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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 List of Design Committee Members: Scott H. Sicherer, MD, and Hugh
articles in this issue. Please note the following instructions. A. Sampson, MD
Method of Physician Participation in Learning Process: The core ma- Activity Objectives
terial for these activities can be read in this issue of the Journal or online at 1. To describe the current epidemiology of food allergy.
the JACI Web site: www.jacionline.org. The accompanying tests may only 2. To learn pearls and pitfalls regarding the diagnosis of food allergy.
be submitted online at www.jacionline.org. Fax or other copies will not be
3. To understand the management of food allergy, including attention to
accepted. quality-of-life issues.
Date of Original Release: February 2014. Credit may be obtained for
these courses until January 31, 2015. Recognition of Commercial Support: This CME activity has not
Copyright Statement: Copyright 2014-2015. All rights reserved. received external commercial support.
Overall Purpose/Goal: To provide excellent reviews on key aspects of Disclosure of Significant Relationships with Relevant Commercial
allergic disease to those who research, treat, or manage allergic disease. Companies/Organizations: S. H. Sicherer is on the American Board of
Target Audience: Physicians and researchers within the field of allergic Allergy and Immunology; has received consultancy fees from Novartis and
disease. Food Allergy Research & Education; has received research support from the
Accreditation/Provider Statements and Credit Designation: The National Institute of Allergy and Infectious Diseases (NIAID) and Food Al-
American Academy of Allergy, Asthma & Immunology (AAAAI) is ac- lergy Research & Education; and receives royalties from UpToDate. H. A.
credited by the Accreditation Council for Continuing Medical Education Sampson has received research support from the NIAID/National Institutes
(ACCME) to provide continuing medical education for physicians. The of Health and Food Allergy Research & Education; has received travel sup-
AAAAI designates this journal-based CME activity for a maximum of 1 port as Chair of the PhARF Award review committee; has received consul-
AMA PRA Category 1 Credit. Physicians should claim only the credit tancy fees from Allertein Therapeutics and Regeneron; and has received
commensurate with the extent of their participation in the activity. lecture fees from Thermo Fisher Scientific, UCB, and Pfizer.

This review focuses on advances and updates in the tick bites. Component-resolved diagnosis is being rapidly
epidemiology, pathogenesis, diagnosis, and treatment of food incorporated into clinical use, and sophisticated diagnostic tests
allergy over the past 3 years since our last comprehensive that indicate severity and prognosis are on the horizon. Current
review. On the basis of numerous studies, food allergy likely management relies heavily on avoidance and emergency
affects nearly 5% of adults and 8% of children, with growing preparedness, and recent studies, guidelines, and resources
evidence of an increase in prevalence. Potentially rectifiable risk provide insight into improving the safety and well-being of
factors include vitamin D insufficiency, unhealthful dietary fat, patients and their families. Incorporation of extensively heated
obesity, increased hygiene, and the timing of exposure to foods, (heat-denatured) forms of milk and egg into the diets of children
but genetics and other lifestyle issues play a role as well. who tolerate these foods, rather than strict avoidance,
Interesting clinical insights into pathogenesis include discoveries represents a significant shift in clinical approach.
regarding gene-environment interactions and an increasing Recommendations about the prevention of food allergy and
understanding of the role of nonoral sensitizing exposures atopic disease through diet have changed radically, with
causing food allergy, such as delayed allergic reactions to rescinding of many recommendations about extensive and
carbohydrate moieties in mammalian meats caused by prolonged allergen avoidance. Numerous therapies have
sensitization from homologous substances transferred during reached clinical trials, with some showing promise to
dramatically alter treatment. Ongoing studies will elucidate
improved prevention, diagnosis, and treatment. (J Allergy Clin
From the Elliot and Roslyn Jaffe Food Allergy Institute, Division of Allergy and
Immunology, Kravis Childrens Hospital, Department of Pediatrics, Icahn School of Immunol 2014;133:291-307.)
Medicine at Mount Sinai, New York, NY.
Received for publication November 4, 2013; revised November 25, 2013; accepted for Key words: Food allergy, food hypersensitivity, oral tolerance,
publication November 25, 2013. gastrointestinal food hypersensitivity, food allergens, anaphylaxis
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. Discuss this article on the JACI Journal Club blog: www.jaci-
E-mail: scott.sicherer@mssm.edu. online.blogspot.com.
0091-6749/$36.00
2013 American Academy of Allergy, Asthma & Immunology This article is an update to our comprehensive review of the
http://dx.doi.org/10.1016/j.jaci.2013.11.020 diagnosis and management of food allergy published in 2010.1

291
292 SICHERER AND SAMPSON J ALLERGY CLIN IMMUNOL
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obtained in the National Health and Nutrition Examination Sur-


Abbreviations used vey (NHANES) in the United States (2005-2006), Liu et al14 esti-
AD: Atopic dermatitis mated clinical allergy to cows milk, egg, and peanut at 1.8% each
APT: Atopy patch test in children age 1 to 5 years. The 2 most recent NHANES
CMA: Cows milk allergy performed from 2007-2010 with 20,686 US participants included
COFAR: Consortium of Food Allergy Research
queries on self-reported food allergies. Overall, 8.96% reported
CRD: Component-resolved diagnostics
EHCF: Extensively hydrolyzed casein formula
food allergy, with 6.53% among children.15 Self-report or
EoE: Eosinophilic esophagitis reliance on serology is notoriously inaccurate,15,16 but few studies
FLG: Filaggrin include oral food challenges (OFCs) on a population level.
a-Gal: Galactose-a-1,3-galactose Osborne et al17 evaluated a population-based cohort of 2848
LR: Likelihood ratio (73% participation rate) 1-year-old infants in Melbourne,
NHANES: National Health and Nutrition Examination Survey Australia, in a study that included OFCs and estimated prevalence
OFC: Oral food challenge as follows: peanut, 3.0%; raw egg, 8.9%; and sesame, 0.8%.
