IgE-Mediated Food Allergy

Clinical Reviews in Allergy & Immunology (2019) 57:244–260
https://doi.org/10.1007/s12016-018-8710-3
IgE-Mediated Food Allergy

Sara Anvari 1 & Jennifer Miller 1 & Chih-Yin Yeh 1 & Carla M. Davis 1
Published online: 29 October 2018

# The Author(s) 2018
Abstract
Food allergies are defined as adverse immune responses to food proteins that result in typical clinical symptoms involving the
dermatologic, respiratory, gastrointestinal, cardiovascular, and/or neurologic systems. IgE-mediated food-allergic disease differs
from non-IgE-mediated disease because the pathophysiology results from activation of the immune system, causing a T helper 2
response which results in IgE binding to Fcε receptors on effector cells like mast cells and basophils. The activation of these cells
causes release of histamine and other preformed mediators, and rapid symptom onset, in contrast with non-IgE-mediated food
allergy which is more delayed in onset. The diagnosis of IgE-mediated food allergy requires a history of classic clinical symptoms
and evidence of food-specific IgE by either skin-prick or serum-specific IgE testing. Symptoms of IgE-mediated food allergies
range from mild to severe. The severity of symptoms is not predicted by the level of specific IgE or skin test wheal size, but the
likelihood of symptom onset is directly related. Diagnosis is excluded when a patient can ingest the suspected food without
clinical symptoms and may require an in-office oral food challenge if testing for food-specific IgE by serum or skin testing is
negative or low. Anaphylaxis is the most severe form of the clinical manifestation of IgE-mediated food allergy, and injectable
epinephrine is the first-line treatment. Management of food allergies requires strict avoidance measures, counseling of the family
about constant vigilance, and prompt treatment of allergic reactions with emergency medications. Guidelines have changed
recently to include early introduction of peanuts at 4–6 months of life. Early introduction is recommended to prevent the
development of peanut allergy. Future treatments for IgE-mediated food allergy evaluated in clinical trials include epicutaneous,
sublingual, and oral immunotherapy.
Keywords Food allergy . IgE . Mast cell . Tolerance . Sensitization . Anaphylaxis . Pathophysiology . Food allergy diagnosis .
Treatment of food allergy . Food immunotherapy
Introduction disease, allergic contact dermatitis, and food protein-induced

