrhea may occur immediately or be delayed for a few hours5.
• Pollen-food allergy syndrome: it is usually a localized reaction characterized by itching of the throat,
and occasionally mild oral edema that occur immediately upon the ingestion of certain foods, most
commonly raw fruits and vegetables. These symptoms are due to specific IgE antibodies directed to
aeroallergens that cross-react with certain food proteins (i.e. hazelnut (Cor a 9 and 14) and peanut (Ara
h 8) with the birch pollen cross-reactive protein, Bet v 1). This kind of reaction is usually not systemic
and improves without therapy6.
• Chronic Constipation
• Eosinophilic Esophagitis: many children with eosinophilic esophagitis (EoE) have an IgE-mediated food
allergy and atopy, but the underlying immunopathogenic mechanism of EoE is not IgE-mediated and
routine allergy tests are generally not helpful in identifying foods provoking symptoms. The diagnosis
is usually done with the clinical history, the symptoms, and a biopsy of the affected region.
When EoE is not under control and becomes chronic, the patient usually has strictures of the esophagus
and therapy is needed (endoscopic dilation) for these esophageal strictures.

Cardiovascular Symptoms
• Children: respiratory compromise followed by a drop of blood pressure and shock.
• Adults: sudden onset of cardiovascular symptoms before any other symptoms occur.

Anaphylaxis7
The working definition of anaphylaxis is ‘a serious allergic reaction that is rapid in onset and may cause death.’
Anaphylactic reaction may also occur due to drugs, latex, venom, etc. In children the most common cause of
anaphylaxis is food allergy, in particular milk, eggs, fish, peanuts, hazelnuts, etc.

There are 3 clinical pictures of anaphylactic reaction (fig. 2), i.e. anaphylaxis is highly likely when any one of the
following 3 criteria is fulfilled:

Clinical Picture 1: It is unknown whether the patient is allergic or not. There is sudden onset of an illness
(minutes to several hours), with involvement of the skin, mucosal tissue, or both (e.g. generalized hives, itching
or flushing, swollen lips-tongue-uvula), and at least one of the following:

3
Nausea, abdominal pain and cramps are considered as subjective symptoms in the context of an oral challenge test, i.e.
these symptoms are not considered as objective symptoms of having a food allergy. Therefore, when the oral food
challenge test is performed, it is needed to continue with the administration of the food allergen, even if the child
complains about the abovementioned symptoms, because it is needed to demonstrate the objective symptoms, which
are vomiting and/or diarrhea, and only then it is possible to stop the test.
4
Once the child vomits, he/she improves and returns to normal function quickly. This is because the child has released all,
or most, of the allergen.
5
In case the diarrhea is delayed and occurs after 2-4 hours from the ingestion of the food allergen, it is considered as a
food protein-induced enterocolitis syndrome (explained later).
6
This is not the situation of other several allergic reactions in which it is needed to give therapy with antihistamines.
7 It is very important to know how to recognize anaphylaxis and to treat it accordingly!

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 • Sudden respiratory symptoms and signs: shortness of breath, wheezes, cough, stridor, hypoxemia
• Sudden reduced BP or symptoms of end organ dysfunction: hypotonia, (collapse), incontinence

Clinical Picture 2: Two or more of the following that occur suddenly after exposure to a likely allergen or other
trigger for that patient (minutes to several hours):
• Sudden skin or mucosal symptoms and signs: generalized hives, itch-flush, swollen lips-tongue-uvula
• Sudden respiratory symptoms and signs: shortness of breath, wheezes, cough, stridor, hypoxemia
• Sudden reduced BP or symptoms of end organ dysfunction: hypotonia, (collapse), incontinence
• Sudden gastrointestinal symptoms: crampy abdominal pain, vomiting.