OR: Odds ratio A United Kingdom study on early childhood peanut allergy,
sIgE: Allergen-specific serum IgE which included OFCs, estimated a peanut allergy prevalence of
PPV: Positive predictive value
2% at age 8 years.18 A population-based study on the prevalence
SPT: Skin prick test
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
Since that publication, an expert panel sponsored by the National 5% in adults and approaching 8% in children, with a number of
Institute of Allergy and Infectious Diseases defined food allergy estimates nearing 2% for peanut allergy. Whether perceived
as an adverse health effect arising from a specific immune or confirmed allergy, the economic,20,21 emotional,22 and safety
response that occurs reproducibly on exposure to a given food burden is substantial.
and food intolerance as nonimmune reactions that include Data generally support an increase in prevalence. A 2013 data
metabolic, toxic, pharmacologic, and undefined mechanisms.2 brief from the US Centers for Disease Control and Prevention
We encourage readers seeking an overview to refer to practice relying on data from a single question in the US National Health
parameters, guidelines, and international consensus papers that Interview Survey concluded that among children age 0 to 17
emphasize key points in the diagnosis and management of food years, the prevalence of food allergies increased from 3.4% in
allergy3-5 and related disorders.6,7 Companion articles in this 1997-1999 to 5.1% in 2009-2011.23 Estimates based on a single
issue of the Journal focus on oral, sublingual, and epicutaneous query are suspect, but a number of pediatric studies also support
immunotherapy8 and insights obtained from murine models of an increased prevalence. A US survey24 repeated on 3 occasions
food allergy,9 and therefore we will not review these topics in presented the opportunity to compare results from 1997 to
detail. We highlight recent clinical observations and advances 2008 in surrogate-reported peanut allergy in children. The
that inform prevention, diagnosis, and management now and, rate increased significantly from 0.4% to 1.4%. Limitations
hopefully, in the near future. 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
EPIDEMIOLOGY AND NATURAL HISTORY of studies using various methodologies, including OFCs, around
Prevalence the same period. Additional recent publications focusing on
Accurate determinations of food allergy prevalence are elusive peanut allergy indicated increases with a doubling (United
because factors such as allergy definitions, study populations, Kingdom)25 or tripling (United States)26 in diagnoses.
methodologies, geographic variation, ages, dietary exposures, A cross-sectional study of infants from a single clinic in China
and other factors influence the estimates.10 A comprehensive over a 10-year period used OFCs for diagnosis and estimated an
review of the literature concluded that food allergy affects increase in food allergy from 3.5% to 7.7% (P 5 .17).27
more than 1% to 2% but less than 10% of the population and Although there are methodological limitations, the impression
that it remains unclear whether the prevalence is increasing.11 of an international increase in allergy and food allergy remains
A number of recent studies provide spectacularly high estimates strong.3,10
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, Risk factors
and approximately 3% experience severe reactions. Soller A plethora of risk factors are proposed to influence food
et al13 surveyed 9667 subjects from 10 Canadian provinces for allergy or sensitization, including sex (male sex in children),
self-reported food allergy and found an overall rate of 8%. race/ethnicity (increased among Asian and black children
When they excluded adults reporting unlikely allergies and compared with white children), genetics (familial associations,
adjusted for nonresponders, the final estimates were 6.7% in the HLA, and specific genes), atopy (comorbid atopic dermatitis
overall population, with 7.1% of children and 6.6% of adults [AD]), vitamin D insufficiency, dietary fat (reduced consumption
reporting food allergy. Cows milk (2.2%), peanut (1.8%), and of omega-3-polyunsaturated fatty acids), reduced consumption of
tree nuts (1.7%) were the most common allergens in children, antioxidants, increased use of antacids (reducing digestion of
and shellfish (1.9%), fruits (1.6%), and vegetables (1.3%) were allergens), obesity (being an inflammatory state),28 increased
the most common allergens in adults. Taking a different perspec- hygiene, and the timing and route of exposure to foods
tive using food allergenspecific serum IgE (sIgE) results (increased risk for delaying allergens with possible environmental
J ALLERGY CLIN IMMUNOL SICHERER AND SAMPSON 293
VOLUME 133, NUMBER 2

sensitization).29,30 Some of these factors might provide opportu- by means of a survey and found food allergy decreased with
nities for prevention or treatment. increasing birth order, possibly reflecting exposure to more infec-
Recent studies provide additional insights regarding risk tion from siblings. The NHANES database was used to evaluate
factors. For example, a study evaluating 3136 children and rates of food sensitization against urinary levels of endocrine-
adolescents in the 2005-2006 NHANES found that vitamin D disrupting compounds, and only the compound triclosan, which
levels of less than 15 ng/mL compared with levels of greater than has an antimicrobial effect, was associated with an increased
30 ng/mL were associated with an increased risk (P <.005) of pea- risk for food sensitization (among male subjects).47 However, in
nut sensitization (odds ratio [OR], 2.39; 95% CI, 1.29-4.45).31 An a systematic review of studies looking at microbial exposure in-
Australian study32 using a well-characterized cohort undergoing fluence on food allergy, including cesarean section, having sib-
OFCs showed a latitude gradient for IgE-mediated egg and peanut lings, attending childcare, and treatment with probiotics, there
allergy, with higher rates in regions farther from the equator with was a lack of clear evidence to support microbial protection and
less ambient UV radiation. Additional studies supporting the too much study heterogeneity for a meta-analysis.48 Although a
vitamin D hypothesis include the following: season of birth is a murine model recently provided impressive evidence of the influ-
risk factor,33 pediatric food-induced anaphylaxis is more common ence of the microbiota on food allergy,49 more human studies are
in northern areas of the United States,34 vitamin D sufficiency is needed.