enteropathy/enterocolitis syndrome. Although celiac disease
Food allergies, defined as adverse immune responses to food is an immune-mediated disease triggered by gluten, a food
proteins, are becoming increasingly common conditions. protein, it is not typically classified as a food-allergic disease.
Food allergy is very distinct from food intolerance, which is As such, manifestations of food allergies differ significantly,
defined as a non-immune reaction that includes metabolic, depending on the immune mechanism involved and the affect-
toxic, pharmacologic, and undefined mechanisms [1]. Food ed target organ, ranging from the prototypical acute urticaria/
allergy is not one disease but a spectrum of clinicopathological angioedema to more chronic conditions such as eczema or
disorders [2]. Diseases associated with immune-mediated eosinophilic gastrointestinal disease (Fig. 1). Diagnostic tools
food allergy include acute urticaria/angioedema, oral allergy for food allergies must be used in the context of the clinical
syndrome, atopic dermatitis, eosinophilic gastrointestinal symptoms for accurate disease assessment (Fig. 2).
Food allergies can be grouped in two general categories:
IgE-mediated and non-IgE-mediated [1]. IgE-mediated reac-
tions are typically of rapid onset with clinical symptoms usually
* Carla M. Davis developing within minutes to a few hours of ingestion. Non-
carlad@bcm.edu IgE-mediated disease is typically chronic and may be more
1
difficult than IgE-mediated disease to control with food avoid-
Section of Immunology, Allergy and Rheumatology, Baylor College
of Medicine, Texas Children’s Hospital, 1102 Bates Avenue, MC ance alone. IgE-mediated food-allergic disease is associated
330.01, Houston, TX 77030, USA with fatal anaphylaxis, especially with peanut, tree nuts, and
Clinic Rev Allerg Immunol (2019) 57:244–260 245
Fig. 1 Classification of adverse reactions to food (adapted from Sampson et al. [2])
seafood. The potential for this devastating outcome and the be an important public health issue. Physician awareness of the
widespread media coverage of this epidemic has resulted in limitations of clinical history alone in diagnostic accuracy for
increased awareness of food allergies and fear for those affect- food allergies and judicious use of testing will help decrease
ed. More people believe they have food allergies than preva- false diagnoses. This review article will address the pathophys-
lence estimates show based on physician diagnosis. Up to one iology, clinical manifestations, diagnostic approaches, and
third of the population believes they have a food allergy, but the management of IgE-mediated food allergies.
prevalence is 5% of adults and 8% of children [2]. The preva-
lence has been increasing over the past decade, causing this to
Pathophysiology
Patient history concerning for an The immune system plays an integral role in the maintenance
immediate IgE-mediated food allergy
of tolerance to innocuous antigens. IgE-mediated food aller-
gies occur as a result of a loss of integrity in the key immune
components that maintain a state of tolerance and prevent
benign food antigens from being recognized as pathogens.
Recommend sIgE and/or More specifically, oral tolerance to foods is defined as the
SPT crossing of food antigen across the mucosal barrier, process-
ing by dendritic cells in a non-activated state, and the induc-
tion of suppressive cytokines, such as interleukin 10, by those
antigen-presenting cells. This in turn results in the differenti-
ation of naïve T cells into T regulatory cells and suppression of
Testing Testing
food antigen-specific Th2 cells, as well as increased IgA and
Negative Positive
IgG4 production and a decrease in IgE by B cells. Finally,
there is immune suppression of eosinophils, basophils, and
mast cells, effector cells which cause symptoms.
Sensitization is defined as the state of having detectable
Low Risk –
Recommend Strict food-specific IgE which can be a precursor to the development
Home Introduction
Avoidance of Food of clinical food allergy. It occurs when food crosses disrupted
Allergen
High Risk – Referral
and Referral to barrier and as a result of this disruption, danger signals and
for Graded Oral inflammatory cytokines are released which activate dendritic
Specialist
Food Challenge
cells into phenotypes that are normally acquired during the
defense against pathogens. These activated dendritic cells in
Fig. 2 Diagnostic algorithm for food allergy diagnosis turn activate naïve T cells into acquiring a T helper cell 2 (Th2)
246 Clinic Rev Allerg Immunol (2019) 57:244–260
phenotype, which in turn promote inflammatory signals which the antigenic peptide along with the class 2 major histocompat-
induce food Ag-specific B cells to class switch and produce ibility complex (MHC) to naïve T cells. Furthermore, in the
food antigen-specific IgE. In short, sensitization is mistaken presence of TGF-β and retinoic acid secreted from the DCs,
identification of food antigen as pathogen. All patients with naïve T cells are promoted toward a tolerant phenotype and can
IgE-mediated food allergies are sensitized to food allergen. differentiate to T regulatory cells [5].
This section will discuss five key components of the immune Conversely, the breakdown of tolerance due to a compro-
system involved in the development of tolerance and sensiti- mised epithelial barrier, promotes the epithelial release of pro-
zation or allergy to food: the epithelium, innate immune cells, inflammatory chemical mediators, such as IL-25, IL-33, and
T cells, B cells, and finally, the effector cells of the allergic TSLP [7, 8]. These mediators act upon antigen presenting
response, mast cells, eosinophils, and basophils (Fig. 3). cells and innate lymphoid cells, to further promote sensitiza-
tion by a Th2 phenotype. Activated dendritic cells promoting
Epithelial Barrier allergy, express surface OX40L, also known as tumor necrosis
factor ligand superfamily member 4 (TNFSF4) and migrate to
The epithelial barrier serves a major role in defense against the draining lymph node where they encounter and present
pathogens. In the context of IgE-mediated food allergies, the antigen to naïve T cells [10]. The MHC of the dendritic cell
epithelial barrier prevents unnecessary entry of antigens. An presents antigenic food peptides to naïve T cells and with the
intact epithelial barrier is important in the maintenance of tol- interaction between OX40L on DCs and OX40 on naïve T
erance, as it prevents the entry of danger signals and subse- cells, differentiation occurs from naïve T cells into Th2 T cells,
quently prevent the production of inflammatory cytokines, in thus promoting the allergic state.
conjunction with food antigens. Antigens cannot freely pass an In addition to activated dendritic cells, type 2 innate lym-
intact epithelial barrier. Instead, in an intact epithelium, antigen phoid cells (ILC2) have also been shown to play a critical role
is often transported through Bassisted^ mechanisms. These in the induction of food allergy. ILC2s expand in an antigen-
mechanisms include: paracellular diffusion, active transport independent manner while in the presence of the cytokines
via the enterocytes, microfold (M) cells, or goblet cells, and TSLP, IL-25, and IL-33 and promote a Th2 cell-mediated
by specialized macrophages projecting through epithelial [3]. immune response [11]. As a result, ILC2s produce large quan-
Food antigens recognized by specialized antigen presenting tities of TH2 cytokines, such as IL-5, IL-13, IL-4, and IL-9
cells in the absence of pro-inflammatory or danger signals will [12–14]. The secretion of the cytokine IL-4 and IL-13 from
further promote the maintenance of tolerance through the re- ILC2s can disrupt allergen-specific T regulatory cell induction
lease of chemical mediators such as interleukin 10 (IL-10) and/ and their suppressive functions, as well as enhance mucosal
or transforming growth factor beta (TGF-β), which will pro- mast cell activation, thereby sustaining dysregulation and pro-
mote the development of regulatory T cells [4–6]. moting the induction of food allergies [11].
When the integrity of the epithelial barrier is compromised,
sensitization to food allergens can occur, leading to the devel- T Cells
opment of food allergy. Epithelial damage or inflammation can
allow antigens to pass freely through the gut barrier, along with The appropriate milieu of cytokine and innate cell mediators
other pathogens. Damaged epithelium also promotes the re- promote the development of tolerance through naïve T cells.
lease of pro-inflammatory epithelial cytokines, such as interleu- Naïve T cells reside in the draining lymph nodes and await for
kin 25 (IL-25), IL-33, and thymic stromal lymphopoeitin the upstream signals, and, in combination with the presented
(TSLP) [7, 8]. The epithelial cytokines released can foster the antigens, promote the development of T regulatory cells.
activation of an allergic phenotype by signaling to antigen pre- Specifically, antigen presenting cells secreting TGF-β,
senting cells and other innate immune cells at or below the retinoic acid, or IL-10, foster the development of antigen-
epithelial barrier. When food antigen uptake occurs by activat- specific T regulatory cells from the naïve T cells [4–6].