Clinical Picture 3: The patient has a known allergen: reduced blood pressure after exposure to a known allergen
for that patient (minutes to several hours):
• Infants and children: low systolic BP (age-specific) or greater than 30% decrease in systolic BP
• Adults: systolic BP of less than 90 mmHg or greater than 30% decrease from that person’s baseline.
Therefore, a sudden collapse in a patient with a known allergen, even though he/she has no skin or
respiratory or GI symptoms, is considered as an anaphylaxis.

Figure 2: clinical pictures of anaphylaxis

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In any of the abovementioned criteria, the first line therapy is an immediate intramuscular injection of
epinephrine. As said before, the involvement of 2 (or more) organs is the main criteria for the diagnosis of
anaphylaxis and it is very important to know what to do in these cases.

Anaphylaxis: Unique Aspects of Clinical Diagnosis and Management of Infants

Infants (birth to 2 years of age) can present with a cow’s milk allergy. In this case, the mother does not lactate
but uses specific formulas of cow’s milk to feed the baby. If the baby has an allergy it may cause anaphylaxis.
Anaphylaxis in infants is not so common, but it may happen as well. When anaphylaxis does occur in neonates,
usually, objective symptoms such as vomiting, urticaria, or respiratory symptoms, are preceded by behavioral
changes, such as irritability, tachycardia and hypotension (fig. 3).

Figure 3: anaphylaxis in infants and its differential diagnosis

Anaphylaxis in infants may resemble other diseases, and so the differential diagnosis in infants should include
sepsis (because in the early phase of sepsis in infants there is hypoxemia or only tachycardia), food protein-
induced enterocolitis syndrome (FPIES), a metabolic condition that presents with consistent vomiting and
metabolic acidosis8. When there is persistent vomiting, it is important to also think about a congenital pyloric
stenosis, or a GI obstruction, etc. Therefore, the differential diagnosis of anaphylaxis in infants is very wide.

These were the IgE-mediated reactions to food allergens, from mild to severe – mild symptoms such as urticaria,
atopic dermatitis, vomiting, diarrhea, to severe symptoms such as anaphylaxis (when at least 2 organs are
involved). Next, non-IgE-mediated reactions to food are discussed.

Non-IgE Immune-Mediated Reactions to Food

Non-IgE immune-mediated reactions to food include:
• Celiac disease
• Eosinophilic gastrointestinal disorders, such as eosinophilic esophagitis
• Food protein-induced enterocolitis syndrome (FPIES)
• Food protein-induced proctocolitis syndrome

8
Sbob’s note: Although the professor mentioned only vomiting as a symptom, after searching online there is also important
diarrhea (sometimes bloody) in FPIES, which is probably the reason for the metabolic acidosis generally seen in these
patients.
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Eosinophilic Gastrointestinal Disorders
Eosinophilic Esophagitis
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Primary eosinophilic esophagitis (EoE) is an emerging clinicopathologic entity that is characterized clinically by
symptoms related to esophageal dysfunction and histologically by an eosinophil-rich inflammation that is
limited to the esophagus.
In 2007, a multidisciplinary group proposed a consensus definition for the diagnosis of EoE based on the typical
clinical presentation and pathologic findings in the absence of other known causes of tissue eosinophilia.
This group defined primary EoE as a clinicopathological disease characterized by the following:
• Symptoms including, but not restricted to, food impaction and dysphagia in adults and feeding
intolerance and gastroesophageal reflux disease (GERD) symptoms in children
• Presence of 15 or more eosinophils per high power field (hpf) on esophageal biopsy
• Exclusion of other disorders associated with similar clinical, histological, or endoscopic features,
especially GERD (use of high-dose proton pump inhibitor [PPI] treatment or normal pH monitoring)

