Clinical reviews in allergy and immunology
Series editors: Donald Y. M. Leung, MD, PhD, and Dennis K. Ledford, MD
Food allergy: Epidemiology, pathogenesis, diagnosis, and
treatment
Scott H. Sicherer, MD, and Hugh A. Sampson, MD New York, NY
INFORMATION FOR CATEGORY 1 CME CREDIT
Credit can now be obtained, free for a limited time, by reading the review
articles in this issue. Please note the following instructions.
Method of Physician Participation in Learning Process: The core ma-
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Date of Original Release: February 2014. Credit may be obtained for
these courses until January 31, 2015.
Copyright Statement: Copyright 2014-2015. All rights reserved.
Overall Purpose/Goal: To provide excellent reviews on key aspects of
allergic disease to those who research, treat, or manage allergic disease.
Target Audience: Physicians and researchers within the field of allergic
disease.
Accreditation/Provider Statements and Credit Designation: The
American Academy of Allergy, Asthma & Immunology (AAAAI) is ac-
credited by the Accreditation Council for Continuing Medical Education
(ACCME) to provide continuing medical education for physicians. The
AAAAI designates this journal-based CME activity for a maximum of 1
AMA PRA Category 1 Credit. Physicians should claim only the credit
commensurate with the extent of their participation in the activity.
This review focuses on advances and updates in the
epidemiology, pathogenesis, diagnosis, and treatment of food
allergy over the past 3 years since our last comprehensive
review. On the basis of numerous studies, food allergy likely
affects nearly 5% of adults and 8% of children, with growing
evidence of an increase in prevalence. Potentially rectifiable risk
factors include vitamin D insufficiency, unhealthful dietary fat,
obesity, increased hygiene, and the timing of exposure to foods,
but genetics and other lifestyle issues play a role as well.
Interesting clinical insights into pathogenesis include discoveries
regarding gene-environment interactions and an increasing
understanding of the role of nonoral sensitizing exposures
causing food allergy, such as delayed allergic reactions to
carbohydrate moieties in mammalian meats caused by
sensitization from homologous substances transferred during
From the Elliot and Roslyn Jaffe Food Allergy Institute, Division of Allergy and
Immunology, Kravis Childrens Hospital, Department of Pediatrics, Icahn School of
Medicine at Mount Sinai, New York, NY.
Received for publication November 4, 2013; revised November 25, 2013; accepted for
publication November 25, 2013.
Available online December 31, 2013.
Corresponding author: Scott H. Sicherer, MD, Division of Allergy/Immunology, Mount
Sinai Hospital, Box 1198, One Gustave L. Levy Place, New York, NY 10029-6574.
E-mail: scott.sicherer@mssm.edu.
0091-6749/$36.00
2013 American Academy of Allergy, Asthma & Immunology
http://dx.doi.org/10.1016/j.jaci.2013.11.020
List of Design Committee Members: Scott H. Sicherer, MD, and Hugh
A. Sampson, MD
Activity Objectives
1. To describe the current epidemiology of food allergy.
2. To learn pearls and pitfalls regarding the diagnosis of food allergy.
3. To understand the management of food allergy, including attention to
quality-of-life issues.
Recognition of Commercial Support: This CME activity has not
received external commercial support.
Disclosure of Significant Relationships with Relevant Commercial
Companies/Organizations: S. H. Sicherer is on the American Board of
Allergy and Immunology; has received consultancy fees from Novartis and
Food Allergy Research & Education; has received research support from the
National Institute of Allergy and Infectious Diseases (NIAID) and Food Al-
lergy Research & Education; and receives royalties from UpToDate. H. A.
Sampson has received research support from the NIAID/National Institutes
of Health and Food Allergy Research & Education; has received travel sup-
port as Chair of the PhARF Award review committee; has received consul-
tancy fees from Allertein Therapeutics and Regeneron; and has received
lecture fees from Thermo Fisher Scientific, UCB, and Pfizer.
tick bites. Component-resolved diagnosis is being rapidly
incorporated into clinical use, and sophisticated diagnostic tests
that indicate severity and prognosis are on the horizon. Current
management relies heavily on avoidance and emergency
preparedness, and recent studies, guidelines, and resources
provide insight into improving the safety and well-being of
patients and their families. Incorporation of extensively heated
(heat-denatured) forms of milk and egg into the diets of children
who tolerate these foods, rather than strict avoidance,
represents a significant shift in clinical approach.
Recommendations about the prevention of food allergy and
atopic disease through diet have changed radically, with
rescinding of many recommendations about extensive and
prolonged allergen avoidance. Numerous therapies have
reached clinical trials, with some showing promise to
dramatically alter treatment. Ongoing studies will elucidate
improved prevention, diagnosis, and treatment. (J Allergy Clin
Immunol 2014;133:291-307.)
Key words: Food allergy, food hypersensitivity, oral tolerance,
gastrointestinal food hypersensitivity, food allergens, anaphylaxis
Discuss this article on the JACI Journal Club blog: www.jaci-
online.blogspot.com.
This article is an update to our comprehensive review of the
diagnosis and management of food allergy published in 2010.1
291
292 SICHERER AND SAMPSON
Abbreviations used
AD: Atopic dermatitis
APT: Atopy patch test
CMA: Cows milk allergy
COFAR: Consortium of Food Allergy Research
CRD: Component-resolved diagnostics
EHCF: Extensively hydrolyzed casein formula
EoE: Eosinophilic esophagitis
FLG: Filaggrin
a-Gal: Galactose-a-1,3-galactose
LR: Likelihood ratio
NHANES: National Health and Nutrition Examination Survey
OFC: Oral food challenge
OR: Odds ratio
sIgE: Allergen-specific serum IgE
PPV: Positive predictive value
SPT: Skin prick test
Since that publication, an expert panel sponsored by the National
Institute of Allergy and Infectious Diseases defined food allergy
as an adverse health effect arising from a specific immune
response that occurs reproducibly on exposure to a given food
and food intolerance as nonimmune reactions that include
metabolic, toxic, pharmacologic, and undefined mechanisms.2
We encourage readers seeking an overview to refer to practice
parameters, guidelines, and international consensus papers that
emphasize key points in the diagnosis and management of food
allergy3-5 and related disorders.6,7 Companion articles in this
issue of the Journal focus on oral, sublingual, and epicutaneous
immunotherapy8 and insights obtained from murine models of
food allergy,9 and therefore we will not review these topics in
detail. We highlight recent clinical observations and advances
that inform prevention, diagnosis, and management now and,
hopefully, in the near future.
EPIDEMIOLOGY AND NATURAL HISTORY
Prevalence
Accurate determinations of food allergy prevalence are elusive
because factors such as allergy definitions, study populations,
methodologies, geographic variation, ages, dietary exposures,
and other factors influence the estimates.10 A comprehensive
review of the literature concluded that food allergy affects
more than 1% to 2% but less than 10% of the population and
that it remains unclear whether the prevalence is increasing.11
A number of recent studies provide spectacularly high estimates
of food allergy. Gupta et al12 used an electronic US household
survey (n 5 38,480) in 2009-2010 and estimated that 8% of
children have food allergy, 2.4% have multiple food allergies,
and approximately 3% experience severe reactions. Soller
et al13 surveyed 9667 subjects from 10 Canadian provinces for
self-reported food allergy and found an overall rate of 8%.
When they excluded adults reporting unlikely allergies and
adjusted for nonresponders, the final estimates were 6.7% in the
overall population, with 7.1% of children and 6.6% of adults
reporting food allergy. Cows milk (2.2%), peanut (1.8%), and
tree nuts (1.7%) were the most common allergens in children,
and shellfish (1.9%), fruits (1.6%), and vegetables (1.3%) were
the most common allergens in adults. Taking a different perspec-
tive using food allergenspecific serum IgE (sIgE) results
J ALLERGY CLIN IMMUNOL
FEBRUARY 2014
obtained in the National Health and Nutrition Examination Sur-
vey (NHANES) in the United States (2005-2006), Liu et al14 esti-
mated clinical allergy to cows milk, egg, and peanut at 1.8% each
in children age 1 to 5 years. The 2 most recent NHANES
performed from 2007-2010 with 20,686 US participants included
queries on self-reported food allergies. Overall, 8.96% reported
food allergy, with 6.53% among children.15 Self-report or
reliance on serology is notoriously inaccurate,15,16 but few studies
include oral food challenges (OFCs) on a population level.
Osborne et al17 evaluated a population-based cohort of 2848
(73% participation rate) 1-year-old infants in Melbourne,
Australia, in a study that included OFCs and estimated prevalence
as follows: peanut, 3.0%; raw egg, 8.9%; and sesame, 0.8%.
A United Kingdom study on early childhood peanut allergy,
which included OFCs, estimated a peanut allergy prevalence of
2% at age 8 years.18 A population-based study on the prevalence
of cows milk proteininduced enterocolitis syndrome revealed a
cumulative incidence of 0.34% (44/13019) in Israel.19 Taken
together, these studies substantiate food allergy rates nearing
5% in adults and approaching 8% in children, with a number of
estimates nearing 2% for peanut allergy. Whether perceived
or confirmed allergy, the economic,20,21 emotional,22 and safety
burden is substantial.
Data generally support an increase in prevalence. A 2013 data
brief from the US Centers for Disease Control and Prevention
relying on data from a single question in the US National Health
Interview Survey concluded that among children age 0 to 17
years, the prevalence of food allergies increased from 3.4% in
1997-1999 to 5.1% in 2009-2011.23 Estimates based on a single
query are suspect, but a number of pediatric studies also support
an increased prevalence. A US survey24 repeated on 3 occasions
presented the opportunity to compare results from 1997 to
2008 in surrogate-reported peanut allergy in children. The
rate increased significantly from 0.4% to 1.4%. Limitations
of the studies included decreasing participation rates and
self-assessment of allergy. However, as indicated above, similar
or higher rates of peanut allergy were determined in a number
of studies using various methodologies, including OFCs, around
the same period. Additional recent publications focusing on
peanut allergy indicated increases with a doubling (United
Kingdom)25 or tripling (United States)26 in diagnoses.
A cross-sectional study of infants from a single clinic in China
over a 10-year period used OFCs for diagnosis and estimated an
increase in food allergy from 3.5% to 7.7% (P 5 .17).27
Although there are methodological limitations, the impression
of an international increase in allergy and food allergy remains
strong.3,10
Risk factors
A plethora of risk factors are proposed to influence food
allergy or sensitization, including sex (male sex in children),
race/ethnicity (increased among Asian and black children
compared with white children), genetics (familial associations,
HLA, and specific genes), atopy (comorbid atopic dermatitis
[AD]), vitamin D insufficiency, dietary fat (reduced consumption
of omega-3-polyunsaturated fatty acids), reduced consumption of
antioxidants, increased use of antacids (reducing digestion of
allergens), obesity (being an inflammatory state),28 increased
hygiene, and the timing and route of exposure to foods
(increased risk for delaying allergens with possible environmental
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sensitization).29,30 Some of these factors might provide opportu-