ed antigen presenting cells in the presence of inflammatory Specifically, retinoic acid from DCs promotes the expression
cytokines, the benign antigen is now seen as a Bthreat.^ of homing receptor α4β7 on T regulatory cells thereby
allowing for the translocation to the intestinal lamina propria,
Antigen Presenting Cells and Innate Lymphoid Cells where they exhibit suppressive activity via CTLA-4 binding
to effector [15, 16]. Furthermore, cytokines secreted from T
In the absence of sensitizing chemical mediators, CX3CR1+ regulatory cells, such as IL-10 and TGF-β, can also suppress
macrophages can sample antigen and produce the cytokine IL- effector cells [17].
10, which will allow for the differentiation of naïve T cells to Th2-differentiated cells can migrate out of the draining
regulatory T cells. CD103+ dendritic cells can also capture lymph nodes into the lamina propria and secrete pro-
antigen directly or from transfer by the macrophage [9]. inflammatory cytokines, such as IL-5 and IL-13 to further
CD103+ DCs will migrate to draining lymph nodes and present promote the differentiation of downstream pro-inflammatory
Fig. 3 Comparative overview of the tolerogenic versus allergic response thymic stromal lymphopoietin (TSLP) are secreted and promote the
to food antigen in the gut. Tolerance (left): food antigens are sampled expansion of type 2 innate lymphoid cells (ILCs) and activation of
from the intestinal lumen by CX3CR1 macrophages, which then transfer dendritic cells. Activated DCs, in the presence of these pro-
the antigen to dendritic cells in the gut lamina propria. Dendritic cells inflammatory cytokines, will take up and process antigen to peptide and
(DCs) can transfer processed antigen to the draining lymph nodes, and in upregulate the expression of the surface protein OX40L. The peptide:
the context of non-inflammatory mediators, such as transforming growth major histocompatibility complex (MHC) on DCs and TCR on the
factor-beta (TFG-β) and retinoic acid, DCs present food peptide by way naïve T cells interact, as well as the OX40L on DCs and OX40 on
of the major histocompatibility complex (MHC) to the T cell receptors naïve T cells. This interaction promotes the differentiation of naïve T
(TCR) on naïve T cells. This interaction promotes the differentiation of cells to type 2 helper T cells (Th2). Th2 cells and ILCs can secrete pro-
naïve T cells into food antigen-specific T regulatory cells (Tregs). Food- inflammatory cytokines such IL-5 and IL-13, thereby promoting
specific Tregs then travel to the lamina propria via α4β7 where they eosinophil and basophil recruitment in the gut lamina propria leading to
encourage the maintenance of tolerance to food antigen via CTLA-4 downstream target effects that promote allergic sensitization. Th2 cells
expression and the release of cytokines TGF-β and IL-10. CTLA-4 also secrete IL-4, which allows for B cell class switching to promote food-
inhibits Th2 T cells while TGF-β and IL-10 suppress the effector cells specific IgE production. Th9 cells also play a major role in the
that promote allergy such as mast cells and also encourages the development of the allergic response by secretion of IL-9, which
maintenance of IgA in the lumen. Allergy (right): in the presence of gut promotes the recruitment of mast cells
epithelial damage, pro-inflammatory cytokines, such as IL-33, IL-25, and
effector cells such as eosinophils and basophils. IL-4, which is peripheral vasodilation, and coronary and pulmonary artery va-
produced by Th2 cells, promotes B cell class switching to soconstriction, acting to recruit basophils, eosinophils, dendritic
produce IgE in order to further establish sensitization and an cells, and Th2 cells and enhance the release of histamine from
allergic response to food. In addition to Th2 cell activation, basophils. Leukotrienes are also lipid mediators with a slow onset
naïve T cells have also been shown to differentiate to T helper of action. They cause smooth muscle contraction, mucus secre-
9 cells. Th9 cells contribute to the development of the allergic tion and cause increase vascular permeability. They are also im-
response by secreting IL-9, which further promotes the accu- portant in the recruitment of allergic inflammatory cells and mod-
mulation of tissue residing mast cells [18]. ulating the production of inflammatory cytokines.
The five components of the immune system, the epithelium,
innate immune cells, T cells, B cells, and effector cells (mast
Effector Cells (Mast Cells and Basophils) cells, eosinophils, and basophils), can either promote tolerance
to food antigens or sensitization, leading to allergic manifesta-
Tissue residing mast cells and circulating basophils are impor- tions. Genetic and environmental factors can influence the im-
tant in the allergic process. In the presence of IL-10 and mune system. As more is discovered about these influences, the
TGF-β, B cells can produce IgA antibodies which are impor- underlying pathophysiology of IgE-mediated food allergy may
tant in the maintenance of tolerance. Elevated food-specific be altered to promote tolerance or a state of desensitization
IgA antibodies are associated with desensitization and the (absence of clinical symptoms on exposure to food).
state of sustained unresponsiveness in patients who have oral
immunotherapy to food. The exact mechanism of the facilita-
tion of tolerance by IgA is not known but seems dependent
upon the innate immune system [19, 20]. Furthermore, toler- Clinical Manifestations
ance occurs in the absence of food-specific IgE. In its absence,
the effector mast cells and basophils cannot degranulate. IgE-mediated food-allergic reactions are type I hypersensitiv-
In the presence of IL-4, B cell class switching occurs and ity reactions which occur when patients develop IgE antibod-
food-specific IgE is produced, thereby promoting a state of ies against the culprit food protein followed by an exposure to
sensitization and allergy. Antigen food-specific IgE binds to that protein [1, 23]. Usually, there are preformed circulating
the FcεRI receptors on mast cells and basophils. Upon expo- IgE antibodies in the peripheral circulation. Therefore, when
sure to antigen, cross-linking of IgE and the IgE receptors occur the culprit food protein penetrates through the intestine lining,
on the surface of mast cells and basophils resulting in the re- IgE antibodies bind to the food protein. Two adjacent IgE
lease of preformed mediators into circulation. The mediators molecules binding to the food protein cause degranulation of
involved in anaphylaxis include: histamine, tryptase, platelet the mast cell and basophil followed by preformed mediator
activating factor, prostaglandins, and leukotrienes [20]. release within minutes of exposure [20]. Therefore, the typical
Histamine is one of the most important preformed media- symptoms of an IgE-mediated food-allergic reaction are usu-
tors of anaphylaxis. Once released from the activated mast cell ally rapid in onset and can cause death. The typical symptoms
or basophil, histamine’s onset of action is rapid (within 5 min); can involve almost every organ system, including the skin,
however, it is quickly metabolized (half-life 30 min). In ana- respiratory tract, gastrointestinal, cardiovascular, and neuro-
phylaxis, histamine acts upon H1 and H2 receptors and stim- logical systems [24, 25] (Table 1).
ulation of these receptors leads to vasodilation, increased vas- Cutaneous manifestations include erythematous rashes,
cular permeability, increased heart rate, increased cardiac con- pruritus, urticaria, and angioedema. Mild symptoms may pres-
traction, and increased glandular secretion. ent as occasional scratching or persistent pruritus with or with-
Tryptase, another preformed mediator primarily stored in mast out hives. Hives consist of circumscribed dermal edema
cells, has limited diffusion from an activated mast cell because it surrounded by erythema which usually blanches with pressure
is secreted as an active proteoglycan complex [21]. Tryptase and are characteristically pruritic. They usually occur imme-
levels peak at 60–90 min after the onset of [22]. In anaphylaxis, diately after ingestion of the culprit food and can last for hours
tryptase can cause angioedema by the activation of the contact without treatment. Angioedema usually presents as eyelid,
(kallikrein-kinin) system. Platelet activating factor is a potent face, and/or lip swelling and can cause significant amount of
mediator of anaphylaxis. It causes bronchoconstriction, increased discomfort. Erythematous macular rash without hives can be
vascular permeability, chemotaxis, and degranulation of eosino- one of the manifestations as well. Eczematous rashes can also
phils and neutrophils. Prostaglandins are lipid mediators that are be a symptom of IgE-mediated food allergy, although non-
released from activated mast cells during anaphylaxis. Basophils IgE-mediated immune mechanisms also play a role. Severity
do not produce prostaglandin D2 (PGD2), a prostaglandin only of the cutaneous symptoms in IgE-mediated food allergy can
produced in mast cells. PGD2 causes bronchoconstriction, be determined by the percentage of the involved skin [26].
Table 1 Clinical manifestations of IgE-mediated food allergy by organ system
Organ systems Symptoms Mild Moderate Severe
Skin Rash Faint erythema Erythema Generalized marked erythema (more