The disease appears to be increasing in

prevalence, and there might be a
correlation with some foods.
The pathogenetic mechanism underlying
EoE (and probably all the other eosinophilic
GI disorders) can be seen in fig. 410. In EoE
there is an immune reaction, usually with
an underlying genetic predisposition. There
is an allergen that disrupts the epithelial
esophageal barrier. The allergen then
activates the antigen-presenting cells,
causing a shift of the immune response to a
Th2 immune response. Then, a production
of IL-4 and IL-5 occurs which, in turn,
stimulates the eosinophils to infiltrate the
esophagus.
Figure 4: pathophysiology of eosinophilic esophagitis
In the later phases of the immune reaction,
there is a massive infiltration of the wall of
the esophagus and a shift of the epithelial esophageal cells to mesenchymal cells because there is an over-
production of TGF-β, i.e. there is formation of fibrosis in the esophagus. The later stages of the inflammation,
i.e. fibrosis formation, is generally not seen in children, but in adults. These adults will have strictures in their
esophagus, causing dysphagia to both solid and liquid foods. In the case of children, there are usually symptoms
resembling GERD.

Food Protein-Induced Enterocolitis Syndrome (FPIES)

FPIES is a non-IgE-mediated reaction against milk11. In FPIES, there is no detection of IgE against milk and there
is a negative skin prick test for milk. The most common trigger is milk, but other triggers can be soy, rice, and
oats.
The clinical presentation usually includes vomiting, lethargy, diarrhea, and hypotension. The blood tests
generally show acidemia12, leukocytosis, thrombocytosis, and methemoglobinemia.
In the case of the abovementioned symptomatic presentation in infants, it may mimic sepsis – the child is
lethargic, vomits, etc. The clinical picture of FPIES is generally seen in infants that are fed with an infant’s

9
A short explanation about EoE form MedScape.
10
Currently, there is not much knowledge about all these eosinophilic GI disorders, but there is a better knowledge
regarding EoE.
11
FPIES is the contralateral disease on the spectrum of milk reactions – on one side there is an IgE-mediated milk allergy,
and on the other side there is FPIES (not-IgE-mediated).
12
It is also possible to see metabolic alkalosis in these children, but usually, when they arrive to the clinic, they present
with metabolic acidosis.

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formula13. They develop the abovementioned signs and symptoms, and so it is needed to stop feeding them
with the formula, rehydrate them, and use a special formula instead. For infants with milk or soy FPIES, it is
needed to use an extensively-hydrolyzed casein-based formula rather than a soy or milk formula due to
common (up to 50%) concomitant FPIES to these foods. Also, avoid oats/rice as first solids.
Onset of FPIES after the age of 1 year is uncommon, and FPIES typically resolves in the first 1 to 5 years.
Children with detectable milk-specific IgE antibodies have a more protracted course than those without IgE
antibodies; some may convert to immediate IgE-mediated milk allergy.

According to the professor, there are two special kinds of formulas – one is a hydrolyzed formula, and the other
is an amino acid-based formula. The latter is indicated only in case of FPIES and in case of an anaphylactic
reaction to cow’s milk. All the other children with other clinical pictures of cow’s milk allergy can be fed with a
hydrolyzed casein-based formula (usually an extensively-hydrolyzed formula).

Some information about infant formulas14:

The most commonly used infant formulas contain purified cow's milk whey and casein as a protein source, a
blend of vegetable oils as a fat source, lactose as a carbohydrate source, a vitamin-mineral mix, and other
ingredients depending on the manufacturer.
There are infant formulas using soybean as a protein source in place of cow's milk, and formulas using protein
hydrolyzed into its component amino acids for infants who are allergic to other proteins.
Infant formulas come in a variety of types:
• Milk-based formulas: milk-based formulas offer complete nutrition, but babies sometimes develop an
allergy or intolerance to the cow's milk protein in these formulas.
• Soy formulas: soy formulas are no less allergenic than cow's milk-based formulas. 8-14% of infants with
cow's milk allergy will react to soy. Some infants will develop proctocolitis or enterocolitis. If proctocolitis
or enterocolitis occurs, 25-60% will react to soy formulas. For this reason, soy formulas are not
recommended in the treatment of cow's milk allergy.
• Partially-hydrolyzed formulas: partially-hydrolyzed formulas take a cow's milk protein whey and break
it into large pieces. Unfortunately, most babies allergic to cow’s milk will react to these large pieces of
milk protein. So, these formulas are not used for infants allergic to cow's milk.
• Extensively-hydrolyzed formulas: extensively-hydrolyzed formulas are hypoallergenic. They offer
complete nutrition for infants who cannot digest intact cow's milk protein. They also help infants who
are intolerant or allergic to intact cow's milk protein. These formulas break casein into pieces. Casein is
a cow's milk protein. 90% of cow's milk-allergic babies will not recognize the piece of protein as an
allergen. These formulas are also useful in some cases of malabsorption.
• Amino acid-based formulas: amino acid-based formulas offer complete nutrition for infants. These
formulas are for infants who are unable to tolerate extensively-hydrolyzed formulas. Amino acid-based
formulas are also known as “elemental” formulas.