protective against food allergy,35 and maternal intake of vitamin Studies focusing on food allergy outcomes also identify
D during pregnancy is associated with decreased risk of food combinations of factors that conspire to define risk. Koplin
sensitization.36 Not all studies support the theory; for example, et al50 evaluated 453 Australian infants with egg allergy
Weisse et al37 reported 378 mother-infant pairs studied in a confirmed by using OFCs from a population-based sample of
German cohort in which increased maternal vitamin D levels 5276 infants and identified a number of risk factors: parental or
were associated with the children receiving a diagnosis of food sibling allergy history and parents born in East Asia rather than
allergy (OR, 3.66; 95% CI, 1.36-9.87). Controlled trials will be Australia, as well as protective factors, such as older siblings
needed to determine whether interventions can affect outcomes.38 and having a dog in the home. Du Toit et al,51 in preparing a cohort
In the past several years, attention has shifted from assumptions of 4- to 10-month-olds for evaluation of the effect of early intro-
that early infant allergen exposure was a risk factor for food duction of peanut on peanut allergy, noted that egg allergy and se-
allergy to the opposite notion that prolonged allergen avoidance vere eczema were the strongest predictors of peanut sensitization.
might be a risk factor because oral tolerance induction would be Comorbidities might identify patients at risk for increased food
bypassed while alternative sensitizing routes of exposure, allergy morbidity. For example, several studies have indicated
particularly through the skin (especially nonintact inflamed that having food allergy might be a risk for problematic asthma
epidermis in patients with AD), was ongoing. Epidemiologic and having asthma might be a risk for severe/fatal food
studies have mostly continued to support this hypothesis, which is allergy.14,52,53 Overall, the risk factors discussed add insights
discussed further below in the context of approaches to allergy about outcomes and provide avenues for prevention, such as pro-
prevention.39-41 biotics, and possibly future treatments, such as nutritional
A number of risk factors are immutable but might provide interventions.
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 Natural course
increased affluence,25 suggesting lifestyle influence. Racial and The course of resolution of food allergy has been well
ethnic differences in food allergies are being increasingly characterized and recently reviewed.3 In general, childhood
explored. In telephone surveys shellfish allergy was reported at food allergies to milk, egg, wheat, and soy typically resolve dur-
a significantly higher rate among black/African American than ing childhood, whereas allergies to peanut, tree nuts, fish, and
white subjects (3.1% vs 1.8%).42 Non-Hispanic black subjects shellfish are persistent. Prognosis also varies by disorder; for
also had increased risks of having serologic results, indicating example, food allergyrelated eosinophilic esophagitis (EoE)
likely food allergy in the NHANES study (OR, 3.1).14 An inter- appears to have a relatively poor chance of resolution.54 There
esting example is the very high rate of shellfish sensitization is evidence that resolution rates have slowed for allergies that
among inner-city atopic children, which might relate to exposure have been commonly outgrown, such as those to milk, egg,
to cross-reactive proteins in cockroach, the clinical ramifications wheat, and soy. For example, Savage et al55 reported in a referral
of which remain mostly unexplored.43,44 Keet et al45 used data practice that soy allergy resolved in 25% by age 4 years, 45% by
from NHANES 2005-2006 to investigate how sensitization to age 6 years, and only 69% by age 10 years.
foods in those less than 21 years of age related to being born in Early prediction of future tolerance would be useful in planning
or outside of the United States and the age of immigration. whether to apply immunotherapeutic interventions and to provide
They found that US-born children were at greater risk (OR, personalized insights on prognosis. Higher early sIgE levels
2.05; 95% CI, 1.5-2.8; P < .001), and among those born outside appear to carry a poorer prognosis than lower values, and
the United States, arriving before age 2 years was a risk factor decreases in these test results over time might signal resolution.56
(OR, 2.68; 95% CI, 1.2-6.1; P < .02); however, among children The possibility of providing long-term prognostic information
born in the United States, children of immigrants were at higher based on early markers is evolving. Elizur et al57 reported on 54
risk. These findings suggest a relative environmental risk factor children with IgE-mediated cows milk allergy (CMA) who
for US residents but also indicate a complex interaction of ge- were identified in a population-based study and followed for as
netics and environment. long as 5 years. Thirty-one (57.4%) infants resolved their allergy,
Exposure to microbes might also influence food allergy risk. and risk factors for persistence included a reaction to less than 10
For example, Kusunoki et al46 evaluated 11,454 Japanese children mL of milk on OFC (or on first exposure, P 5 .01), a larger skin
294 SICHERER AND SAMPSON J ALLERGY CLIN IMMUNOL
FEBRUARY 2014

prick test (SPT) wheal size (P 5 .014), and age of 30 days or less was associated with clinical allergy to milk and sensitization to
at the time of the first reaction (P 5 .05). Early markers of milk and peanut. This was noted in the absence of increased
resolution of CMA were also evaluated in the Consortium of GATA3 mRNA expression, identifying a potential marker but
Food Allergy Research (COFAR) observational study in which also raising a question about the IL-4 not being of T-cell origin.