than 50% of the body surface area)
Urticaria/angioedema < 3 areas of hives; mild lip edema More than 3 areas of hives; Generalized involvement of swelling
significant lip or face edema face/lips/eyelids
Pruritus Occasional scratching Scratching continuously Continuous scratching; excoriations
Upper airway Sneezing/itching Occasional sniffing Intermittent rubbing of nose or eyes; Continuous rubbing of nose or eyes;
frequent sniffing periocular swelling; persistent
rhinorrhea
Lower airway Wheezing Expiratory wheezing Inspiratory and expiratory wheezing Use of accessory muscles; audible
wheezing; increased work of
breathing
Laryngeal manifestation Episodes of throat clearing or cough; Hoarseness, frequent cough Stridor
persistent throat tightness
Gastrointestinal tract Subjective symptoms Nausea or mild abdominal pain Moderate abdominal pain with Notably distressed due to GI
normal activity symptoms with decreased activity
Objective symptoms 1 episode of emesis or diarrhea More than 1 but less than 3 episodes More than 3 episodes of emesis or
emesis or diarrhea diarrhea
Cardiovascular/Neurological Subjective weakness, dizziness; Drop in blood pressure; significant Severe cardiovascular collapse;
tachycardia change in mental status (anxiety, unconsciousness
confusion)
Other Loss of bladder control Pelvic pain
Cutaneous manifestations are the most common IgE-mediated Symptoms such as failure to thrive, bloody diarrhea, consti-
food-allergic symptoms. pation, weight loss, long-term malabsorption, emesis, or diar-
IgE-mediated food-allergic respiratory symptoms can in- rhea after 4 h of food ingestion are typically not IgE-mediated
volve the upper and lower airway tract. Mild symptoms present food-allergic manifestations, but non-IgE mediated, usually
as mild occasional sniffing or rubbing of the nose. Moderate to occurring as a result of cellular innate and adaptive immune
severe symptoms can present as persistent rhinorrhea or nasal mechanisms [1].
congestion, including a complete blockage of the nares. Other Cardiovascular system and neurological involvement are the
than the upper airway tract, ocular symptoms can occur in most severe manifestations of IgE-mediated food-allergic reac-
isolation or in combination with the upper airway symptoms. tions in patients. Subjective symptoms include dizziness or
Conjunctival involvement can present as lacrimation, eye red- weakness; objective signs may include tachycardia, hypotension,
ness, and/or itching, and ocular severe symptoms can manifest change in mental status, severe cardiovascular collapse, uncon-
as significant periorbital swelling [1, 24, 25]. sciousness, and death. Cardiovascular symptoms and neurologi-
Lower upper respiratory tract symptoms include wheezing cal involvement usually occur with other organ involvement,
with mild symptoms of expiratory wheeze and increasing such as respiratory or cutaneous manifestations [1, 24].
symptom severity including inspiratory wheeze, audible Anaphylaxis is a severe form of an IgE-mediated hypersen-
wheezing, use of accessory muscles. or an asthma exacerba- sitivity allergic reaction that involves multiple organs. It is
tion. Asthma exacerbation can also occur when inhalation of rapid in onset and is potentially fatal. A non-anaphylactic mild
the food protein has occurred, mediated by a type I hypersen- allergic reaction is defined by acute reactions caused by gen-
sitivity reaction. Laryngeal manifestations in IgE-mediated eralized release of mediators restricted to one system; for ex-
food-allergic reactions include throat clearing, cough, throat ample, a patient could have that or other cutaneous findings,
tightness, or throat pain. Moderate laryngeal symptoms in- such as pruritus, erythematous rash, urticaria, local edema, or
clude hoarseness and increased frequency of dry cough. The angioedema with no other system involvement. Anaphylaxis
most-severe symptom could be stridor followed by complete is by definition a severe allergic reaction with more than one
airway obstruction. Stridor as an abnormally high-pitched system involved (Table 2). Anaphylaxis symptoms can in-
sound occurs in inspiratory phase due to tissue swelling volve the above cutaneous reactions along with respiratory,
caused by allergic mediators in laryngeal tissues, such as the gastrointestinal, cardiovascular, or neurological system in-
supraglottis, glottis, subglottis, or trachea, and subsequently volvement. Even though it is rare, anaphylaxis can also pres-
interrupting and narrowing the airway passage [24]. ent with only cardiovascular or neurological symptoms, such
Gastrointestinal involvement includes subjective and ob- as dizziness, weakness, tachycardia, hypotension, cardiovas-
jective symptoms. Subjective symptoms include itching of cular collapse, or unconsciousness [24].
mouth or throat, nausea, or abdominal pain. Objective symp- The World Health Organization classified anaphylaxis into
toms include vomiting and intermittent or persistent diarrhea. five grades [27] (Table 3). Grade I is defined when only one
The onset of the gastrointestinal system symptoms is usually organ system is involved—including cutaneous, respiratory, oc-
immediate, often within minutes and not more than 2 to 4 h. ular, or others. Cutaneous signs and symptoms according to this
Table 2 Definition of anaphylaxis anaphylaxis occurs when symptoms of laryngeal, uvular, or