FPIES is diagnosed with an oral food challenge test (as with cow’s milk allergy), i.e. the gold-standard for
diagnosing food allergy, both IgE-mediated and non-IgE-mediated, is the oral food challenge test. The typical
clinical history and the blood tests are very suggestive but are not considered to be sufficient for diagnosing
food allergy, and it is needed to perform the oral food challenge test. In some cases, the test is not performed,
in particular if the patient had an anaphylactic reaction. In fact, anaphylaxis is a contraindication to perform an
oral food challenge test. Other situations in which the test is not done could be when the child is very small or
very young, or the patients are afraid to do the test, or in case there are very high levels of IgE in the blood,
which predicts a positive reaction to the oral food challenge test (explained later).

13
FPIES for oats and rice as solid foods is generally not seen in older children, though it may occur.
14
For more information: https://www.kidswithfoodallergies.org/page/formula-options-infants-food-allergies.aspx
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Non-Immunologic Reactions to Food
Toxic Reactions
• Food poisoning
• Scombroid fish poisoning15, which occurs due to histamine in poorly-prepared histidine-containing fish.
It is usually seen when one eats fish or sushi that contain spoiled fish. There are a lot of children that
have this kind of reaction. These children are not allergic to fish, but they eat a spoiled fish that contains
histamine that causes symptoms to develop, without any immunological reaction. The high amount of
histamine causes the typical symptoms of an IgE-mediated food reaction to occur, however it is not an
IgE-mediated reaction and not even an immunologic reaction.

Non-Toxic Reactions
• Auriculotemporal syndrome (Frey’s syndrome)
• Gustatory rhinitis
• Lactose intolerance (may be confused with milk allergy). In both cases there is diarrhea after the
ingestion of milk but performing the lactose breath test will help to diagnose lactose intolerance.
• Carbohydrate malabsorption caused by fructose in fruit and especially fruit juice

Psychological Reactions to Food

Psychological reactions to food are very rare.
Some parents harbor strongly held beliefs about specific foods that trigger various symptoms in their children,
including behavioral changes. These beliefs are usually imposed on children by their parents and may lead to
food aversions.
Clinicians must be vigilant to ensure these beliefs and dietary restrictions do not lead to malnutrition or
deficiency in specific nutrients. In these cases, it is possible to do a double-blind oral food challenge test with a
placebo.
Occasionally, Münchausen syndrome by proxy must be considered, most often related to behavioral changes
or other subjective symptoms.

Evaluation of Food Allergy

• Clinical history: a detailed history is the most important part of the evaluation and will determine which
specific laboratory tests to order, which food challenges and treatments may be required, and the
education that will be needed regarding the results and avoidance of food triggers.
• Physical examination: the exam is usually normal, unless the reaction is occurring acutely. In most of
the cases, the parents took photos to document the reaction which can also help with the diagnosis.
• Laboratory Studies:
- Skin testing
- In vitro testing
- Food challenges

Skin Testing
Prick Test (fig. 5)
• Food allergens eliciting wheal diameters of at least 3 mm or larger than the negative control are
considered positive test results
• Negative skin tests have a high negative predictive accuracy, thus usually excluding food allergy to
common foods
• Histamine is used as the positive control, whereas saline is used as the negative control