154 (52.6%) subjects experienced CMA resolution at a median The importance of considering the route of sensitization on
age of 63 months.58 Baseline (age, 3-15 months) characteristics food allergy has been recently highlighted,73 such as sensitization
that were most predictive of resolution included milk sIgE levels, through nonoral routes. It has long been appreciated that respira-
SPT-induced wheal sizes, and AD severity (all P < .001). tory sensitization can result in food allergy, as demonstrated by
A calculator to estimate resolution probabilities using these pollen-foodrelated allergies, as well as some more esoteric ex-
frequently obtained variables was devised for use in the clinical amples, including cat-porkrelated allergy (pork meat allergy
setting when evaluating children 3 to 15 months of age (available attributed to initial environmental sensitization to cat serum albu-
at www.cofargroup.org), although more validation is needed. min)74 and wheat allergy induced by using wheat proteinbased
Advanced tests evaluating the specific proteins to which IgE binds soap.75 Here again environment and genetics conspire. Skin expo-
in a food, the epitopes within the protein that are recognized, and sure to environmental food allergens might be a sensitizing route,
the affinity of binding might carry additional prognostic indica- particularly when there is epithelial barrier dysfunction, such as in
tors.59-61 Additional studies, perhaps combining clinical and those with AD.76 This theory was supported by a study showing
additional laboratory investigations, might provide more insight that filaggrin (FLG) loss-of-function mutations are associated
into prognostication. 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
PATHOGENESIS (n 5 700) from a large cohort that was extensively tested for
There is a complex interplay of environmental influence and sensitization and clinical food allergy.77 After adjusting for
genetics that underlie the immunopathogenesis of food allergy eczema, FLG mutations were associated with food sensitization
and the manifestations of various food-induced allergic disorders. (OR, 3.0; 95% CI, 1.0-8.7; P 5 .043). However, after adjustment
In this issue of the Journal, Oyoshi et al9 describe insights on for risk of clinical food allergy among those sensitized, there was
etiology determined from murine models. Prior reviews address no further influence of FLG mutations, suggesting this mutation is
the role of antigen-presenting cells, T cells, humoral immune not playing a role in progression of sensitization to clinical
responses, homing receptors, signaling pathways, dietary factors, allergy.
underlying inflammatory states, microbiota, effector cell func- A very interesting and novel form of food allergy that is
tion, and other aspects of the immune response to dietary manifested clinically by delayed allergic responses and anaphy-
antigens.62-67 Here we consider several observations from clinical laxis hours after ingestion of mammalian meat has been linked
studies that have recently revised our understanding of the cause to sensitization to carbohydrate galactose-a-1,3-galactose (a-
of food allergy. Gal).78 The route of sensitization appears to be from tick bites
Elucidating gene-environment interactions is crucial for un- based on clinical circumstances and detection of a-Gal in the
derstanding pathogenesis. For example, in a prospective study of gut of the tick Ixodes ricinus.79-81 The a-Gal epitope is a major
970 children, breast-feeding was associated with an increased risk blood group substance of nonprimate mammals, and there is
of food sensitization, but the effect was dependent on functional likely a predilection for sensitization among those with
genetic variants in the IL-12 receptor b1, Toll-like receptor 9, and B-negative blood groups.82 The reason for the delayed reactions
thymic stromal lymphopoietin genes.68 In another study taking a remains to be elucidated. Thus a-Gal allergy is unique for the
deeper look at the vitamin D hypothesis, Liu et al69 evaluated a allergen being a carbohydrate, the exposure being through the
Boston birth cohort (n 5 649) and did not find an association of intracutaneous route, and the time course of the reaction being
cord blood vitamin D levels with sensitization to food allergens delayed. Elucidating these factors further will likely provide
in early childhood. However, when examined with candidate more insights on the pathophysiology of other food allergies
gene single nucleotide polymorphisms, a significant interaction as well.
indicating a risk for sensitization was identified for an IL4 gene The manner of food preparation and processing and the
polymorphism and 3 other genes. nonprotein components of foods also likely play a role in
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- destroys some relevant food allergens, such as birch homologous
biotics is an avenue of therapy in response to this influence. The proteins in fruits or tertiary protein structures in milk or egg, or
immune consequences are slowly being elucidated. Forsberg creates more potent allergens, such as through the Maillard
et al71 reported on children undergoing probiotic supplementation reaction of nonenzymatic browning in which heating results in a
in a controlled trial and found that this supplementation was asso- chemical reaction between reducing sugars and proteins to form
ciated with decreased allergen-induced production of IL-5 and advanced glycation end-products in roasted peanut.83 For
IL-10 and higher levels of ovalbumin-induced CXCL10 at birth example, invariant natural killer T cells can be activated by sphin-
and CCL17 at 24 months, suggesting a greater capacity for im- golipids presented through CD1d molecules to produce TH2 cyto-
mune regulation. kines, raising the possibility that these components in foods might
The key immune factors responsible for allergy outcomes are direct an allergic response to foods. In a series of experiments
under intense investigation. In the COFAR cohort described comparing PBMC responses from children with CMA, egg
above,72 mononuclear cell allergen stimulation screening was allergy with tolerance of milk, and healthy control subjects,
performed with PCR analysis to 7 key markers of immune regu- Jyonouchi et al84 showed that milk sphingomyelin can induce
lation and TH1/TH2 bias. Only allergen-induced IL4 expression invariant natural killer T-cell activation and TH2 cytokine
J ALLERGY CLIN IMMUNOL SICHERER AND SAMPSON 295
VOLUME 133, NUMBER 2

production and that the response is more exuberant in children elimination diet with 36 children, finding that one food was a
with CMA. Ilchmann et al83 observed that heating ovalbumin trigger for 72% and that milk (74%), wheat (26%) and egg
with glucose enhanced activation of ovalbumin-specific CD41 (16%) were the 3 most common causes.