Anaphylaxis is highly likely when any 1 of the following 3 criteria is tongue tissue edema occur with or without stridor or when the
fulfilled: FEV1 drops by 40% with no bronchodilator response. Grade IV
Acute onset of an illness (minutes to several hours), with involvement of symptoms include respiratory failure or hypotension. Grade V
the skin, mucosal tissue, or both (e.g., generalized urticaria, itching or anaphylaxis is death. Biphasic reactions occur in ~ 10% of ana-
flushing, swollen lips/tongue/uvula), and at least 1 of the following: (1) phylactic episodes.
respiratory compromise (e.g., dyspnea, wheeze/bronchospasm, stridor,
hypoxemia) or (2) reduced blood pressure or associated symptoms of Many studies had shown that clinical manifestations differ
end-organ dysfunction (e.g., hypotonia (collapse), syncope, inconti- among different age groups. Infants with anaphylaxis more often
nence) present with vomiting and hives; preschool age children with
2 or more of the following that occur suddenly after exposure to a likely anaphylaxis often present with wheezing and stridor. Subjective
allergen for that patient (minutes to several hours): (1) involvement of symptoms including difficulty breathing or difficulty swallowing
the skin/mucosal tissue (e.g., generalized urticaria, itch/flush, swollen
lips/tongue/uvula), (2) respiratory compromise (e.g., dyspnea,
are the more common presenting symptoms for anaphylaxis in
wheeze/bronchospasm, stridor, hypoxemia), (3) reduced blood pres- teenager age group. Three percent of children have hypotension
sure or associated symptoms (e.g., hypotonia (collapse), syncope, as their presenting symptom of anaphylaxis [28].
incontinence), or (4) persistent gastrointestinal symptoms (e.g., crampy Eight foods cause 90% of IgE-mediated food-allergic reac-
abdominal pain, vomiting)
tions: cow’s milk, egg, soy, wheat, shellfish, fish, peanuts, and
Reduced blood pressure after exposure to a known allergen for that
patient (minutes to several hours): (1) for infants and children, low
tree nuts [1]. The natural history of cow’s milk, egg, soy, and
systolic blood pressure (age-specific) or greater than 30% decrease in wheat IgE-mediated allergy is resolution from childhood to
systolic blood pressure and (2) for teenagers and adults, systolic blood adulthood. Shellfish, fish, peanut, and tree nut allergies rarely
pressure of less than 90 mmHg or greater than 30% decrease from that resolve, with only 20% of peanut-allergic children and 10% of
person’s baseline
tree nut-allergic children having resolution. Resolution of
food-allergic disease is accompanied by a decrease in serum
classification include generalized pruritus, urticaria, flushing, or food-specific IgE level so these levels can be serially followed
sensation of heat or warmth or angioedema not involved in la- to help predict disease resolution [2]. Egg- and cow’s milk-
ryngeal, tongue, or uvular tissues. Localized hives or angioedema allergic patients begin to tolerate extensively baked goods
alone would not be considered anaphylaxis. Upper respiratory with denaturation of the proteins before tolerating unbaked
tract symptoms include sneezing, rhinorrhea, nasal pruritus and/ milk and egg [29].
or nasal congestion, throat clearing, itchy throat, and coughing.
Conjunctival symptoms include conjunctival erythema, pruritus,
or tearing. Other symptoms may include nausea, metallic taste, or Diagnostic Approaches
headache. Grade II anaphylaxis is defined when there are two
organ systems involved or lower respiratory tract involvement, The initial food allergy workup begins with obtaining a de-
gastrointestinal involvement, or uterine cramping. Lower respi- tailed clinical history and physical exam. The information
ratory tract symptoms in grade II anaphylaxis include wheezing, provided in the history can support the necessary testing, in
shortness of breath, and a drop of the forced expiratory volume in order to identify the cause of the reaction. The diagnosis relies
1 s (FEV1) by 40% which is responsive to bronchodilator med- on the history and test results; however, testing is not 100%
ication. Gastrointestinal symptoms in grade II anaphylaxis in- diagnostic and results should be interpreted carefully. The
cludes abdominal cramping, vomiting, or diarrhea. Grade III gold standard to diagnosing a food allergy is to perform an
Table 3 World allergy organization grading and definition of types of anaphylaxis
Grade Definition
Anaphylaxis
Grade I Only 1 organ system is involved—including cutaneous, respiratory, ocular
Grade II 2 organ systems involved or lower respiratory tract, gastrointestinal involvement, or uterine cramping
Grade III Symptoms of laryngeal, uvular, or tongue tissue edema occur with or without stridor or when the FEV1
drops by 40% with no bronchodilator response.
Grade IV Respiratory failure or hypotension
Grade V Death
Biphasic anaphylaxis New or worsening anaphylactic symptoms after resolution of the primary/first reaction. Usually occurs
within 6 h after the resolution of the primary reaction.
Refractory anaphylaxis Anaphylactic reaction that does not respond to initial treatment
oral food challenge. Herein, the current diagnostic approaches unnecessary dietary eliminations. In addition, a 4–6-week
to identifying an IgE-mediated food allergy are discussed. waiting period after an anaphylaxis episode should be given
before skin testing is performed.
Clinical History and Physical Exam Immediate hypersensitivity skin testing (IHST) is a rapid
method of screening for the presence of food-specific IgE
One of the most essential aspects in the workup for food aller- antibodies bound to cutaneous mast cells. The test is per-
gies is obtaining an accurate and detailed history. When formed by using a device coated with commercial extract or
obtaining the history, the following questions should be ad- fresh food and scratching the surface of the skin. This intro-
dressed: (1) the exact food causing the symptoms and its prep- duces the food protein through the skin, which can then bind
aration (cooked or uncooked); (2) the amount of food triggering to specific IgE on cutaneous mast cells and trigger degranula-
the reaction; (3) the symptoms experienced at the time of reaction of preformed mediators like histamine. The activation of
tion; (4) the time from ingestion to symptom development; (5) the local mast cells produces a wheal and flare visualized at
factors that may have contributed to the reaction (i.e., viral the site where the allergen was introduced through the skin.
illness, medications, exercise); (6) treatments used to stop the The wheal is measured 15 min after the prick and the diameter
reaction; (7) the presence of a biphasic reaction following the of the wheal provides information on the likelihood of clinical
initial symptoms; (7) reproducibility following a subsequent reactivity. A mean wheal diameter ≥ 3mm larger than the
exposure; and (8) length of time since the last reaction. In negative control is considered a positive skin test and could
addition to the details of the reaction, the clinician should also suggest the likelihood of clinical reactivity [32]. However, a
focus on patient’s history of other forms of atopy, such as atopic positive skin-prick test (SPT) only reflects the presence of
dermatitis, asthma, or allergic rhinitis. There is a strong associ- specific IgE antibodies bound to mast cells and is not diag-
ation between atopic dermatitis and the development of food nostic of clinical reactivity. The presence of specific IgE anti-
allergies, especially when the severe atopic dermatitis is ac- bodies without clinical reactivity is called sensitization.
quired in the first 3 months of life [30, 31]. Hill et al. described Therefore, caution should be made when interpreting results
a birth cohort of 480 children followed for development of and only suspected food allergens should be tested, since food
atopic dermatitis. The relative risk of an infant with atopic skin testing has a low specificity [33, 34].
dermatitis having IgE-mediated food allergy was 5.9 for the A positive skin test cannot differentiate between sensitization
most severely affected group [30]. In population-based studies, and a true IgE-mediated allergy; therefore, it is important that the
the likelihood of food sensitization was up to six times higher in clinician combine a detailed clinical history and the results of a
patients with AD versus healthy control subjects at 3 months of test to determine the need for additional diagnostic testing to
age [31]. Thus, with eczema being a risk factor for the devel- support an IgE-mediated food allergy. Although wheal size does
opment of food allergies, clinicians should inquire about the not correlate with disease severity, positive predictive values for