15
Scombroid food poisoning is a foodborne illness that typically results from eating spoiled fish. Symptoms may include
flushed skin, headache, itchiness, blurred vision, abdominal cramps, and diarrhea. Onset of symptoms is typically 10-60
minutes after eating and can last for up to 2 days. It occurs from eating fish high in histamine due to inappropriate storage
or processing. Some fish (e.g. tuna, mackerel, sardine, anchovy) naturally have high levels of histidine, which is converted
to histamine when bacterial growth occurs during improper storage. Subsequent cooking, smoking, or freezing does not
eliminate the histamine. Source: Wikipedia.
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 • The most common food allergens in children are usually tested,
such as milk, soy, rice, peanuts, hazelnuts, peach, etc.
• A strongly positive history incriminating a specific food in the
face of a negative skin test must be evaluated further, e.g.
food-specific serum IgE determination and/or physician-
supervised oral food challenge.

Prick by Prick (fig. 6)

Commercial skin test extracts vary considerably in allergen content. It
is often very useful to use fresh fruits and vegetables for skin testing by
Figure 5: skin prick test
the technique referred to as ‘prick to prick’.

Limitations of skin testing include a number of variables:

• Commercially prepared extracts often lack labile proteins
responsible for IgE-mediated sensitization to most fruits and
vegetables
• Skin testing on skin surfaces that have been treated with topical
steroids may induce smaller wheals than those measured on
untreated skin
• Negative prick skin tests with commercial extracts that do not
confirm convincing histories of food reactions should be repeated
with the fresh food before concluding that IgE is absent Figure 6: skin prick by prick test
• Long-term, high-dose systemic steroid therapy may reduce
allergen wheal size.

In Vitro Testing
There are some predictive values of food-
specific IgE (table 2)16. For example, when there
is a probable reaction to milk, one has to
perform the skin prick by prick test and to
measure the specific IgE. In the case of milk, if
the IgE is 15 or more (as seen in the table), there
is a high probability to have a positive oral food
challenge test. The oral food challenge test is
stressful for the child, for the parents, and even
for the doctors. Therefore, in these situations –
when there is a clear clinical history, a positive
skin test and high levels of IgE – it is possible to
avoid the oral food challenge test and start with Table 2: predictive values of food-specific IgE
the elimination diet because it is highly likely
that the child will have a positive result in the oral food challenge test. The test can be performed later in life,
when the child grows, and then there is a high possibility that there will be an oral tolerance.
In case there is IgE (against milk) of 7 and below, there is the need to perform the oral food challenge test.
However, it is not always done clinically because sometimes the child is very young and the parents are worried
of performing the test, and so it is better to wait for the child to grow and perform the oral food challenge test
only later in life.

In vitro measurements are preferred in a number of situations:

• Patients with extensive dermatographism
• Patients with extensive skin disease (atopic dermatitis or urticaria) → contraindication for skin prick
test

16
There are no standardized food-specific IgE values for all allergens. The decision whether the child is considered allergic
to a specific food or not is decided case-by-case.
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 • Patients who cannot discontinue antihistamine
• Use by non-specialists who do not perform skin testing to evaluate children for potential food allergy.

At present, most allergists use the two tests (skin test and in vitro test) together to decide whether or not to do
challenges, and the probability of the challenge being positive for a particular food.

Food Challenges
The double-blind, placebo-controlled food challenge (DBPCFC) is the gold standard for precise diagnosis of
allergic reactions to foods and has provided a standard by which to evaluate other tests.
All food challenges are designed to confirm or refute patient histories with the double-blind technique being
the most precise, but also the most cumbersome.
Challenges that use both active and placebo foods may generally be given on two separate days or one set
(active or placebo) in the morning and the other set (placebo or active) after lunch.
In the clinical setting, open food challenges are very useful for refuting food allergy histories and may be useful
when the challenge is positive with objective symptoms that recapitulate symptoms that have been reported
in the history. Open challenges are also useful for determining if there are foods that have never been ingested
but for which there is a positive diagnostic test with low likelihood.