nities for prevention or treatment.
Recent studies provide additional insights regarding risk
factors. For example, a study evaluating 3136 children and
adolescents in the 2005-2006 NHANES found that vitamin D
levels of less than 15 ng/mL compared with levels of greater than
30 ng/mL were associated with an increased risk (P <.005) of pea-
nut sensitization (odds ratio [OR], 2.39; 95% CI, 1.29-4.45).31 An
Australian study32 using a well-characterized cohort undergoing
OFCs showed a latitude gradient for IgE-mediated egg and peanut
allergy, with higher rates in regions farther from the equator with
less ambient UV radiation. Additional studies supporting the
vitamin D hypothesis include the following: season of birth is a
risk factor,33 pediatric food-induced anaphylaxis is more common
in northern areas of the United States,34 vitamin D sufficiency is
protective against food allergy,35 and maternal intake of vitamin
D during pregnancy is associated with decreased risk of food
sensitization.36 Not all studies support the theory; for example,
Weisse et al37 reported 378 mother-infant pairs studied in a
German cohort in which increased maternal vitamin D levels
were associated with the children receiving a diagnosis of food
allergy (OR, 3.66; 95% CI, 1.36-9.87). Controlled trials will be
needed to determine whether interventions can affect outcomes.38
In the past several years, attention has shifted from assumptions
that early infant allergen exposure was a risk factor for food
allergy to the opposite notion that prolonged allergen avoidance
might be a risk factor because oral tolerance induction would be
bypassed while alternative sensitizing routes of exposure,
particularly through the skin (especially nonintact inflamed
epidermis in patients with AD), was ongoing. Epidemiologic
studies have mostly continued to support this hypothesis, which is
discussed further below in the context of approaches to allergy
prevention.39-41
A number of risk factors are immutable but might provide
insights into the cause. Boys appear to be at higher risk than
girls14 and perhaps women more than men,42 suggesting genetic
or endocrinologic influences. One study showed a higher risk for
increased affluence,25 suggesting lifestyle influence. Racial and
ethnic differences in food allergies are being increasingly
explored. In telephone surveys shellfish allergy was reported at
a significantly higher rate among black/African American than
white subjects (3.1% vs 1.8%).42 Non-Hispanic black subjects
also had increased risks of having serologic results, indicating
likely food allergy in the NHANES study (OR, 3.1).14 An inter-
esting example is the very high rate of shellfish sensitization
among inner-city atopic children, which might relate to exposure
to cross-reactive proteins in cockroach, the clinical ramifications
of which remain mostly unexplored.43,44 Keet et al45 used data
from NHANES 2005-2006 to investigate how sensitization to
foods in those less than 21 years of age related to being born in
or outside of the United States and the age of immigration.
They found that US-born children were at greater risk (OR,
2.05; 95% CI, 1.5-2.8; P < .001), and among those born outside
the United States, arriving before age 2 years was a risk factor
(OR, 2.68; 95% CI, 1.2-6.1; P < .02); however, among children
born in the United States, children of immigrants were at higher
risk. These findings suggest a relative environmental risk factor
for US residents but also indicate a complex interaction of ge-
netics and environment.
Exposure to microbes might also influence food allergy risk.
For example, Kusunoki et al46 evaluated 11,454 Japanese children
SICHERER AND SAMPSON 293
by means of a survey and found food allergy decreased with
increasing birth order, possibly reflecting exposure to more infec-
tion from siblings. The NHANES database was used to evaluate
rates of food sensitization against urinary levels of endocrine-
disrupting compounds, and only the compound triclosan, which
has an antimicrobial effect, was associated with an increased
risk for food sensitization (among male subjects).47 However, in
a systematic review of studies looking at microbial exposure in-
fluence on food allergy, including cesarean section, having sib-
lings, attending childcare, and treatment with probiotics, there
was a lack of clear evidence to support microbial protection and
too much study heterogeneity for a meta-analysis.48 Although a
murine model recently provided impressive evidence of the influ-
ence of the microbiota on food allergy,49 more human studies are
needed.
Studies focusing on food allergy outcomes also identify
combinations of factors that conspire to define risk. Koplin
et al50 evaluated 453 Australian infants with egg allergy
confirmed by using OFCs from a population-based sample of
5276 infants and identified a number of risk factors: parental or
sibling allergy history and parents born in East Asia rather than
Australia, as well as protective factors, such as older siblings
and having a dog in the home. Du Toit et al,51 in preparing a cohort
of 4- to 10-month-olds for evaluation of the effect of early intro-
duction of peanut on peanut allergy, noted that egg allergy and se-
vere eczema were the strongest predictors of peanut sensitization.
Comorbidities might identify patients at risk for increased food
allergy morbidity. For example, several studies have indicated
that having food allergy might be a risk for problematic asthma
and having asthma might be a risk for severe/fatal food
allergy.14,52,53 Overall, the risk factors discussed add insights
about outcomes and provide avenues for prevention, such as pro-
biotics, and possibly future treatments, such as nutritional
interventions.
Natural course
The course of resolution of food allergy has been well
characterized and recently reviewed.3 In general, childhood
food allergies to milk, egg, wheat, and soy typically resolve dur-
ing childhood, whereas allergies to peanut, tree nuts, fish, and
shellfish are persistent. Prognosis also varies by disorder; for
example, food allergyrelated eosinophilic esophagitis (EoE)
appears to have a relatively poor chance of resolution.54 There
is evidence that resolution rates have slowed for allergies that
have been commonly outgrown, such as those to milk, egg,
wheat, and soy. For example, Savage et al55 reported in a referral
practice that soy allergy resolved in 25% by age 4 years, 45% by
age 6 years, and only 69% by age 10 years.
Early prediction of future tolerance would be useful in planning
whether to apply immunotherapeutic interventions and to provide
personalized insights on prognosis. Higher early sIgE levels
appear to carry a poorer prognosis than lower values, and
decreases in these test results over time might signal resolution.56
The possibility of providing long-term prognostic information
based on early markers is evolving. Elizur et al57 reported on 54
children with IgE-mediated cows milk allergy (CMA) who
were identified in a population-based study and followed for as
long as 5 years. Thirty-one (57.4%) infants resolved their allergy,
and risk factors for persistence included a reaction to less than 10
mL of milk on OFC (or on first exposure, P 5 .01), a larger skin
294 SICHERER AND SAMPSON
prick test (SPT) wheal size (P 5 .014), and age of 30 days or less
at the time of the first reaction (P 5 .05). Early markers of
resolution of CMA were also evaluated in the Consortium of
Food Allergy Research (COFAR) observational study in which
154 (52.6%) subjects experienced CMA resolution at a median
age of 63 months.58 Baseline (age, 3-15 months) characteristics
that were most predictive of resolution included milk sIgE levels,
SPT-induced wheal sizes, and AD severity (all P < .001).
A calculator to estimate resolution probabilities using these
frequently obtained variables was devised for use in the clinical
setting when evaluating children 3 to 15 months of age (available
at www.cofargroup.org), although more validation is needed.
Advanced tests evaluating the specific proteins to which IgE binds
in a food, the epitopes within the protein that are recognized, and
the affinity of binding might carry additional prognostic indica-
tors.59-61 Additional studies, perhaps combining clinical and
additional laboratory investigations, might provide more insight
into prognostication.
PATHOGENESIS
There is a complex interplay of environmental influence and
genetics that underlie the immunopathogenesis of food allergy
and the manifestations of various food-induced allergic disorders.
In this issue of the Journal, Oyoshi et al9 describe insights on
etiology determined from murine models. Prior reviews address
the role of antigen-presenting cells, T cells, humoral immune
responses, homing receptors, signaling pathways, dietary factors,
underlying inflammatory states, microbiota, effector cell func-
tion, and other aspects of the immune response to dietary
antigens.62-67 Here we consider several observations from clinical
studies that have recently revised our understanding of the cause
of food allergy.
Elucidating gene-environment interactions is crucial for un-
derstanding pathogenesis. For example, in a prospective study of
970 children, breast-feeding was associated with an increased risk
of food sensitization, but the effect was dependent on functional
genetic variants in the IL-12 receptor b1, Toll-like receptor 9, and
thymic stromal lymphopoietin genes.68 In another study taking a
deeper look at the vitamin D hypothesis, Liu et al69 evaluated a
Boston birth cohort (n 5 649) and did not find an association of
cord blood vitamin D levels with sensitization to food allergens
in early childhood. However, when examined with candidate
gene single nucleotide polymorphisms, a significant interaction
indicating a risk for sensitization was identified for an IL4 gene
polymorphism and 3 other genes.
The microbiome is emerging as an important internal pathogenesis. This might go beyond the notion that heating
environmental exposure,70 and treatment with prebiotics and pro-
biotics is an avenue of therapy in response to this influence. The
immune consequences are slowly being elucidated. Forsberg
et al71 reported on children undergoing probiotic supplementation
in a controlled trial and found that this supplementation was asso-
ciated with decreased allergen-induced production of IL-5 and
IL-10 and higher levels of ovalbumin-induced CXCL10 at birth
and CCL17 at 24 months, suggesting a greater capacity for im-
mune regulation.
The key immune factors responsible for allergy outcomes are
under intense investigation. In the COFAR cohort described
above,72 mononuclear cell allergen stimulation screening was
performed with PCR analysis to 7 key markers of immune regu-
lation and TH1/TH2 bias. Only allergen-induced IL4 expression
J ALLERGY CLIN IMMUNOL
FEBRUARY 2014
was associated with clinical allergy to milk and sensitization to
milk and peanut. This was noted in the absence of increased
GATA3 mRNA expression, identifying a potential marker but
also raising a question about the IL-4 not being of T-cell origin.
The importance of considering the route of sensitization on
food allergy has been recently highlighted,73 such as sensitization
through nonoral routes. It has long been appreciated that respira-
tory sensitization can result in food allergy, as demonstrated by
pollen-foodrelated allergies, as well as some more esoteric ex-
amples, including cat-porkrelated allergy (pork meat allergy
attributed to initial environmental sensitization to cat serum albu-
min)74 and wheat allergy induced by using wheat proteinbased
soap.75 Here again environment and genetics conspire. Skin expo-
sure to environmental food allergens might be a sensitizing route,
particularly when there is epithelial barrier dysfunction, such as in
those with AD.76 This theory was supported by a study showing
that filaggrin (FLG) loss-of-function mutations are associated