T cells and increased IL-4 levels. Myeloid dendritic cell uptake Spergel et al92 performed a review of 941 patients, of whom
of the processed ovalbumin was enhanced, and specific dendritic 319 had definitive food-responsive disease diagnosed based on bi-
cell receptors were identified that mediated the process. Masila- opsy results. An empiric 6-food elimination diet or removal of
mani et al85 showed that dietary isoflavones suppressed allergic foods eliciting positive test results had a success rate of 53%,
sensitization to peanut; these are abundant in soy and not peanut, although test-directed diets resulted in an average of only 3 foods
perhaps explaining why one legume is more allergenic than removed. Milk, egg, wheat, and soy were the most common cul-
another. These observations and others86 set the stage for addi- prits. Removal of foods identified on skin testing with empiric
tional work to identify characteristics of foods that promote elimination of milk led to resolution in 77% of patients, milk
allergic responses and might elucidate immune intervention alone had a 30% response, and milk, egg, wheat, soy, and meats
strategies. 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
DIAGNOSIS foods revealed that 36% of the responding patients had 1 trigger
The overarching approach to diagnosis requires a careful and 31% had 3 or more triggers. Overall, although there is
history linked to an understanding of the clinical manifestations, some debate about the utility of diagnostic tests,6 a diagnosis of
an understanding of the epidemiology and immune cause, and EoE should raise suspicion about food triggers, with a motivation
incorporation and interpretation of appropriate tests.1,2 A detailed to attempt dietary treatment.
familiarity with the gamut of food-induced allergic disorders
and their pathophysiology is necessary to achieve a successful
diagnosis. Diagnostic approaches
The general approach to diagnosis of food allergy has been
reviewed previously.1 Modalities that were recommended in the
Clinical disorders 2010 Expert Panel Guidelines include medical history and phys-
The National Institute of Allergy and Infectious Diseases ical examination, elimination diets, SPTs, sIgE measurements,
Expert Panel identified 4 categories of immune-mediated adverse and OFCs.2 Among tests not recommended or not recommended
food reactions (eg, food allergies), namely IgE-mediated, non for routine use were intradermal tests, total serum IgE measure-
IgE-mediated, mixed, or cell-mediated reactions, and placed ments, APTs, and the use of APTs, sIgE measurements, and
celiac disease among nonIgE-mediated disorders and allergic SPTs in combination, and a number of nonstandardized and
contact dermatitis among cell-mediated disorders.2 Considering unproved tests were specifically not recommended, including
that various target organs can be affected by food allergies (eg, measurement of basophil histamine release, applied kinesiology,
the skin, gut, respiratory tract, and cardiovascular system) and allergen-specific IgG4 measurement, electrodermal testing, and
the numerous immune pathologies, a wide spectrum of disease several others.
falls under the umbrella of food allergies. Table E1 in this articles Since the time of the expert panel guidelines, a number of
Online Repository at www.jacionline.org shows clinical disor- studies have refined the way currently available testing can be
ders, their key features, immunopathophysiology, natural course, used, including the next generation of sIgE tests, those evaluating
and diagnostic considerations.1,2,78,87-89 There are a number of components or specific proteins within foods, often termed
disorders that are not food allergies but might appear similar. component-resolved diagnostics (CRD). However, the basic
For example, toxic reactions, such as scombroid fish poisoning, approach to diagnosis remains essentially unchanged and is
in which spoiled dark meat fish contains histamine-like toxins; summarized in Fig 1. The medical history is used to estimate the
neurologic responses, such as auriculotemporal syndrome, in chance (prior probability) of allergy and culprit food(s), and appro-
which foods that trigger increased salivation also result in a reflex priately selected and interpreted minimally invasive tests are used
facial vasodilation of the lower cheek; or gustatory rhinitis, in to arrive at a posttest probability of allergy.94 Short of a conclusion
which spicy foods result in rhinorrhea, all mimic food allergies. that there is a high probability or extremely low probability of al-
It is important to recognize that chronic asthma and chronic lergy, an OFC might be required for a final diagnosis. Allergists
rhinitis are not likely solely related to food-induced allergic appear to avoid performing OFCs, apparently because of risk,
reactions. Similarly, although food can trigger AD in a subset cost, time, and other factors.95 However, it is crucial to include
of patients, many additional triggers exist, including irritants, OFCs in the diagnostic armamentarium. Recent studies underscore
infection, and environmental allergens. why. Concerning efficacy, in a study of 125 children primarily with
Recent studies have further elucidated the important role of AD who were avoiding foods for a variety of reasons, 89% of 364
foods in patients with EoE. Henderson et al90 evaluated their di- OFC results were negative, allowing significant dietary expan-
etary approach using 98 children with EoE and found remission sion.96 Regarding safety, an office-based study of 701 OFCs had
for 96% among 49 patients treated with an elemental diet, 81% 19% positive challenge results, with only 2% of the challenges
for 26 patients on a 6-food elimination diet (2 variations were requiring treatment with epinephrine.97 Additionally, performing
used, with avoidance of milk, egg, wheat, soy, peanuts, tree OFCs can improve quality of life, particularly when results are
nuts, fish, and shellfish for all, and 15 avoided additional foods favorable.98 It is important to ensure a full portion of the tested
that resulted in positive test results), and 65% for 23 patients food is successfully ingested to reduce the risk that an uneventful
whose diets were determined by SPTs, atopy patch tests OFC is followed by allergic reactions on a subsequent ingestion,
(APTs), or both. Similarly, Kagalwalla et al91 used a 6-food which theoretically could be due to gradual escalating portions
296 SICHERER AND SAMPSON J ALLERGY CLIN IMMUNOL
FEBRUARY 2014

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- oil based (oleosins) and might otherwise have negative test results
based OFCs100 was devised, and a consensus report toward with standard reagents.105 Although evaluating sIgE in the context
standardizing double-blind, placebo-controlled OFCs was pub- of total IgE is not recommended based on one study,113 another
lished.101 In 2013, 2 new Current Procedural Terminology codes recent study114 noted correlations in total to specific IgE levels