age of onset of the eczema and its severity. clinical reactivity have been reported based on the size of the
Further information in the clinical history should also in- wheal diameter. For example, a mean wheal diameter size ≥8
clude the patient’s family history of atopy, including food mm for cow’s milk, ≥7 mm for hen egg, and ≥8 mm for peanut
allergies. The information obtained from the clinical history was 95% predictive of reaction if challenged [35]. Skin-prick
will not only provide information to identify the potential tests have a relatively high NPV and can be particularly useful
trigger causing the reaction but will also determine the neces- in ruling out IgE-mediated food allergy to a specific food.
sary tests to facilitate the diagnosis of a food allergy. Overall, However, clinical reactivity occasionally occurs with a negative
the history provides the necessary information to determine skin-prick test [2]. Intracutaneous testing, also called intradermal
the necessity for any testing and whether a food challenge testing, for the diagnosis of food allergy is not recommended
would be appropriate. given the risk of serious adverse reactions [2].
Food-specific and food-component IgE antibody testing are
Testing—Skin Testing and Serum-Specific IgE Testing additional diagnostic measurements that can be used to mea-
sure food-specific IgE antibodies. The measurement of IgE is
In addition to the detailed medical history and physical exam- performed by the technique of fluorescence enzyme labelling.
ination, when suspecting an IgE-mediated food allergy, the The patient’s serum is incubated with a surface-fixed allergen,
practitioner can utilize clinically approved tests, to aid in the and food-specific IgE from the patient binds to the allergen.
diagnostic workup. Commonly utilized tests such as the im- The food-specific IgE is then identified with a fluorescently
mediate hypersensitivity skin test and food-specific IgE anti- labeled anti-IgE antibody. The measurement provides evidence
body tests are utilized in the evaluation of an IgE-mediated of unbound circulating allergen-specific IgE levels produced.
food allergy. It is important for general practitioners and aller- Food-specific IgE levels correlating with a 95% positive pre-
gists to be aware of the dangers of ordering large panels of dictive value for several foods have been previously deter-
tests which can lead to false-positive results and potentially mined and can potentially correlate with a reaction to a given
food. One hundred children (62% male; median age, 3.8 years; a vehicle, and the doses are increased every 15–30 min until
range, 0.4–14.3 years) were evaluated for food allergy and all steps have been completed or until symptoms present. In
diagnosed by history or oral food challenge. On the basis of preparation for an oral challenge, patients discontinue medi-
the previously established 95% predictive decision points for cations, such as antihistamines or corticosteroids, which can
egg, milk, peanut, and fish allergy, greater than 95% of food interfere with the results of the challenge. Furthermore,
allergies diagnosed in this prospective study were correctly coexisting conditions such as asthma, uncontrolled urticarial
identified by quantifying serum food-specific IgE concentra- or eczema, or a concurrent respiratory tract infection should be
tions [36, 37]. For example, the positive predictive value for a evaluated before performing an oral food challenge. Thirty-
peanut IgE level greater than 14 kU L−1 and the peanut com- two cases of fatal food anaphylaxis cases have been docu-
ponent Ara h2 greater than 5 kU L−1 has been shown to be 100 mented and uncontrolled asthma identified as a comorbid con-
and 96%, respectively [36, 38]. A diagnostic prediction model dition in 97% of these cases. Patients with uncontrolled asth-
for peanut allergy in children using six predictors: sex, age, ma should be carefully evaluated and controlled before under-
history, skin-prick test, peanut-specific immunoglobulin E going an oral food challenge as they could be at risk of a
(sIgE), and total IgE minus peanut sIgE. When building the severe fatal reaction [2].
model with sIgE to peanut components, Ara h2 was the only
predictor, with a discriminative ability of 90%. The outcome of Other Tests
the food challenge could be predicted with 100% accuracy in
59% (updated model) and 50% (Ara h2) of the patients. The use of alternative tests, such as the allergen-specific IgG
Therefore, values above 5 kU L−1 are highly suggestive of an or IgG4 testing, lymphocyte stimulation, cytotoxicity assays,
IgE-mediated peanut allergy. mediator release test, provocation neutralization, applied ki-
Ultimately, specific IgE levels should be interpreted with nesiology, or hair analysis testing have not been currently
caution when the history is not supportive of an IgE-mediated recommended as validated tools in the diagnostic workup for
allergy, especially given the high false-positive rates. In cases IgE-mediated food allergies [2]. Although many patients may
where the history is strongly supportive of tolerance to a food, have these tests performed, the interpretation of these tests has
for example, if the patient has eaten a large amount of the food not been rigorously assessed as reliable. Patients should be
recently without symptoms, it is better to avoid testing specific discouraged from having these tests because they are very
IgE levels. Like food allergen skin testing, the sensitivity of costly and could result in unnecessary dietary avoidance.
serum IgE testing is greater than 90%; however, the specificity
of both tests can be less than 50% when assessing foods, due
to possible cross-reactivity between related proteins [2] Treatment of IgE-Mediated Food Allergies
(Table 4). Therefore, these tests cannot rule out a food allergy
and cannot differentiate between sensitization versus a true Anaphylaxis to IgE-mediated food allergies leads to symp-
IgE-mediated allergy. The information obtained from the clin- toms which have been previously described including but
ical history is crucial and should help guide the interpretation not limited to rash, vomiting, diarrhea, abdominal pain,
of the results obtained from these tests. Patients should be wheezing, chest pain, clearing throat, tongue swelling, lip
considered for a supervised oral food challenge when testing swelling, and hypotension. These IgE-mediated reactions
is negative for skin and blood and there has been diet avoid- need immediate management to stabilize the patient as well
ance of the food. If there are discrepant test results and clari- as long-term management and monitoring.
fication of a diagnosis is needed, a challenge is helpful.
Acute Management
Oral Food Challenge
a. Recognize anaphylaxis
An oral food challenge can provide a definitive diagnosis for
an IgE-mediated food allergy, and the double-blind placebo- The first step in management of a suspected IgE-mediated
controlled food challenge (DBPCFC) is the gold standard to allergic reaction to food is assessment to identify anaphylaxis,
diagnosing food allergies in clinical trials or standardized which is a potentially life-threatening condition. A large, in-
studies [39]. The history and test results will allow the clini- ternational study published in April 2016 collected anaphy-
cian to determine whether or not to pursue the challenge. laxis data from July 2007 to March 2015. Patients with ana-
Performing an oral challenge requires an experienced clinician phylaxis were referred to 1 of 90 tertiary allergy centers in ten
who can quickly recognize and treat symptoms of anaphylax- European countries. This allowed assessment of anaphylaxis
is. In addition to a DBPCFC, food challenges can also be open in 1970 patients. The study showed symptoms included skin
or single blind. The patient undergoing an oral challenge be- in 92% of children which were further characterized as angio-
gins with ingesting very small amounts of the food, masked in edema (53%), urticarial (62%), pruritus (37%), and erythema/
Table 4 Diagnostic cut-offs for immediate hypersensitivity skin-prick testing and serum food-specific IgE testing (positive predictive value (PPV),
negative predictive value (NPV))
Testing modality Foods Sensitivity (%) Specificity (%) PPV 95% NPV (50%)
Skin-prick testing
Peanut 95 61 ≥ 8 mm < 3 mm
Hen egg 92 58 ≥ 7 mm < 3 mm
Cow milk 88 68 ≥ 8 mm –
Wheat 73 73 – –
Soy 55 55 – –
Testing modality Foods Sensitivity (%) Specificity (%) PPV ≥ 95% (≤ 2 years)
IgE testing
Peanut 96 59 14 kU L−1
Ara h2 5 kU L−1
Hen egg 93 49 7 (2 kU L−1)
Cow milk 87 48 15 (5 kU L−1)
Wheat 83 43 26 kU L−1 (PPV 74%)
Soy 83 38 30 kU L−1 (PPV 73%)
flush (29%). The anaphylaxis symptoms also included gastro- normal saline, oxygen, vital sign monitoring, and cardiopul-