with peanut allergy, and interestingly, the association remained
significant (P 5 .0008) after controlling for coexistent AD.73
FLG loss-of-function mutations were determined in a subset
(n 5 700) from a large cohort that was extensively tested for
sensitization and clinical food allergy.77 After adjusting for
eczema, FLG mutations were associated with food sensitization
(OR, 3.0; 95% CI, 1.0-8.7; P 5 .043). However, after adjustment
for risk of clinical food allergy among those sensitized, there was
no further influence of FLG mutations, suggesting this mutation is
not playing a role in progression of sensitization to clinical
allergy.
A very interesting and novel form of food allergy that is
manifested clinically by delayed allergic responses and anaphy-
laxis hours after ingestion of mammalian meat has been linked
to sensitization to carbohydrate galactose-a-1,3-galactose (a-
Gal).78 The route of sensitization appears to be from tick bites
based on clinical circumstances and detection of a-Gal in the
gut of the tick Ixodes ricinus.79-81 The a-Gal epitope is a major
blood group substance of nonprimate mammals, and there is
likely a predilection for sensitization among those with
B-negative blood groups.82 The reason for the delayed reactions
remains to be elucidated. Thus a-Gal allergy is unique for the
allergen being a carbohydrate, the exposure being through the
intracutaneous route, and the time course of the reaction being
delayed. Elucidating these factors further will likely provide
more insights on the pathophysiology of other food allergies
as well.
The manner of food preparation and processing and the
nonprotein components of foods also likely play a role in
destroys some relevant food allergens, such as birch homologous
proteins in fruits or tertiary protein structures in milk or egg, or
creates more potent allergens, such as through the Maillard
reaction of nonenzymatic browning in which heating results in a
chemical reaction between reducing sugars and proteins to form
advanced glycation end-products in roasted peanut.83 For
example, invariant natural killer T cells can be activated by sphin-
golipids presented through CD1d molecules to produce TH2 cyto-
kines, raising the possibility that these components in foods might
direct an allergic response to foods. In a series of experiments
comparing PBMC responses from children with CMA, egg
allergy with tolerance of milk, and healthy control subjects,
Jyonouchi et al84 showed that milk sphingomyelin can induce
invariant natural killer T-cell activation and TH2 cytokine
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production and that the response is more exuberant in children
with CMA. Ilchmann et al83 observed that heating ovalbumin
with glucose enhanced activation of ovalbumin-specific CD41
T cells and increased IL-4 levels. Myeloid dendritic cell uptake
of the processed ovalbumin was enhanced, and specific dendritic
cell receptors were identified that mediated the process. Masila-
mani et al85 showed that dietary isoflavones suppressed allergic
sensitization to peanut; these are abundant in soy and not peanut,
perhaps explaining why one legume is more allergenic than
another. These observations and others86 set the stage for addi-
tional work to identify characteristics of foods that promote
allergic responses and might elucidate immune intervention
strategies.
DIAGNOSIS
The overarching approach to diagnosis requires a careful
history linked to an understanding of the clinical manifestations,
an understanding of the epidemiology and immune cause, and
incorporation and interpretation of appropriate tests.1,2 A detailed
familiarity with the gamut of food-induced allergic disorders
and their pathophysiology is necessary to achieve a successful
diagnosis.
Clinical disorders
The National Institute of Allergy and Infectious Diseases
Expert Panel identified 4 categories of immune-mediated adverse
food reactions (eg, food allergies), namely IgE-mediated, non
IgE-mediated, mixed, or cell-mediated reactions, and placed
celiac disease among nonIgE-mediated disorders and allergic
contact dermatitis among cell-mediated disorders.2 Considering
that various target organs can be affected by food allergies (eg,
the skin, gut, respiratory tract, and cardiovascular system) and
the numerous immune pathologies, a wide spectrum of disease
falls under the umbrella of food allergies. Table E1 in this articles
Online Repository at www.jacionline.org shows clinical disor-
ders, their key features, immunopathophysiology, natural course,
and diagnostic considerations.1,2,78,87-89 There are a number of
disorders that are not food allergies but might appear similar.
For example, toxic reactions, such as scombroid fish poisoning,
in which spoiled dark meat fish contains histamine-like toxins;
neurologic responses, such as auriculotemporal syndrome, in
which foods that trigger increased salivation also result in a reflex
facial vasodilation of the lower cheek; or gustatory rhinitis, in
which spicy foods result in rhinorrhea, all mimic food allergies.
It is important to recognize that chronic asthma and chronic
rhinitis are not likely solely related to food-induced allergic
reactions. Similarly, although food can trigger AD in a subset
of patients, many additional triggers exist, including irritants,
infection, and environmental allergens.
Recent studies have further elucidated the important role of
foods in patients with EoE. Henderson et al90 evaluated their di-
etary approach using 98 children with EoE and found remission
for 96% among 49 patients treated with an elemental diet, 81%
for 26 patients on a 6-food elimination diet (2 variations were
used, with avoidance of milk, egg, wheat, soy, peanuts, tree
nuts, fish, and shellfish for all, and 15 avoided additional foods
that resulted in positive test results), and 65% for 23 patients
whose diets were determined by SPTs, atopy patch tests
(APTs), or both. Similarly, Kagalwalla et al91 used a 6-food
SICHERER AND SAMPSON 295
elimination diet with 36 children, finding that one food was a
trigger for 72% and that milk (74%), wheat (26%) and egg
(16%) were the 3 most common causes.
Spergel et al92 performed a review of 941 patients, of whom
319 had definitive food-responsive disease diagnosed based on bi-
opsy results. An empiric 6-food elimination diet or removal of
foods eliciting positive test results had a success rate of 53%,
although test-directed diets resulted in an average of only 3 foods
removed. Milk, egg, wheat, and soy were the most common cul-
prits. Removal of foods identified on skin testing with empiric
elimination of milk led to resolution in 77% of patients, milk
alone had a 30% response, and milk, egg, wheat, soy, and meats
had a 77% response rate. Lucendo et al93 used a food elimination
diet for 67 adults, avoiding milk, egg, cereals, fish/shellfish, pea-
nut/legumes, and soy with a 73% response rate. Reintroducing
foods revealed that 36% of the responding patients had 1 trigger
and 31% had 3 or more triggers. Overall, although there is
some debate about the utility of diagnostic tests,6 a diagnosis of
EoE should raise suspicion about food triggers, with a motivation
to attempt dietary treatment.
Diagnostic approaches
The general approach to diagnosis of food allergy has been
reviewed previously.1 Modalities that were recommended in the
2010 Expert Panel Guidelines include medical history and phys-
ical examination, elimination diets, SPTs, sIgE measurements,
and OFCs.2 Among tests not recommended or not recommended
for routine use were intradermal tests, total serum IgE measure-
ments, APTs, and the use of APTs, sIgE measurements, and
SPTs in combination, and a number of nonstandardized and
unproved tests were specifically not recommended, including
measurement of basophil histamine release, applied kinesiology,
allergen-specific IgG4 measurement, electrodermal testing, and
several others.
Since the time of the expert panel guidelines, a number of
studies have refined the way currently available testing can be
used, including the next generation of sIgE tests, those evaluating
components or specific proteins within foods, often termed
component-resolved diagnostics (CRD). However, the basic
approach to diagnosis remains essentially unchanged and is
summarized in Fig 1. The medical history is used to estimate the
chance (prior probability) of allergy and culprit food(s), and appro-
priately selected and interpreted minimally invasive tests are used
to arrive at a posttest probability of allergy.94 Short of a conclusion
that there is a high probability or extremely low probability of al-
lergy, an OFC might be required for a final diagnosis. Allergists
appear to avoid performing OFCs, apparently because of risk,
cost, time, and other factors.95 However, it is crucial to include
OFCs in the diagnostic armamentarium. Recent studies underscore
why. Concerning efficacy, in a study of 125 children primarily with
AD who were avoiding foods for a variety of reasons, 89% of 364
OFC results were negative, allowing significant dietary expan-
sion.96 Regarding safety, an office-based study of 701 OFCs had
19% positive challenge results, with only 2% of the challenges
requiring treatment with epinephrine.97 Additionally, performing
OFCs can improve quality of life, particularly when results are
favorable.98 It is important to ensure a full portion of the tested
food is successfully ingested to reduce the risk that an uneventful
OFC is followed by allergic reactions on a subsequent ingestion,
which theoretically could be due to gradual escalating portions
296 SICHERER AND SAMPSON
FIG 1. General approach to diagnosis of adverse reactions to foods. See text and Tables 1 and E1 for details.
that result in temporary desensitization.99 A manual for office-
based OFCs100 was devised, and a consensus report toward
standardizing double-blind, placebo-controlled OFCs was pub-
lished.101 In 2013, 2 new Current Procedural Terminology codes
replaced a single prior code for OFCs, likely improving reimburse-
ment, and hopefully resulting in increased use of the procedure.
Clearly, physicians and patients would prefer to have better
diagnostic tests to avoid OFCs. Standard SPTs and sIgE tests go a
long way in assisting in diagnosis. Lessons learned from a number
of studies are compiled in Table I,1,2,92,94,100,102-112 showing
pearls and pitfalls. Unfortunately, there remain relatively few
studies correlating food allergy outcomes against skin test size
or sIgE concentration, and it is clear that such calculations are
influenced by referral base, decisions to undergo testing by
patient/family and physician, geography, test characteristics,
interpretation of OFC outcomes, age of patients, underlying
disease, and other factors.100 For example, in a unique
population-based Australian cohort of infants who underwent
testing and OFCs, 95% predictive values for allergic reactions
were determined as follows: egg (SPT wheal, > _4 mm; sIgE level,
_1.7 kUA/L), peanut (SPT wheal, >
> _8 mm; sIgE level, >
_34 kUA/L,
when history is not taken into consideration), sesame (SPT wheal,
_8 mm),102 and these results vary from those of studies with other
> to component proteins might disclose relevant reactivity. However,
cohorts.1 Additional recent observations of clinical note are that
fresh fruits can be frozen and then reused for fresh skin
testing104 and that a sesame oil contact test might be helpful
to identify patients who are reactive to sesame proteins that are
J ALLERGY CLIN IMMUNOL
FEBRUARY 2014
oil based (oleosins) and might otherwise have negative test results
with standard reagents.105 Although evaluating sIgE in the context
of total IgE is not recommended based on one study,113 another
recent study114 noted correlations in total to specific IgE levels
for children tested to egg, milk, soy, and peanut, and another noted
that consideration of total IgE levels was helpful in predicting al-
lergy in combination with other parameters.115 More studies are