replaced a single prior code for OFCs, likely improving reimburse- for children tested to egg, milk, soy, and peanut, and another noted
ment, and hopefully resulting in increased use of the procedure. that consideration of total IgE levels was helpful in predicting al-
Clearly, physicians and patients would prefer to have better lergy in combination with other parameters.115 More studies are
diagnostic tests to avoid OFCs. Standard SPTs and sIgE tests go a needed to elucidate whether evaluating ratios of levels of
long way in assisting in diagnosis. Lessons learned from a number sIgE to total IgE is informative over sIgE levels alone. For
of studies are compiled in Table I,1,2,92,94,100,102-112 showing nonIgE-mediated allergy, the utility of the APT for
pearls and pitfalls. Unfortunately, there remain relatively few EoE remains controversial,90,92 but studies now suggest the
studies correlating food allergy outcomes against skin test size approach does not elucidate reactivity in food proteininduced
or sIgE concentration, and it is clear that such calculations are enterocolitis.87,88
influenced by referral base, decisions to undergo testing by The increasing availability of CRD is further refining the
patient/family and physician, geography, test characteristics, diagnosis of IgE-mediated allergy. The reasons that evaluating IgE
interpretation of OFC outcomes, age of patients, underlying binding to specific proteins within a food might provide additional
disease, and other factors.100 For example, in a unique diagnostic information includes the following possibilities: (1)
population-based Australian cohort of infants who underwent recognition of specific proteins that behave as potent allergens (ie,
testing and OFCs, 95% predictive values for allergic reactions ones that are stable to digestion) might be relevant compared with
were determined as follows: egg (SPT wheal, > _4 mm; sIgE level, recognition of proteins that are heat labile or homologous to pollens;
_1.7 kUA/L), peanut (SPT wheal, >
> _8 mm; sIgE level, >
_34 kUA/L, (2) binding to multiple proteins within an allergen might carry
when history is not taken into consideration), sesame (SPT wheal, diagnostic significance; and (3) differentiation of degrees of binding
_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 the methods suffer from some of the same limitations that the
fresh fruits can be frozen and then reused for fresh skin standard tests carry. For example, the degree of binding is relevant,
testing104 and that a sesame oil contact test might be helpful specific test platforms might differ, and there could be differences by
to identify patients who are reactive to sesame proteins that are geography, age, and target organ reactivity. More studies are needed
J ALLERGY CLIN IMMUNOL SICHERER AND SAMPSON 297
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TABLE I. Pearls and pitfalls regarding diagnosis of food allergy1,2,94,100,102-112


Pearl/observation Additional details Clinical application

A positive skin test or serum Screening with indiscriminate panels of tests is poorly informative. History and epidemiologic
food-specific IgE test result Screening tests with common allergens that have not been ingested and tolerated but pose considerations should guide
indicates sensitization but not increased risk can be considered (eg, tree nuts for a child who reacted to peanut but has not test selection.
necessarily clinical allergy. 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).
Dose, manner of preparation, and d Alcohol, NSAIDs, and exercise are among eliciting factors that might d History should focus on
ancillary (eliciting) factors facilitate a reaction. amounts triggering a reaction
might alter reaction outcomes. 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.
IgE binding to homologous Rates of clinical cross-reactivity: d Care should be taken in not
proteins among food groups overtesting.
and between foods and pollens Allergy to: Related food Approximate clinical d For some categories, food
might have variable clinical reaction rate avoidance of entire group might
relevance. 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%
Tests for serum food-specific IgE In the United States, there are 3 major test manufacturers. Care must be taken in evaluating test
might not provide comparable results over time when different
results among manufacturers. manufacturers are used.
Component testing might Food Labile Stable Concentration of IgE binding to
differentiate clinical reactivity Peanut Ara h 8 Ara h 1, Ara h 2, Ara h 3, components also relates to
(IgE binding to potent stable Ara h 6 outcomes, but similar to standard
allergens) from less clinically Hazelnut Cor a 1, Cor a 2 Cor a 9, Cor a 11, Cor a 14 tests, correlations have not been
relevant sensitization (binding Soy Gly m 3, Gly m 4 Gly m 5, Gly m 6 established and vary by, for
to labile proteins). example, center and patient
selection.
Caution: severe reactions can occur
despite lack of noted binding to
measured allergen (see text).
Serum/skin test results might be d This could be due to reagent lacking relevant protein. d Do not discount a convincing
negative despite clinical d This could be because the reaction is not IgE mediated. history because of a negative
reactivity. 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.
Increasingly high serum d Correlation of tests with outcomes vary by center, age, and disease (equivalent d Test results should not be
food-specific IgE levels or results are generally more predictive of allergy in a younger patient). viewed solely as positive/
increasingly larger skin test d Results are not highly correlated with severity. negative.
wheal size indicate higher d Results can be followed over
chances of clinical allergy. time to monitor allergy persis-
tence/resolution.
d Specific correlative values
might not be applicable over all
patient groups.

(Continued)
298 SICHERER AND SAMPSON J ALLERGY CLIN IMMUNOL
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TABLE I. (Continued)
Pearl/observation Additional details Clinical application
At specific high levels of IgE Food Mean age, 5 y; Mean age, 5 y; Age <2 y; d OFCs can be deferred, particu-
or large skin tests, clinical 50% react* ;95% react ;95% react larly if there is a clinical history.
reactivity is highly likely; Egg 2 7 2 d When evaluating individual
however, studies are limited, Milk 2 15 5 studies, predictive values might
and variations in diagnostic Peanut 2/5 14 not apply to populations with
cutoff values are reported. different demographic and
referral patterns.

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 to these proteins has been observed in some patients with severe
populations, but proof of concept has been attained for many foods, reactions to peanut. Of note, the predictive value of SPTs remains
including egg,116 milk,117 wheat,118 soy,119 fruits,120-123 shrimp,124 competitive with these serum tests.138
hazelnut,125 peanut,94,106-110 and others. As indicated above, CRD for additional foods are emerging.