intestinal symptoms (45%), respiratory in 80%, cardiac in monary resuscitation [41]. In a recently published study, when
41%, and neurologic in 26% [40]. Being able to diagnose a a tertiary pediatric emergency department compared 2003/
patient with anaphylaxis is essential to the treatment. A patient 2004 with 2012 with a similar volume of total emergency
may react the first time they consume a food or after previ- room visits, 92 cases were coded and verified for anaphylaxis
ously tolerating a food. After initial exposure, subsequent ex- in 2003/2004 versus 159 cases in 2012. More of these cases
posures can result in more severe reactions. were treated with epinephrine in 2012 (28%) as well as given
outpatient follow-up with allergy specialist (99.4%) and an
b. Epinephrine outpatient prescription for an epinephrine auto-injector
(81%) compared with 2003/2004 (12, 88, and 53%, respec-
After the diagnosis of anaphylaxis, the first-line treatment tively) [42]. A key component of the management of food-
is intramuscular epinephrine. Epinephrine can help allergic patient who present to the emergency department or
vasoconstrict the blood vessels to maintain blood pressure, physician’s office includes discharge management plans. This
bronchodilate the airways to improve respirations, and de- study shows patients received better care as anaphylaxis was
crease edema that may be causing airway collapse. The dosing better identified, proper treatment was given, followed by in-
for epinephrine is 0.01 up to 0.3 mg kg−1. This should be structions for follow-up care.
placed into the lateral thigh intramuscularly, as subcutaneous
epinephrine injection does not result in quick systemic absorp- c. Anti-histamines and glucocorticoids
tion. The dose of epinephrine autoinjectors are typically 0.15
and 0.30 mg, although a 0.10-mg autoinjector has recently Following the use of intramuscular epinephrine, H1-anti-
been approved by the US Food and Drug Administration. histamines are the next treatment which should be used for
For patients under 25 kg, the 0.15-mg dose is recommended, anaphylactic symptoms. These should never be used alone for
and for those greater than 25 kg, the 0.3-mg dose is recom- the treatment of anaphylaxis. They can help relieve symptoms
mended [41]. All patients who have experienced one of the as a single agent or in addition with H2-antihistamines. As
symptoms of anaphylaxis and have a diagnostic test positive allergic reactions can cause histamine release, giving medica-
for food-specific IgE should be given epinephrine in the event tions that block the H1 and H2 receptors can improve the
of an accidental exposure to the culprit food, especially be- vasculature integrity and maintenance of the blood pressure
cause of the relationship between fatal anaphylaxis and de- and heart rate [43]. Glucocorticoids are often used in emer-
layed epinephrine administration. gency room visits for anaphylaxis. In a prospective study pub-
Patients in the midst of anaphylaxis require constant mon- lished in 2017, anaphylaxis cases were evaluated from 2013 to
itoring. Furthermore, they may require fluid resuscitation with 2014. Upon review, in 180 anaphylactic patients identified,
83% received glucocorticoids while only 25% received adren- allergic children (mean age 18.9 months) were compared with
aline [44]. There is an overall lack of evidence for clear benefit controls and, at baseline, energy and protein intakes were low-
of glucocorticoids, but it is frequently used. It is essential to er in children with food allergy (91 kcal kg−1 day−1) than in
remember that similar to anti-histamines, glucocorticoids are controls (96 kcal kg−1 day−1) (p < 0.001). A weight-to-length
not first-line treatment for anaphylaxis and should not be used ratio < 2 standard deviations was more frequent in children
in place of epinephrine. Although education has improved, with food allergy compared with controls (21 versus 3%;
further progress is needed. p < 0.001). At 6 months following dietary counseling, the total
energy intake of children with food allergy normalized.
Long-term Management Dietary counseling also resulted in a significant improvement
in markers of nutritional status.
a. Diagnosis of reaction (skin-prick testing) On 1 January 2006 through the Food Allergen Labeling
and Consumer Protection Act (FALCPA) of 2004, it became
A patient must wait 4–6 weeks after an anaphylaxis episode law for food manufacturing companies to list the eight major
to have skin testing performed. As discussed in the BDiagnostic allergens including milk, egg, peanut, tree nuts, fish, crusta-
Approaches^ section, testing earlier than this increases the cean shellfish, wheat and soy, on food labels. This law re-
chance of a false negative. The diagnosis of IgE-mediated food quires even trace amounts of the protein to be included.
allergy is discussed extensively in an earlier section and in- Apart from the FALCPA, companies are not regulated regard-
cludes a combination of clinical history assessment of risk of ing advisory statements including Bmay contain…^ or
food allergy and a test to document presence of food-specific Bprocessed in a factory…^ This is a misconception about this
IgE (skin-prick testing or specific IgE testing) [2, 34, 35]. law. A 2007 study discussed these advisory statements specif-
ically related to peanut allergy [47], showing consumers were
b. Avoidance of the food more likely to buy products that stated as Bmade in a facility
that processes peanut^ over products labels as Bmay contain
The first long-term management strategy of IgE-mediated peanut.^ The study found peanut protein in 10% of the 200
food allergies is strict food allergen avoidance. The reason for food products with an advisory statement and clinically sig-
subsequent reactions following initial diagnosis of IgE- nificant levels of peanut with > 1 mg of peanut or > 0.25 mg of
mediate food allergy is often the failure to avoid the known peanut protein in 13 products [47]. Because these products can
allergen. There are a number of concepts to discuss that ulti- cause reactions if eaten by patients with IgE-mediated food
mately affect a patient’s ability to avoid a food allergen. allergy, all food with precautionary labels or containing food
allergen should be avoided.
i. Reading labels A more recent study in 2017 that addressed the food allergy
labeling and purchasing habits in the USA and Canada, with
Every patient diagnosed with IgE-mediated food allergy 6684 participants, 84.3% caregivers to a child with food aller-
should be counseled, preferably by a registered dietitian, about gies. The survey showed 12.3% would purchase food labeled
the strategies and vigilance required to avoid specific food as Bmay contain allergen,^ 40.3% would purchase labeled as
allergens. This endeavor can be overwhelming for families Bmanufactured in a facility that also processes allergen^, and
and quite costly. A cross-sectional survey was conducted from 16.7% would purchase labeled as Bmanufactured on shared
28 November 2011 to 26 January 2012 in 1643 US caregivers equipment with products containing allergen^. Twenty-nine
of a child with a current food allergy showed that the overall percent of those surveyed did not know there was a law re-
estimated economic cost of food allergy was $24.8 (95% CI, quired to report labels. Twenty-eight percent thought precau-
$20.6–29.4) billion annually ($4184 year−1 child−1). Costs tionary advisory labels were required by law, and almost 17%
borne by the family totaled $20.5 billion annually, with out- did not know if they were required [48]. This study further
of-pocket costs of $5.5 (95% CI, $4.7–6.4) billion annually, verifies that caregivers need to have better education on read-
with 31% stemming from the cost of special foods [45]. Due ing labels for foods as well as understanding of the laws that
to the natural history of egg and milk IgE-mediated food al- enforce food allergen labeling. Since these products with pre-
lergies and the fact that not all patients have to avoid unbaked cautionary labels can have the allergen in them, not under-
(nondenatured) and baked (denatured) egg and milk, the re- standing the labels may lead to the risk of accidental exposure.
quirement to avoid food allergens can be difficult.
Additionally, names for food allergens on labels can be coun- ii. Eating out
ter intuitive (i.e., casein for milk or ovomucoid for egg).
Patients need help to navigate reading labels, and this may In a recently published cross-sectional, qualitative study,
improve their nutritional status. Dietary counseling is an im- food allergies cause a significant problem for families when
portant aspect of the help parents need [46]. Ninety-one food- trying to eat out. It leads to anxieties, limitations, and
sacrifices. Identifying these consequences of food allergies c. Dietician consultation