needed to elucidate whether evaluating ratios of levels of
sIgE to total IgE is informative over sIgE levels alone. For
nonIgE-mediated allergy, the utility of the APT for
EoE remains controversial,90,92 but studies now suggest the
approach does not elucidate reactivity in food proteininduced
enterocolitis.87,88
The increasing availability of CRD is further refining the
diagnosis of IgE-mediated allergy. The reasons that evaluating IgE
binding to specific proteins within a food might provide additional
diagnostic information includes the following possibilities: (1)
recognition of specific proteins that behave as potent allergens (ie,
ones that are stable to digestion) might be relevant compared with
recognition of proteins that are heat labile or homologous to pollens;
(2) binding to multiple proteins within an allergen might carry
diagnostic significance; and (3) differentiation of degrees of binding
the methods suffer from some of the same limitations that the
standard tests carry. For example, the degree of binding is relevant,
specific test platforms might differ, and there could be differences by
geography, age, and target organ reactivity. More studies are needed
J ALLERGY CLIN IMMUNOL
VOLUME 133, NUMBER 2
TABLE I. Pearls and pitfalls regarding diagnosis of food allergy1,2,94,100,102-112
Pearl/observation
A positive skin test or serum
food-specific IgE test result
indicates sensitization but not
necessarily clinical allergy.
Dose, manner of preparation, and
ancillary (eliciting) factors
might alter reaction outcomes.
IgE binding to homologous
proteins among food groups
and between foods and pollens
might have variable clinical
relevance.
Tests for serum food-specific IgE
might not provide comparable
results among manufacturers.
Component testing might
differentiate clinical reactivity
(IgE binding to potent stable
allergens) from less clinically
relevant sensitization (binding
to labile proteins).
Serum/skin test results might be
negative despite clinical
reactivity.
Increasingly high serum
food-specific IgE levels or
increasingly larger skin test
wheal size indicate higher
chances of clinical allergy.
SICHERER AND SAMPSON 297
Additional details Clinical application
Screening with indiscriminate panels of tests is poorly informative. History and epidemiologic
Screening tests with common allergens that have not been ingested and tolerated but pose considerations should guide
increased risk can be considered (eg, tree nuts for a child who reacted to peanut but has not test selection.
ingested nuts). d Tolerated foods generally need
not be tested.
d Differential diagnosis should
include alternative allergen
triggers (environmental aeroal-
lergens) and nonallergic dis-
eases (eg, intolerance).
d Alcohol, NSAIDs, and exercise are among eliciting factors that might d History should focus on
facilitate a reaction. amounts triggering a reaction
d Heating might alter allergenicity (eg, bakery products with egg/milk and ancillary factors.
might be tolerated when whole forms are not and cooked fruits might d History should explore the types
be tolerated when raw fruits are not). of foods tolerated or not toler-
d A low dose might be tolerated while larger amounts are not. ated.
Rates of clinical cross-reactivity: d Care should be taken in not
overtesting.
Allergy to: Related food Approximate clinical d For some categories, food
reaction rate avoidance of entire group might
Peanut Most legumes 5% be prudent, especially to avoid
A tree nut Other tree nut 35% cross-contact in preparation, but
Higher for: walnut-pecan, individualization might be
almond-hazel, cashew- possible.
pistachio
A fish Other fish 50%
Shellfish Another shellfish 75%
Grain Another grain 20%
Milk Goat/sheep milk >90%
Mare milk 5%
Beef 10%
In the United States, there are 3 major test manufacturers. Care must be taken in evaluating test
results over time when different
manufacturers are used.
Food Labile Stable Concentration of IgE binding to
Peanut Ara h 8 Ara h 1, Ara h 2, Ara h 3, components also relates to
Ara h 6 outcomes, but similar to standard
Hazelnut Cor a 1, Cor a 2 Cor a 9, Cor a 11, Cor a 14 tests, correlations have not been
Soy Gly m 3, Gly m 4 Gly m 5, Gly m 6 established and vary by, for
example, center and patient
selection.
Caution: severe reactions can occur
despite lack of noted binding to
measured allergen (see text).
d This could be due to reagent lacking relevant protein. d Do not discount a convincing
d This could be because the reaction is not IgE mediated. history because of a negative
test result.
d Consider testing with fresh food
(prick-prick test); these can be
stored frozen.
d Be cognizant of nonIgE-medi-
ated allergic reactions.
d Correlation of tests with outcomes vary by center, age, and disease (equivalent d Test results should not be
results are generally more predictive of allergy in a younger patient). viewed solely as positive/
d Results are not highly correlated with severity. negative.
d Results can be followed over
time to monitor allergy persis-
tence/resolution.
d Specific correlative values
might not be applicable over all
patient groups.
(Continued)
298 SICHERER AND SAMPSON
TABLE I. (Continued)
Pearl/observation
At specific high levels of IgE Food
or large skin tests, clinical
reactivity is highly likely; Egg
however, studies are limited, Milk
and variations in diagnostic Peanut
cutoff values are reported.
Revised from Sicherer and Sampson.1
NSAIDs, Nonsteroidal anti-inflammatory drugs.
*
Values are kUA/L, the dual notation for peanut indictes with/without a clinical history.
to correlate test results with clinical outcomes in various patient
populations, but proof of concept has been attained for many foods,
including egg,116 milk,117 wheat,118 soy,119 fruits,120-123 shrimp,124
hazelnut,125 peanut,94,106-110 and others.
Studies on peanut provide helpful illustrations of the utility and
limitations of CRD. With regard to geographic differences, a good
example is illustrated by Vereda et al,126 who evaluated component
testing in children with peanut allergy from 3 regions, showing that
Spanish patients were primarily sensitized to lipid transfer protein
(Ara h 9), Swedish patients to birch-related protein (Ara h 8), and
US patients to seed storage proteins (Ara h 1-3). These results also
correlated with severity of outcomes, with the least severe being
related to birch sensitization and the most severe associated with
reactivity to seed storage proteins.
The predictive value of CRD is best studied for peanut allergy.
When binding is only identified to the birch protein homolog Ara h
8, prognosis is excellent. In evaluation of 144 Swedish children only
sensitized to Ara h 8, all but 1 could tolerate peanut ingestion, as
reported from natural ingestion or during OFCs to roasted pea-
nut.127 Binding to Ara h 6, which is not often measured, might be
attributed to missing the diagnosis.128 Interpretation becomes
trickier when there is binding to the stable proteins in peanut
(Ara h 1-3 or Ara h 9). Several studies have suggested that Ara h
2 is the best predictor of reactivity, with advantages over standard
peanut testing.18,129 However, the predictive value of a given result
varies among studies. For example, at an Ara h 2 concentration of 2
kUA/L, probabilities of reactions were as follows: positive predic-
tive value (PPV) of 0.96 and likelihood ratio (LR) of 50 (Australian
birth cohort; age, 1 year); PPV of 0.87 and LR of 7.8 (Netherlands
suspected allergy; median age, 6 years); and PPVof 0.75 and LR of
4.1 (US referral population; mean age, 7 years, selected for OFC at
low peanut IgE) levels. Additionally, the Ara h 2 level does not seem
to clearly predict severity.107 It is likely the case that severity is diffi-
cult to predict because variables not relevant to the test might be
involved, including dose eaten, state of health, and cellular and
target organ reactivity. However, despite earlier studies to the con-
trary,130,131 recent studies are increasingly suggesting that peanut
IgE levels might relate to severity132-134 and that CRD might add
additional information. For example, among children with persis-
tent peanut allergy in a referral population, initial peanut-specific
IgE levels of greater than 24.8 to 99.9 kUA/L had an OR of 2.0
and peanut-specific IgE levels of greater than 100 kU/L had an
OR of 3.3 compared with having an initial peanut-specific IgE level
of less than 4.8 kU/L for severe reactions.56 A number of studies
suggest that severity correlates with binding to multiple proteins,
such as several from among Ara h 1 to Ara h 3.135-137 Nonetheless,
clinicians should be cautious because binding to Ara h 1 to Ara h 3
does not necessarily diagnose a severe reaction and lack of binding
J ALLERGY CLIN IMMUNOL
FEBRUARY 2014
Additional details Clinical application
Mean age, 5 y; Mean age, 5 y; Age <2 y; d OFCs can be deferred, particu-
50% react* ;95% react ;95% react larly if there is a clinical history.
2 7 2 d When evaluating individual
2 15 5 studies, predictive values might
2/5 14 not apply to populations with
different demographic and
referral patterns.
to these proteins has been observed in some patients with severe
reactions to peanut. Of note, the predictive value of SPTs remains
competitive with these serum tests.138
As indicated above, CRD for additional foods are emerging.
With regard to milk and egg, clinical reactivity to whole or
baked forms has garnered diagnostic interest, pitting standard
tests against component testing.139,140 Considering egg, studies
have suggested that IgE binding to ovomucoid is superior to
standard tests,141,142 but there are contrary results.116 Caubet
et al143 related outcomes of baked egg OFCs to levels of
specific IgE and IgG4 to ovomucoid and ovalbumin, establish-
ing whether IgE/IgG4 ratios were additionally informative. The
rationale for this approach is that IgG4 levels increase during
successful immunotherapy. Indeed, baked eggreactive children
had higher ratios, and inclusion of IgG4 levels in logistic
regression models was more informative than sIgE levels alone.
However, standard sIgE tests provide helpful information that
should not be ignored. Lieberman et al144 reported the results
of 100 OFCs to baked egg in children, with a 66% rate of
tolerance. Measurement of serum IgE levels to egg white
and SPTs was performed. The skin test wheal size was not
informative for predicting outcomes, but an egg white sIgE
level of 2.5 kUA/L had a negative predictive value of 0.89,
and a level of 10 kUA/L had a PPV of 0.60. The median level
for those who reacted was 5.85 kUA/L compared with
2.81 kUA/L in those who were tolerant.
Ultimately, stepped approaches to testing might be the most
effective. Dang et al138 compared 5 strategies for diagnosing
peanut allergy by evaluating test parameters in 200 Australian
children with a median age of 14 months, with the test population
derived from a population-based study. They considered using
high/low diagnostic values of peanut IgE of greater than 15 or
less than 0.35 kUA/L, SPT wheal sizes of greater than 8 or less
than 3 mm, or Ara h 2 levels of greater than 1.0 or less than
0.01 kUA/L based on prior studies. Using peanut IgE alone
would have resulted in 95 OFCs, SPT alone would have resulted
in 50 OFCs, and Ara h 2 would have resulted in the need for
44 OFCs. However, a stepped approach of testing peanut IgE
followed by Ara h 2 would have reduced the need for OFCs
to 32, and SPTs followed by Ara h 2 would have reduced the
need to only 21 OFCs. In a further sophistication of using avail-
able data, Dunn Galvin et al115 showed that by using a predictive
model based on 6 parameters, SPT, serum food-specific IgE,
total IgE, symptom history, sex, and age, they could
calculate the likelihood of reactions (97% accuracy) or tolerance
(94% accuracy) to peanut, milk, and egg better than with
individual parameters. This approach was validated in another
setting.145
J ALLERGY CLIN IMMUNOL SICHERER AND SAMPSON 299
VOLUME 133, NUMBER 2