Studies on peanut provide helpful illustrations of the utility and With regard to milk and egg, clinical reactivity to whole or
limitations of CRD. With regard to geographic differences, a good baked forms has garnered diagnostic interest, pitting standard
example is illustrated by Vereda et al,126 who evaluated component tests against component testing.139,140 Considering egg, studies
testing in children with peanut allergy from 3 regions, showing that have suggested that IgE binding to ovomucoid is superior to
Spanish patients were primarily sensitized to lipid transfer protein standard tests,141,142 but there are contrary results.116 Caubet
(Ara h 9), Swedish patients to birch-related protein (Ara h 8), and et al143 related outcomes of baked egg OFCs to levels of
US patients to seed storage proteins (Ara h 1-3). These results also specific IgE and IgG4 to ovomucoid and ovalbumin, establish-
correlated with severity of outcomes, with the least severe being ing whether IgE/IgG4 ratios were additionally informative. The
related to birch sensitization and the most severe associated with rationale for this approach is that IgG4 levels increase during
reactivity to seed storage proteins. successful immunotherapy. Indeed, baked eggreactive children
The predictive value of CRD is best studied for peanut allergy. had higher ratios, and inclusion of IgG4 levels in logistic
When binding is only identified to the birch protein homolog Ara h regression models was more informative than sIgE levels alone.
8, prognosis is excellent. In evaluation of 144 Swedish children only However, standard sIgE tests provide helpful information that
sensitized to Ara h 8, all but 1 could tolerate peanut ingestion, as should not be ignored. Lieberman et al144 reported the results
reported from natural ingestion or during OFCs to roasted pea- of 100 OFCs to baked egg in children, with a 66% rate of
nut.127 Binding to Ara h 6, which is not often measured, might be tolerance. Measurement of serum IgE levels to egg white
attributed to missing the diagnosis.128 Interpretation becomes and SPTs was performed. The skin test wheal size was not
trickier when there is binding to the stable proteins in peanut informative for predicting outcomes, but an egg white sIgE
(Ara h 1-3 or Ara h 9). Several studies have suggested that Ara h level of 2.5 kUA/L had a negative predictive value of 0.89,
2 is the best predictor of reactivity, with advantages over standard and a level of 10 kUA/L had a PPV of 0.60. The median level
peanut testing.18,129 However, the predictive value of a given result for those who reacted was 5.85 kUA/L compared with
varies among studies. For example, at an Ara h 2 concentration of 2 2.81 kUA/L in those who were tolerant.
kUA/L, probabilities of reactions were as follows: positive predic- Ultimately, stepped approaches to testing might be the most
tive value (PPV) of 0.96 and likelihood ratio (LR) of 50 (Australian effective. Dang et al138 compared 5 strategies for diagnosing
birth cohort; age, 1 year); PPV of 0.87 and LR of 7.8 (Netherlands peanut allergy by evaluating test parameters in 200 Australian
suspected allergy; median age, 6 years); and PPVof 0.75 and LR of children with a median age of 14 months, with the test population
4.1 (US referral population; mean age, 7 years, selected for OFC at derived from a population-based study. They considered using
low peanut IgE) levels. Additionally, the Ara h 2 level does not seem high/low diagnostic values of peanut IgE of greater than 15 or
to clearly predict severity.107 It is likely the case that severity is diffi- less than 0.35 kUA/L, SPT wheal sizes of greater than 8 or less
cult to predict because variables not relevant to the test might be than 3 mm, or Ara h 2 levels of greater than 1.0 or less than
involved, including dose eaten, state of health, and cellular and 0.01 kUA/L based on prior studies. Using peanut IgE alone
target organ reactivity. However, despite earlier studies to the con- would have resulted in 95 OFCs, SPT alone would have resulted
trary,130,131 recent studies are increasingly suggesting that peanut in 50 OFCs, and Ara h 2 would have resulted in the need for
IgE levels might relate to severity132-134 and that CRD might add 44 OFCs. However, a stepped approach of testing peanut IgE
additional information. For example, among children with persis- followed by Ara h 2 would have reduced the need for OFCs
tent peanut allergy in a referral population, initial peanut-specific to 32, and SPTs followed by Ara h 2 would have reduced the
IgE levels of greater than 24.8 to 99.9 kUA/L had an OR of 2.0 need to only 21 OFCs. In a further sophistication of using avail-
and peanut-specific IgE levels of greater than 100 kU/L had an able data, Dunn Galvin et al115 showed that by using a predictive
OR of 3.3 compared with having an initial peanut-specific IgE level model based on 6 parameters, SPT, serum food-specific IgE,
of less than 4.8 kU/L for severe reactions.56 A number of studies total IgE, symptom history, sex, and age, they could
suggest that severity correlates with binding to multiple proteins, calculate the likelihood of reactions (97% accuracy) or tolerance
such as several from among Ara h 1 to Ara h 3.135-137 Nonetheless, (94% accuracy) to peanut, milk, and egg better than with
clinicians should be cautious because binding to Ara h 1 to Ara h 3 individual parameters. This approach was validated in another
does not necessarily diagnose a severe reaction and lack of binding setting.145
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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 diagnostic efficiency was higher when binding to individual
improved prognostics and less reliance on OFCs, will likely be epitopes rather than when specific proteins were used, and more
based on cellular and humoral testing and more sophisticated intense and diverse epitope recognition defined those with clinical
algorithms to interpret test results. Beyond CRD, one can measure allergy rather than clinically irrelevant sensitization.146 Another
binding to specific epitopes within proteins, evaluating binding example with CMA61 compared the progression of epitope
patterns, degree, and affinity. Considering shrimp as an example, binding of milk proteins in children with resolved or persistent
300 SICHERER AND SAMPSON J ALLERGY CLIN IMMUNOL
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allergy. Binding patterns were stable over time for those with with those not being bullied, but parental awareness of the
persistent allergy, but among those with early recovery, IgG4 bullying was associated with a significantly less affected quality
epitope binding increased while IgE binding to corresponding of life. The educational advice responsive to these study findings,
epitopes decreased. Different epitope-binding patterns were as well as selected key management issues from other publica-
also noted to differentiate clinical phenotypes of CMA59: a wider tions, are incorporated in Table II.2,3,152,157-163 School food
diversity of IgE epitope binding was noted for those with allergy management guidelines from the US Centers for Disease
persistent CMA and more severe reactions and was more likely Control and Prevention are now available (www.cdc.gov/
to occur in children who could not tolerate extensively heated HealthyYouth), and educational materials developed and vali-
forms of milk (eg, in muffins) compared with those who could dated through COFAR161 are available at www.cofargroup.org.