will allow providers and support networks to help the fam-
ilies cope with their concerns [49]. Data was collected from Having an IgE-mediated food allergy can be difficult to
food service workers at 278 randomly selected restaurants to work into day-to-day life. Furthermore, having a food allergy
identify their understanding of food allergens and treatment. can indicate that an important nutrient of the diet must be
Overall the managers, food workers, and servers were removed thus dietary consultation is important as well as close
knowledgeable about food allergens and had positive atti- monitoring of weight in patients with IgE-mediated food al-
tudes about accommodating those with food allergies; how- lergy. A study done in 2002 further discusses the importance
ever, it was noted that 10% of workers thought a person of assessing height, weight, and body mass index in patients
with a food allergy could safely consume a small amount with food allergies. Furthermore, it compared allergy patients
of the allergen. The study also showed that allergy training with non-allergy-matched patients. It showed that children
improved attitudes towards the patients with food allergies with two or more food allergies were shorter, based on
but not the knowledge [50]. For patient safety, discussing height-for-age percentiles, than those with one food allergy.
eating out as well as tactics on how to do it successfully are The study showed that the number of children who did not
essential. meet 67% of the DRI for calcium and vitamin D was statisti-
cally higher for those without nutrition counseling compared
iii. School attendance with those who had counseling [54, 55]. The study did not spec-
ify the extent of counseling but overall implies the importance of
Children spend a great deal of time at school thus as the any nutrition counseling. A systematic review in 2013 comparing
incidence of IgE-mediated food allergy increases, the schools four studies overall concluded that children with multiple food
need to act. A retrospective study performed in Maryland allergies have a higher risk of growth impairment and inadequate
compared peanut-free schools, schools with peanut-free ta- nutrient intake thus monitoring nutrition is essential [56].
bles, and schools with no food policy. The research showed
that the schools with a peanut-free table compared with the
schools without a peanut-free table had lower rates of epi- Prevention
nephrine administration. The incidence rate was 0.2 per
10,000 students for the peanut-free table school and then 0.6 There has been an ongoing debate of whether to introduce a
per 10,000 students for the school without a policy in place. common allergen to a baby as early as possible or delay intro-
There was not a significant difference noted in peanut free duction. In January 2017, the American Academy of Pediatric
schools versus schools with a peanut-free table. This study changed their stance on when to introduce allergen following
enforces the importance of having a policy in place that allows the publication of a landmark study known as the Learning
increased avoidance for the students with food allergy [51]. Early About Peanut (LEAP) trial. The LEAP study included
640 infants ages 4–11 months of age with severe eczema and/
iv. Transition of pediatric care into adulthood or egg allergy as well as a negative skin-prick test or one with
1–4 mm in size. They were randomized to two arms with one
As in all pediatric diseases, there is a concern for group avoiding peanuts until 60 months of age and another
compliance in the transition of care into adolescent and group receiving peanuts. Upon completion, those with nega-
adulthood. A recent study conducted from February 2015 tive skin-prick testing who avoided peanuts had a 13.7% prev-
through May 2016 involved evaluating 141 undergradu- alence versus those who consumed it had a 1.9% prevalence
ate college students who have a physician-diagnosed of peanut allergy. In addition, those with slightly positive skin-
food allergy. It found that there is an inconsistent adher- prick testing had a peanut allergy prevalence of 35.3% in those
ence to food avoidance and there is a need for a strategy who avoided and 10.6% in those who consumed. This study
to encourage avoidance to prevent events [52]. A 6-year allowed the medical field to see the importance of early intro-
comparison study was completed by the University of duction of allergens [57, 58].
Michigan looking at the impact of a food allergy aware- A study recently published in February 2018 further evalu-
ness implementation across the campus. The rates of al- ated this early introduction of peanuts and even evaluated in-
ways carrying epinephrine, strict avoidance, and preparer troduction through breast milk. The study noted that 58.2% of
awareness were below 50% even after food allergy mothers ate peanuts while breast-feeding and 22.5% gave pea-
awareness implementation [53]. Teaching patients at an nuts prior to 12 months of age. At 7 years of age, 9.4% of the
early age and continuing the education throughout ado- children had peanut allergy. Interestingly enough, the lowest
lescent and emphasizing it as they transition to young incidence at 1.7% was found in children whose mothers ate
adulthood is important to try and improve the risk of peanuts while breast-feeding and were introduced to peanuts
exposure and the level of preparedness. before 12 months of age. If a mother did not do one of these
actions, there was an increase in incidence of peanut sensitiza- Food Allergy Misconceptions Debunked
tion [59]. This study further supports the American Academy
of Pediatrics newly revised statement [60]. Despite popular belief, food-allergic reactions do not always
result in risk of fatal anaphylaxis. Depending on the disease
Future Management process, fatal allergic reactions secondary to foods are due to
responses. Symptoms associated with IgE-mediated food aller-
a. Oral immunotherapy gies are typically observed within 2–3 h of ingestion. On the
other hand, non-IgE-mediated reactions are more often de-
Oral immunotherapy (OIT) is an emerging treatment for layed, as opposed to IgE-mediated reactions. Patients frequent-
food allergy. It encompasses putting the allergen in a vehicle ly present with gastrointestinal symptoms, such as profuse
including milk and powder form and then giving it to food- vomiting or diarrhea-associated food protein-induced enteroco-
allergic patients in an increasing manner. Giving patient’s in- litis syndrome, bloody stools with milk protein proctocolitis or
creasing doses of the food allows them to build a tolerance to reflux, abdominal pain, poor weight gain, or vomiting with
the food and would ideally allow them to ingest the food with- eosinophilic esophagitis. Cutaneous findings, such as atopic
out anaphylaxis symptoms. There are a variety of clinical trials dermatitis, can also be a manifestation of a non-IgE-mediated
currently underway to assess the different methods of immu- reaction to food. The distinction between the true potential for
notherapy. For OIT, dosing is increased slowly in 2–4-week fatal anaphylaxis versus no potential for death with ingestion is
intervals until a top maintenance dose is achieved. OIT has an important one for families to understand. If symptoms are
been used in milk, egg, wheat, peanut, tree nut, and shellfish consistent with non-IgE-mediated food allergies, the family
allergies. An assessment of the efficacy of OIT with peanut should be counseled about the lack of risk of death from ana-
allergy desensitization was assessed in a phase 2 randomized phylaxis. Strict avoidance is not always necessary in this case.
controlled trial published in Lancet 2014. Desensitization was Avoidance of ingestion of large quantities of the food may be
noted in 62% (24 of 39 participants) in the peanut OIT group, preferred in non-IgE-mediated food allergy.
and none of the control group (0 of 46) tolerated 800 mg pro- Many patients and some physicians believe a positive test is
tein daily. Following that, 54% tolerated a 1400-mg challenge always consistent with true food allergy. Evidence of food sen-
and 91% tolerated daily ingestion. Furthermore, the quality-of- sitization, the presence of a positive SPT wheal or food-specific
life scores improved. This study shows that a patient’s quality IgE (fsIgE), does not necessarily correlate with clinical reactiv-
of life can improve after oral immunotherapy treatment [61]. ity [65, 66]. Furthermore, a positive SPT or food sIgE, cannot
predict the severity of a clinical reaction [67, 68]. Therefore,
b. Epicutaneous immunotherapy test results alone should not be considered diagnostic when
determining whether a patient has a food allergy. It is important
Epicutaneous immunotherapy (EPIT) is a second type of to obtain an accurate clinical history and utilize the information
immunotherapy currently under evaluation for food allergy from SPT and sIgE testing, in order to determine the probability
treatment. It involves placing a patch with food allergen on for a successful oral food challenge. The magnitude of the SPT
the skin to promote systemic tolerance. The food allergen is and/or sIgE for the food, can help predict whether an individual
absorbed through the skin. Randomized double-blind place- may have a clinical reaction and cut-off values have been de-
bo-controlled studies have shown the efficacy for peanut al- termined for milk, egg, peanut, and fish [35, 69–71].
lergy for this treatment to induce systemic tolerance to peanut, Another misconception is that fish allergy is applicable
after 12 months of therapy [62, 63]. to all species if a patient is diagnosed with allergy to one
species. Patients allergic to certain fish may not experi-
c. Sublingual immunotherapy ence clinical reactions to all species of fish. Parvalbumin,
which is the most common allergenic protein in fish, has a
Sublingual immunotherapy (SLIT) is a third of immuno- different chemical structure depending on the species of
therapy currently being explored for food allergy treatment. fish. There are different specific IgE epitope recognition
Food proteins are placed under the tongue in increasing doses. patterns of the protein, therefore an individual may not be
A randomized double-blind placebo-controlled pilot study of allergic to other species of fish if they do not produce IgE
sublingual versus OIT in peanut allergy assessed 21 subjects. to the exact same parvalbumin epitope [72]. Clinical
There was a 10-fold increase in food challenge threshold after cross-reactivity also does not frequently occur with shell-
12 months in all the patients completing the treatments. The fish and mollusks. The vast majority of crustacean-
threshold was significantly greater in active OIT group. allergic patients are not allergic to mollusks [73].
Although adverse reactions were more common with OIT Another misconception is that allergy to one tree nut
over SLIT, the skin testing as well as blood testing for IgE means all nuts should be avoided. Recent studies have
had significant changes [64]. demonstrated that patients allergic to tree nuts are not
necessarily allergic to all tree nuts [74, 75]. Although Open Access This article is distributed under the terms of the Creative
Commons Attribution 4.0 International License (http://
avoidance of all tree nuts could be due to risk of cross- creativecommons.org/licenses/by/4.0/), which permits unrestricted use,
contamination, there are multiple products available now distribution, and reproduction in any medium, provided you give appro-
manufactured in single tree nut allergen factories. priate credit to the original author(s) and the source, provide a link to the
Unfortunately, the responsibility to ensure these products Creative Commons license, and indicate if changes were made.
are free of other allergens falls on the patient, because the
labeling laws do not mandate labeling of specific tree
nuts. It is important that a history of an adverse reaction
to a tree nut be thoroughly investigated and SPT and sIgE
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Compliance with Ethical Standards
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IgE-Mediated Food Allergy

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Clinical Reviews in Allergy & Immunology (2019) 57:244–260

IgE-Mediated Food Allergy

Published online: 29 October 2018

Introduction disease, allergic contact dermatitis, and food protein-induced

Table 1 Clinical manifestations of IgE-mediated food allergy by organ system

Organ systems Symptoms Mild Moderate Severe

Skin Rash Faint erythema Erythema Generalized marked erythema (more

Table 2 Definition of anaphylaxis anaphylaxis occurs when symptoms of laryngeal, uvular, or

Table 3 World allergy organization grading and definition of types of anaphylaxis

sacrifices. Identifying these consequences of food allergies c. Dietician consultation

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