TABLE II. Management considerations (selected examples)

Area Topics Examples of educational advice, pearls, and resources

Avoidance Manufactured products Label reading each purchase, understanding labeling laws, avoidance of products with
advisory warnings
Restaurants Discuss allergy with staff, use written chef cards, educate about severity and cross-contact,
suggest methods to avoid inclusion of allergens (eg, aluminum foil on grill)
Travel Prepare ahead for extra medications, safe meals, nearby medical assistance, consider rooms
with kitchenette, carry written materials
School Written emergency plans in place, avoidance strategies (eg, craft projects), provisions for
mealtimes, field trips, substitute teachers, bus travel, delegation of care
Home Avoid cross-contact in meal preparation, organize cupboards
By age Tight supervision for toddlers; young school age taught not to take food or share; older school
age transition to read labels, speak to restaurant staff, and discuss allergy and symptoms
and therapy; teens carry and know when and how to self-treat and education of peers
Vigilance Education on always having medications ready, plans in place, ensuring safe food, medical
identification jewelry
Experimentation Specify that if there is doubt of a true allergy, ingestion should be discussed in context of
medically supervised food challenge and not home trials
Caregivers Educate all caregivers on avoidance and emergency management
Anxiety, emotional Acknowledge anxiety, potential bullying, need for balance of caution, and maintenance of a
normal lifestyle; refer for mental health support
Nutrition Nutritional counseling and growth monitoring for children
Ingestion vs noningestion Emphasize differences in risk from ingestion exposure (higher risk) vs skin contact (low risk
unless transfer to mouth) vs inhalation (depends on food and density of exposure) with
regard to potential symptom severity and treatment, taking into consideration age, specific
allergies, and circumstances of exposure
Resources (examples) References 2, 152, 157, and 161. Web sites: foodallergy.org; cofargroup.org; aaaai.org, acaai.
org, aafa.org; allergyready.com; www.cdc.gov/HealthyYouth
Emergency Carrying medications Emphasize having medications at all times, even if no planned food ingestion; make
management provisions to increase ease of carrying or access (packs, holsters, and larger purses)
Using medications Review specifics on when (symptoms) and how to use medications and alerting emergency
teams (call 911, not necessarily linked to administration of epinephrine) and educate about
safety of epinephrine and need for early administration, educate not to rely on
antihistamines or inhaled bronchodilators
Preparedness Plans tailored to age, ability to self-treat, allergy, locations, wearing medical identification
jewelry
By age Transition responsibility of anaphylaxis management gradually through preteen to teen years,
carry and know when and how to self-treat
Emergency plans Establish written emergency plans, as well as a team approach to manage a reaction
Dosing Generally transition from a 0.15-mg autoinjector to 0.3 mg around 55 lbs; for infants, weigh
options of autoinjector versus ampule/syringe
Resources (examples) Reference 2
Web sites: foodallergy.org; cofargroup.org; aaaai.org; acaai.org
Commercial autoinjector Web sites
Identification jewelry: medicalert.org
Prevention (primary) Pregnancy Healthy diet, specific allergen avoidance not recommended
Infant Breast-feed (exclusively >_4 months) if at risk of allergy (family history of allergy); if unable
to do so, consider hydrolyzed infant formula (see text); no maternal diet restrictions
recommended
Weaning Not to delay solids beyond 4-6 months, includes allowing allergenic foods (not necessarily as
weaning foods, however)
Resources (examples) References 2, 3, 162, 163
Other
Encourage education about and Resource: clinicaltrials.gov; foodallergy.org
participation in research studies