In literature, there is no doubt that the DBPCFC is the gold-standard for the diagnosis of food allergies, but in
clinical practice it is very expensive, time-consuming, and not so simple to perform in the hospital setting
because the parents, the child, the nurses, and the doctors should not know what is administered to the child.
Therefore, what is done in most cases is an open challenge – when a known food allergen is given to the child.
In case of a psychological reaction to food, it is performed as a single-blind test, i.e. the food is disguised, e.g.
one muffin contains milk and one muffin does not. However, not all types of foods can be manipulated in this
way, such as an apple.
When there is a severe reaction to milk, for example, the test generally starts with warm milk and not with a
fresh milk. This is because the high temperature usually disrupts the allergen (the protein) and so it is more
likely that the patient will tolerate better the allergen.

Each hospital and each allergy center have their own protocol, there are no established worldwide guidelines
regarding how to do the test. The test
is always needed to be adapted to the
age of the child and to his/her
situation.
The guidelines do say when to
perform the test (fig. 7): in case there
is a history consistent with food
allergy and there is probably an IgE-
mediated reaction, it is needed to
check the serum IgE level and to
perform a skin prick test. Consider
also the pre-test probability of a
specific allergy (according to history
and epidemiology). Positive tests may
be confirmatory of an allergy.
Negative tests with a compelling
history, or positive tests with an
ambiguous history may warrant an
oral food challenge test. In other
words, when there is doubt or a
negative test or the history is not
clear (for example the parents say
that the child ate milk, pasta, fruits,
and chocolate, i.e. different types of
Figure 7: diagnostic algorithm
11
foods, and the child suddenly had urticaria but the tests are negative, one should perform an oral food challenge
test for all those foods).
When the history is not consistent with IgE-mediated allergy but might be consistent with atopic dermatitis or
eosinophilic esophagitis, there is the need to evaluate IgE antibodies, but the evaluation mostly relies on
responses to elimination diet for 2 to 4 weeks and an oral food challenge test17.
When the history is not consistent with IgE-mediated allergy, atopic dermatitis or eosinophilic esophagitis, the
evaluation usually requires elimination diets and oral food challenges. However, history may be compelling for
making a presumptive diagnosis.

Key Points about Food Allergy

• A food allergy is an adverse health effect arising from an immune response that occurs reproducibly on
exposure to a given food, whereas a food intolerance is an adverse effect due to a nonimmunologic
response, e.g. metabolic, pharmacologic or toxic
• Food allergies may be ‘immediate’ (IgE-mediated) or ‘delayed’ (non-IgE-mediated) in onset and induce
a variety of symptoms involving the skin, respiratory or gastrointestinal tracts and/or cardiovascular
system
• A detailed history is the most important part of the evaluation and determines which laboratory tests
should be ordered, which food challenges and treatments may be required, and the education that will
be needed regarding the results
• Prick skin tests and food-specific IgE levels confirm sensitization and provide some evidence on the
probability of clinical allergy, but alone are never adequate to make the diagnosis of food allergy
• The oral food challenge remains the gold standard for diagnosing food allergy.

With the diagnosis of food allergy, it is important to provide a suitable diet for the child because, in some cases,
the elimination diet may be a risk for the nutritional status of the child. For example, in the case of cow’s milk
allergy, it is needed to give supplements for calcium and vitamin D.
Children with food allergy should be re-evaluated for their growth and possible nutritional deficits. When one
sees a child with delayed growth, food allergy should be considered in the differential diagnosis18.

17
7-10 days before the test the child should not take antihistamines or corticosteroids.
18
The professor had a case of a girl with rickets due to lack of vitamin D, which should have been given to her because of
her food allergy.
12