Further refinement of diagnosis in the future, with the goal of
improved prognostics and less reliance on OFCs, will likely be
based on cellular and humoral testing and more sophisticated
algorithms to interpret test results. Beyond CRD, one can measure
binding to specific epitopes within proteins, evaluating binding
patterns, degree, and affinity. Considering shrimp as an example,
diagnostic efficiency was higher when binding to individual
epitopes rather than when specific proteins were used, and more
intense and diverse epitope recognition defined those with clinical
allergy rather than clinically irrelevant sensitization.146 Another
example with CMA61 compared the progression of epitope
binding of milk proteins in children with resolved or persistent
300 SICHERER AND SAMPSON
allergy. Binding patterns were stable over time for those with
persistent allergy, but among those with early recovery, IgG4
epitope binding increased while IgE binding to corresponding
epitopes decreased. Different epitope-binding patterns were
also noted to differentiate clinical phenotypes of CMA59: a wider
diversity of IgE epitope binding was noted for those with
persistent CMA and more severe reactions and was more likely
to occur in children who could not tolerate extensively heated
forms of milk (eg, in muffins) compared with those who could
tolerate such foods. In competitive peptide microarray assays,
children with persistent CMA were fully differentiated from those
with resolved allergy or tolerance of extensively heated forms by
having high compared with low affinity binding, respectively.
Increasingly sophisticated approaches are being evaluated. Lin
et al147 used microarray immunoassays to map epitopes on the
major peanut proteins and then used a bioinformatics approach
to identify patterns that were most informative. This approach
performed significantly better than standard methods.
In addition to testing humoral responses, diagnosis with T-cell
proliferative responses,148 metabolomics,149 and basophil activa-
tion140,150,151 are under study.
MANAGEMENT/TREATMENT
Avoidance and emergency management
The current approach to management substantially relies on
allergen avoidance and preparation to promptly treat allergic
reactions. These tenets of treatment require significant patient
education. Aspects of care that have been recently reviewed in this
Journal include the following:2,3,152 circumstances warranting
prescription of self-injectable epinephrine, the importance of
education about prehospital treatment of reactions, education
about avoidance (eg, cross-contact, traveling, restaurants, school
issues, and label reading), legislation regarding labeling,
food manufacturing, and increasing access to epinephrine, the
availability of advocacy organizations, and numerous resources
for education developed by a number of constituencies.
A number of important management lessons were revealed by a
multicenter observational study of 512 infants with likely milk or
egg allergy (COFAR).153 Over a median follow-up of 36 months,
despite receiving care in food allergy centers, the annualized
reaction rate was 0.81 per year for all foods (367/512 subjects
reporting 1171 reactions), with 56% reporting more than 1
reaction. Most reactions were attributed to lack of vigilance
(eg, label checking errors and unintentional ingestion), with
additional errors including cross-contact in meal preparation and
food not provided by the parent. Approximately 11% of reactions
were attributed to nonaccidental exposure, indicating in some
cases that families might have tried a food to explore whether it
would be tolerated outside of medical supervision. Of the 11.4%
of reactions that were severe, only 29% of them were treated
with epinephrine because the caregiver did not recognize the
severity, the epinephrine was unavailable, or the caregiver was
afraid to administer it. Educational opportunities to improve safety
are evident.
Aside from physical reactions, having food allergy can affect
quality of life, and the psychological welfare of children with
food allergies is important to address.22,154,155 Shemesh et al156
noted that 45% of children with food allergies reported being
bullied, most often without parents being aware. The bullied chil-
dren had lower quality of life and increased anxiety compared
J ALLERGY CLIN IMMUNOL
FEBRUARY 2014
with those not being bullied, but parental awareness of the
bullying was associated with a significantly less affected quality
of life. The educational advice responsive to these study findings,
as well as selected key management issues from other publica-
tions, are incorporated in Table II.2,3,152,157-163 School food
allergy management guidelines from the US Centers for Disease
Control and Prevention are now available (www.cdc.gov/
HealthyYouth), and educational materials developed and vali-
dated through COFAR161 are available at www.cofargroup.org.
When completing written emergency anaphylaxis treatment plans
that include an antihistamine, the physician should consider a
recent study indicating the equivalent effectiveness of cetirizine
and diphenhydramine, with more potential of the former to avoid
sedation,164 and address the increasing options for autoinjectors
that are currently available.165
A vexing concern is how to manage advisory (may contain)
food labeling, which is voluntary in most countries. Ford et al166
evaluated a sample of 401 foods for the presence of milk, egg, or
peanut when those foods had advisory labels (eg, may contain)
or did not have such warnings. Overall, 5.3% of the products with
advisory labels had detectable protein, whereas 1.9% of the prod-
ucts with no warnings were contaminated. The latter were primar-
ily accounted for by small companies, and these results were not
observed for peanut. Crotty and Taylor167 focused on products
with advisory labeling for milk and found high rates of contami-
nation (42%) primarily accounted for by chocolates. Although the
level of allergen is low in many cases, there are clearly risks pre-
sent for sensitive patients. To potentially improve this conun-
drum, more data are needed on thresholds of reactivity, which
are emerging,168 and also guidance from regulatory agencies,
consumers, manufacturers, and other stakeholders so that labeling
can be regulated without overestimating or underestimating
risk.169,170 Currently, it is potentially safer to advise patients to
avoid such labeled products, but avoidance carries an effect on
quality of life, and individualizing advice might be rational for
selected patients who are deemed less sensitive. A good example
of allowing some trace exposure (very small risk) against a stron-
ger benefit is the influenza vaccine. The residual amount of egg
protein in the influenza vaccine appears to be low risk, immuniza-
tion is generally recommended, and egg-free vaccines are
becoming more available.171,172
Prevention
Several guidelines contain updated dietary prevention recom-
mendations that rescinded those promulgated more than a decade
ago, particularly expunging prolonged allergen avoidance as a
means to prevent atopic disease or food allergies.2,162,163 Updated
summaries are included in Table II.
Regarding pregnancy diets, allergen avoidance is not recom-
mended, although studies remain conflicting. In a Danish birth
cohort (n 5 61,980),173 children of mothers with frequent intake
of peanut during pregnancy compared with those without were
less likely (OR, 0.66; 95% CI, 0.44-0.98) to have children with
asthma at 18 months of age, with a similar finding for tree nut con-
sumption. In contrast, a study from COFAR174 noted that
maternal ingestion of peanut during pregnancy had a positive
dose-response association with risk of the infant having increased
peanut sIgE antibody levels (however, clinical peanut allergy rates
have not yet been determined). Although exclusive breast-feeding
is recommended for at least 4 months, data about allergy
J ALLERGY CLIN IMMUNOL
VOLUME 133, NUMBER 2
prevention from this approach are also mixed. Among 51,119
randomly selected 8- to 12-year-old schoolchildren in 21 coun-
tries, there was a small increase in the risk of reported eczema
in association with ever having breast-fed (adjusted OR, 1.11;
95% CI, 1.0-1.2), and there was no significant association between
reported eczema ever and breast-feeding for greater than 6 group compared with control subjects were given a diagnosis of
months (adjusted OR, 1.09; 95% CI, 0.9-1.3). For substitutions
of formula, soy is not considered to have a prevention effect, but
for infants at risk of atopic disease, a hydrolyzed formula with a
possibly better advantage of extensively hydrolyzed casein for-
mula (EHCF) might offer protection against eczema over whole
milkbased formulas. However, recent studies on this topic also
remain conflicting, including a single-blind, randomized
controlled trial of a partially hydrolyzed whey-based formula
and a soy or conventional milk-based formula at weaning in
high-risk infants, which did not show differences in outcomes
for eczema, food reactions, or sensitization.175 In contrast, a
10-year follow-up of a randomized trial of 4 formulas as breast
milk substitutes in infants at risk of atopy continued to show a
reduced cumulative relative risk of AD for specific hydrolyzed in-
fant formulas compared with whole cows milk infant formula,
with a relative risk of 0.72 (95% CI, 0.58-0.88) for the extensive
hydrolysate of casein. The protection was noted only for AD
and not sensitization to foods. In another study of 679 infants
who were consistently fed the same formula for the first 6 months
of life, comparing 345 with hydrolyzed formula with 334 with
cows milk formula, the percentage sensitized to milk protein
was significantly lower in the group receiving the hydrolyzed for-
mula (12.7% vs 23.4%, P 5 .048).176 Considering these and past
studies,2,171,172 formula selection might provide some atopy pre-
vention, but results for food allergy prevention are weak or
underpowered.
With regard to the timing and selection of specific complemen-
tary foods, many studies continue to suggest that prolonged
avoidance of solids or specific allergens is not protective and might
be a risk factor with regard to atopy or food allergy prevention.163
For example, Koplin et al39 used a cross-sectional study of 2589 in-
fants and noted that delayed introduction of egg was associated with
increased risk of egg allergy compared with introduction at 4 to 6
months, delaying beyond 12 months carried an adjusted OR of
3.4 (95% CI, 1.8-6.5). In a Finnish birth cohort study of 3781
consecutively born children,177,178 introduction of egg at 11 months
or less was inversely associated with asthma, allergic rhinitis, and
atopic sensitization, whereas introduction of fish at 9 months or
less was inversely associated with allergic rhinitis and atopic sensi-
tization. Less food diversity already at 3 months of age was associ-
ated with a later increase in atopic sensitization. A birth cohort
study in Detroit, Michigan, found that feeding of complementary
foods before 4 months was associated with a reduced risk of food
sensitization to peanut and possibly egg by age 2 or 3 years in a sub-
set of the cohort having a parental history of asthma or allergy.179 If
there is a period of opportunity in which ingestion is tolerizing, it
might vary by food, environmental factors, and genetics. Katz
et al40 evaluated a cohort of greater than 13,000 infants and calcu-
lated an OR of 19.3 (95% CI, 6.0-62.1) for development of
IgE-mediated CMA among infants exposed after 15 days of age.
Yet another study looking at food allergy outcomes180 found no
difference in the presolids infant diet, but those without food
allergies were more likely to ingest a healthy diet of fruits, veg- oral immunotherapy while also treating with anti-IgE antibodies,
etables, and home-prepared foods. Although many studies attempt
to control for reverse causation, there might be a subtle effect in
SICHERER AND SAMPSON 301
which parents of at-risk infants delay allergen exposure, influencing
the conclusions of these studies toward potentially erroneous con-
clusions of an ill effect from delaying introduction. In a controlled
trial randomizing early exposure to egg in 86 infants at risk for egg
allergy, a lower but not significant proportion of infants in the egg
egg allergy at 12 months of age (33% vs 51%, P 5 .11), possibly
suggesting that earlier exposure might not increase egg allergy.
Taken together, the studies indicate that in an otherwise healthy in-
fant, there is no rationale to delay introduction of solids and no ratio-
nale to defer allergenic foods, although it seems that some
cautions are warranted, such as using less allergenic foods as initial
weaning foods, proceeding gradually, and pursuing more evalua-
tions, particularly if the infant shows signs of atopy or food-
induced allergic reactions. A comprehensive approach was recently
outlined.163
An active approach to prevention has focused on prebiotics,
probiotics, synbiotics, and bacterial lysates, essentially
combating the allergy-eliciting nature of a hygienic environment
by providing and nurturing nonpathogenic, health-promoting
bacteria.181 There is some promise, with studies suggesting
certain strains, especially when administered both prenatally
and postnatally, might at least reduce eczema.182 However,
studies remain conflicting and inconclusive. For example, Jensen
et al183 presented 5-year follow-up on a randomized postnatal
study of 6 months of treatment with Lactobacillus acidophilus,
showing no protective effect for any physician-diagnosed allergic
disease, but earlier findings of increased risk for sensitization in
treated children were no longer cumulatively significant.
A Cochrane database review on prebiotics for prevention of al-
lergy in infants, evaluating 4 studies with 1428 infants, concluded
that there is some evidence for eczema prevention but also
concluded that further research is needed before routine use.184
A 2012 World Allergy Organization review concluded that probi-
otics do not have an established role in the prevention or treatment
of allergy.185 Clearly, study results can be affected by strain selec-
tion and other factors. With an increasing number of studies
that are sensitive to the selection of subjects, timing of treatment,
and strain selection, more definitive conclusions are likely to
emerge.
Future therapies
Companion articles in this issue of the Journal8,9 describe ad-
vances in oral, sublingual, and epicutaneous immunotherapies for
foods, as well as a number of approaches under evaluation in murine
models.186,187 It will be interesting to see whether additional
routes, such as intralymphatic immunotherapy, become viable for
food immunotherapy.188 Allergen-specific immunotherapeutic
approaches include not only oral, sublingual, or epicutaneous
immunotherapy with whole allergen but also immunotherapy
with modified proteins that were designed to be hypoallergenic to
reduce the risk of reactions. Unfortunately, in a pilot safety study
of heat-killed, Escherichia coliexpressing modified Ara h 1, 2,
and 3 as rectal immunotherapy, there were frequent allergic reac-
tions, necessitating a redesign of the study dosing or product.189
Additional antigen-specific approaches are under preclinical inves-
tigation, but combination approaches, such as using allergen
has been studied in human subjects, with some promise of
increased safety.190,191 Although not initially considered an
302 SICHERER AND SAMPSON
immunotherapeutic approach, a major recent advance in manage-
ment is the observation that a majority of children with egg or
CMA can tolerate extensively heated forms of these allergens,
such as in bakery goods, and that ingesting these products might
speed recovery. In a long-term follow up of children who were
able to add baked milk products (eg, muffins) to their diet, tolerance
of regular milk was 16 times more likely compared with a group
treated with standard-of-care avoidance.192 The treated group
showed an increase in milk-specific IgG4 levels. Similarly, Leonard
et al193 performed a follow-up study in children with egg allergy
who were successfully challenged with baked egg products and
ate them routinely. These children were 14.6 times more likely
than comparison control subjects (P < .0001) to have tolerance to
unheated egg. However, these were not randomized trials, and not
all studies suggest an immunotherapeutic response.194 A study is
underway in COFAR evaluating baked egg versus egg oral
immunotherapy.
Therapies that are not allergen specific are especially attractive
because many patients have multiple food allergies. These
approaches include various mAbs, traditional Chinese medicine,
probiotics, and others.195,196 A trial of omalizumab for peanut al-
lergy was stopped early for a safety concern related to the food
challenge approach but showed some trend toward efficacy in
increasing the threshold of reactivity.197 An herbal formula to
treat food allergy was evaluated in a safety trial for 6 months
with no significant side effects and a trend toward decreasing
eosinophil and basophil numbers, and in vitro tests showed a
decrease in basophil activation.198 Individual studies are looking
at probiotics for treatment. For example, in one study199 other-
wise healthy infants with CMA were given EHCFs (n 5 55),
EHCF with Lactobacillus rhamnosus GG (n 5 71), hydrolyzed
rice formula (n 5 46), soy formula (n 5 55), or amino acidbased
formula (n 5 33), and OFCs were performed after 12 months to
assess acquisition of tolerance. The rate of tolerance after 12
months was significantly higher (P < .05) in the groups receiving
EHCF (43.6%) or EHCF plus Lactobacillus rhamnosus GG
(78.9%) compared with the other groups: hydrolyzed rice formula
(32.6%), soy formula (23.6%), and amino acidbased formula
(18.2%). More studies are needed to evaluate the safety and
efficacy of all of these approaches, as well as combination
approaches, by using allergen-specific and nonspecific modalities
or combining approaches serially (sublingual immunotherapy
leading to oral immunotherapy) or concomitantly. Table E2
in this articles Online Repository at www.jacionline.org lists
examples of therapies under preclinical and clinical studies.
SUMMARY
In the 3 years since our last review, remarkable advances have
occurred in understanding and managing food allergies. Unfortu-
nately, the intense efforts to improve diagnosis, treatment, and
prevention are partly the result of an unexplained significant increase
in prevalence. Although conflicting studies and disappointing results
in some clinical treatment trials are frustrating, remarkable advances
in diagnosis and treatment are already apparent, and new insights on
cause and pathogenesis are resulting in renewed efforts with novel
approaches toward prevention, diagnosis, and treatment. With
deeper insights into genetics and the microbiome, incorporation of
bioinformatics, and numerous approaches to treatment in preclinical
and clinical studies, we are poised to witness a revolution in our
approach to food allergy over the next several years.
J ALLERGY CLIN IMMUNOL
FEBRUARY 2014
What do we know?
d The prevalence of food allergy is high, up to 10% of the
population, and likely increased in the past decades.
d Numerous genetic and environmental risk factors have
been identified.
d Insights on route of sensitization, allergen characteriza-
tion, and immune response provide insights for diagnosis
and treatment.
d There is a wide spectrum of disease caused by food allergy
related to different immune mechanisms and the target
organs affected. Diagnosis depends on combining a
knowledge of pathophysiology and epidemiology with the
patients history and test results. It is clearly possible to
have sensitization without clinical reactivity and vice versa.
d The use of CRD is entering clinical practice.
d Management currently requires attention to allergen avoid-
ance and emergency treatment, and numerous resources are
available to patients and physicians to promote education
and counseling to improve safety and quality of life.
d Numerous clinical trials are underway for more definitive
therapies.
What is still unknown?
d The cause for an increase in food allergy
d Translation of environmental and genetic risk factors into
improved prevention
d The best diagnostic approaches
d How to maximize safety and quality of life during
management
d The best novel therapeutic options
d A personalized medicine approach to diagnosis and
treatment of food allergy is likely required but remains
elusive.
Key concepts and therapeutic implications
d Identification of food-specific IgE by means of testing in-
dicates sensitization but is not, in isolation, diagnostic.
d Knowledge of the epidemiology, natural course, patho-
physiology, and clinical manifestations of food allergies
and other adverse reactions to foods is required to
approach diagnosis and management. The medical history
is key, noninvasive tests are supportive and possibly diag-
nostic, and the OFC is the most definitive test.
d Management requires attention to education about avoid-
ance and prompt appropriate treatment of anaphylaxis.
d Various approaches to treatment are under investigation,
and patients should be alerted to clinical trials.
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TABLE E1. Food-induced allergic disorders (also see text)E1,E2

VOLUME 133, NUMBER 2

J ALLERGY CLIN IMMUNOL
Diagnostic consider-
ations (in addition to
Additional Most common causal history, possible food
Immunopathology Disorder Key features immunopathology Typical age foods Natural course challenges)

IgE antibody
dependent (acute
onset)
Urticaria/angioedema Triggered by Children > adults Primarily major Depending on food SPT and/or sIgE
ingestion or direct allergens: egg, measurement
skin contact milk, wheat, soy,
(contact urticaria); peanut, tree nuts,
food commonly fish, shellfish
causes acute (20%)
but rarely chronic
(2%) urticaria
Oral allergy syndrome Pruritus, mild edema Sensitization to pollen Onset after pollen Raw fruit/vegetables; Might be long-lived SPT and/or sIgE
(pollen associated, confined to oral proteins through allergy established cooked forms and vary with measurement
food allergy cavity; respiratory route (adult > young tolerated; examples seasons Fresh (raw) prick-
syndrome) uncommonly results in IgE that child) of relationships: prick testing
progresses beyond binds certain birch (apple, peach,
mouth (;7%) or homologous, pear, carrot),
anaphylaxis (1% to typically labile, ragweed (melons)
2%); might food proteins (in
increase after certain fruits/
pollen season vegetables, such as
apple Mal d 1 and
birch bet v 1)
Rhinitis, asthma Symptoms might Infant/child > adult, Generally: major Depending on food SPT and/or sIgE
accompany a food- except for allergens; measurement
induced allergic occupational Occupational: wheat,
reaction but rarely disease (eg, Bakers egg, seafood, for
an isolated or asthma) example
chronic symptom;
might also be
triggered by
inhalation of
aerosolized food

SICHERER AND SAMPSON 307.e2

protein
Immediate Immediate isolated Major food allergens Depends on food SPT and/or sIgE
gastrointestinal vomiting (more measurement
hypersensitivity often,
gastrointestinal
symptoms are
associated with
anaphylaxis)
(Continued)
 307.e3 SICHERER AND SAMPSON
Diagnostic consider-
ations (in addition to
Additional Most common causal history, possible food
Immunopathology Disorder Key features immunopathology Typical age foods Natural course challenges)
Anaphylaxis Rapidly progressive, Massive release of Any Any but more Depending on food SPT and/or sIgE
multiple organ mediators, such as commonly peanut, measurement
system reaction can histamine, although tree nuts, shellfish,
include mast cell tryptase fish, milk, and egg
cardiovascular not always
collapse increased; key role
of platelet-
activating factor
Delayed food-induced Several-hour delay Related to antibodies Related to tick bites Beef, pork, lamb Uncertain Serum test for IgE to
anaphylaxis to after ingestion to carbohydrate a-Gal
mammalian meats moiety a-Gal (see SPT and/or sIgE
text) measurement
Food-associated, Food triggers Exercise presumed to Onset more Wheat, shellfish, Presumed persistent SPT and/or sIgE
exercise-induced anaphylaxis only if alter gut absorption commonly is later celery most measurement
anaphylaxis ingestion followed and/or allergen childhood/ described Component testing
temporally by digestion adulthood Exercise test (might
exercise be poorly
reproducible)
Mixed IgE
antibody-
associated/cell-
mediated
(delayed-onset/
chronic)
AD Associated with food Might relate to Infants> child > adult Major allergens, Typically resolves SPT and/or sIgE
in ;35% of homing of food- particularly egg, measurement
children with responsive T cells milk APT not generally
moderate-to-severe to the skin recommended
rash
Eosinophilic Symptoms vary on Mediators that home Any Multiple Likely persistent Empiric diets
gastroenteropathies site(s)/degree of and activate Endoscopy
eosinophilic eosinophils play a SPT and/or sIgE
inflammation role, such as measurement
Esophageal: eotaxin, IL-5 APT not generally
dysphagia, pain recommended
Generalized:
ascites, weight loss,
edema, obstruction

J ALLERGY CLIN IMMUNOL

NonIgE-mediated
(delayed-onset/
chronic)

FEBRUARY 2014
 Food protein induced Primarily affects Increased TNF-a Infancy Cows milk, soy, rice, Usually resolves SPT and/or sIgE

VOLUME 133, NUMBER 2

J ALLERGY CLIN IMMUNOL
enterocolitis infants response, decreased oat measurements are
syndrome Chronic exposure: response to TGF-b Multiple other solids typically negative
emesis, diarrhea, have been identified but can become
poor growth, positive
lethargy APTs not helpful
Re-exposure after
restriction: emesis,
diarrhea,
hypotension (15%)
2 hours after
ingestion
Food protein induced Mucus-laden bloody Eosinophilic Infancy Milk (through breast- Usually resolves Empiric diets
allergic stools in infants inflammation feeding)
proctocolitis
Heiner syndrome Rare disorder; Infant Milk Undefined No evidence of IgE;
pulmonary might have
infiltrates, upper precipitating milk-
respiratory tract specific IgG
symptoms, failure antibodies
to thrive, iron
deficiency anemia
Celiac disease Autoimmune disorder Might include Might be Gluten (ie, wheat, rye, Lifelong Serologies (while
leading to anemia, poor asymptomatic or barley) ingesting wheat
enteropathy and growth, present at any age including IgA
malabsorption; gastrointestinal against tissue
occurs in persons symptoms, bone transglutaminase,
with a genetic abnormalities, IgA gliadin), HLA
disposition and is deficiency, typing (for DQ2/
triggered by dermatitis DQ8), and biopsies
gliadin, a gluten herpetiformis,
protein found in malignancy risk
wheat and related
grains
Cell mediated
Allergic contact A form of eczema to Similar to other forms Adult Metals APT
dermatitis chemical haptens of contact
that are additives or dermatitis, subtype

SICHERER AND SAMPSON 307.e4

naturally occurring includes systemic
in foods contact dermatitis
(rare) and possibly
fixed food
eruptions
Revised from Sicherer and Sampson.E1
307.e5 SICHERER AND SAMPSON
TABLE E2. Selected immunotherapeutic strategies
Therapy
Standard subcutaneous
immunotherapy (native
allergens)
Sublingual/oral immunotherapy
Epicutaneous immunotherapy
Modified protein vaccine
Peptide vaccine (overlapping
peptides)
Conjugation of immune
stimulatory sequences to
allergen and additional adjuvant
methods
Plasmid DNA-encoded vaccines
Anti-IgE antibodies
Anti-IgE plus oral immunotherapy
Traditional Chinese medicine
Cytokine/anticytokine/antireceptor/
antimediator
Fusion proteins
Probiotics, Trichuris suis ova
Revised from Sicherer and Sampson.E1
Immune rationale
Antigen presentation in
nonmucosal sites results in TH1
skewing
Antigen presentation to mucosal
site provides desensitization and
might induce tolerance
Antigen presentation through skin
Reduced IgE activation by
mutation of IgE-binding
epitopes
Peptides are less likely to cross-
link IgE, avoiding mast cell
activation
Enhance TH2 response by
activating innate immune
receptors (using specific
sequences or whole bacteria)
Endogenous production of allergen
might result in tolerance
Targeted toward Fc portion of
antibody, can inactivate IgE with
reduced risk for activating mast
cells
Might reduce side effects of oral
immunotherapy, speed
desensitization, improve
tolerance
Mechanism appears to include
altered T-cell responses with
increased IFN-g and IL-10
To interrupt inflammatory signals
To inhibit degranulation, enhance
effectiveness of immunotherapy
Alter immune response
Benefits
Proved for venom and respiratory
allergy, possible benefit (pollen)
for oral allergy syndrome
Natural foods, reduced risk of
systemic anaphylaxis compared
with injections
Low risk, natural food
A safer form of immunotherapy
compared with injection of
native protein
No requirement for IgE epitope
mapping/mutation
Increased efficacy, possibly
improved safety
Possible 1-dose treatment
Not food-specific
Food specific but might not require
long periods of anti-IgE
Not food specific
Might allow directed interruption
of inflammatory processes
without need for food restriction
Targeted reduction of effector
responses, possible directed
immunotherapy
Not food specific
J ALLERGY CLIN IMMUNOL
FEBRUARY 2014
Observations to date
Primarily avoided for risk of
anaphylaxis (eg, peanut)
Mounting evidence for
desensitization and relative
safety; unclear effect on
tolerance
Pilot studies show promise for
safety and efficacy, trials
underway
Murine models show promise,
human study of peanut showed
reactions
Limited
Preclinical studies
Murine models reveal strain-
specific response
Preliminary studies showed
improved threshold overall but
did not show uniform protection
Pilot studies show promise, clinical
trials underway
Murine models show efficacy;
human safety studies completed;
clinical trials underway
Primarily preclinical
Preclinical
Mixed results in trials thus far or
too preliminary