tolerate such foods. In competitive peptide microarray assays, When completing written emergency anaphylaxis treatment plans
children with persistent CMA were fully differentiated from those that include an antihistamine, the physician should consider a
with resolved allergy or tolerance of extensively heated forms by recent study indicating the equivalent effectiveness of cetirizine
having high compared with low affinity binding, respectively. and diphenhydramine, with more potential of the former to avoid
Increasingly sophisticated approaches are being evaluated. Lin sedation,164 and address the increasing options for autoinjectors
et al147 used microarray immunoassays to map epitopes on the that are currently available.165
major peanut proteins and then used a bioinformatics approach A vexing concern is how to manage advisory (may contain)
to identify patterns that were most informative. This approach food labeling, which is voluntary in most countries. Ford et al166
performed significantly better than standard methods. evaluated a sample of 401 foods for the presence of milk, egg, or
In addition to testing humoral responses, diagnosis with T-cell peanut when those foods had advisory labels (eg, may contain)
proliferative responses,148 metabolomics,149 and basophil activa- or did not have such warnings. Overall, 5.3% of the products with
tion140,150,151 are under study. 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
MANAGEMENT/TREATMENT observed for peanut. Crotty and Taylor167 focused on products
Avoidance and emergency management with advisory labeling for milk and found high rates of contami-
The current approach to management substantially relies on nation (42%) primarily accounted for by chocolates. Although the
allergen avoidance and preparation to promptly treat allergic level of allergen is low in many cases, there are clearly risks pre-
reactions. These tenets of treatment require significant patient sent for sensitive patients. To potentially improve this conun-
education. Aspects of care that have been recently reviewed in this drum, more data are needed on thresholds of reactivity, which
Journal include the following:2,3,152 circumstances warranting are emerging,168 and also guidance from regulatory agencies,
prescription of self-injectable epinephrine, the importance of consumers, manufacturers, and other stakeholders so that labeling
education about prehospital treatment of reactions, education can be regulated without overestimating or underestimating
about avoidance (eg, cross-contact, traveling, restaurants, school risk.169,170 Currently, it is potentially safer to advise patients to
issues, and label reading), legislation regarding labeling, avoid such labeled products, but avoidance carries an effect on
food manufacturing, and increasing access to epinephrine, the quality of life, and individualizing advice might be rational for
availability of advocacy organizations, and numerous resources selected patients who are deemed less sensitive. A good example
for education developed by a number of constituencies. of allowing some trace exposure (very small risk) against a stron-
A number of important management lessons were revealed by a ger benefit is the influenza vaccine. The residual amount of egg
multicenter observational study of 512 infants with likely milk or protein in the influenza vaccine appears to be low risk, immuniza-
egg allergy (COFAR).153 Over a median follow-up of 36 months, tion is generally recommended, and egg-free vaccines are
despite receiving care in food allergy centers, the annualized becoming more available.171,172
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 Prevention
(eg, label checking errors and unintentional ingestion), with Several guidelines contain updated dietary prevention recom-
additional errors including cross-contact in meal preparation and mendations that rescinded those promulgated more than a decade
food not provided by the parent. Approximately 11% of reactions ago, particularly expunging prolonged allergen avoidance as a
were attributed to nonaccidental exposure, indicating in some means to prevent atopic disease or food allergies.2,162,163 Updated
cases that families might have tried a food to explore whether it summaries are included in Table II.
would be tolerated outside of medical supervision. Of the 11.4% Regarding pregnancy diets, allergen avoidance is not recom-
of reactions that were severe, only 29% of them were treated mended, although studies remain conflicting. In a Danish birth
with epinephrine because the caregiver did not recognize the cohort (n 5 61,980),173 children of mothers with frequent intake
severity, the epinephrine was unavailable, or the caregiver was of peanut during pregnancy compared with those without were
afraid to administer it. Educational opportunities to improve safety less likely (OR, 0.66; 95% CI, 0.44-0.98) to have children with
are evident. asthma at 18 months of age, with a similar finding for tree nut con-
Aside from physical reactions, having food allergy can affect sumption. In contrast, a study from COFAR174 noted that
quality of life, and the psychological welfare of children with maternal ingestion of peanut during pregnancy had a positive
food allergies is important to address.22,154,155 Shemesh et al156 dose-response association with risk of the infant having increased
noted that 45% of children with food allergies reported being peanut sIgE antibody levels (however, clinical peanut allergy rates
bullied, most often without parents being aware. The bullied chil- have not yet been determined). Although exclusive breast-feeding
dren had lower quality of life and increased anxiety compared is recommended for at least 4 months, data about allergy
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prevention from this approach are also mixed. Among 51,119 which parents of at-risk infants delay allergen exposure, influencing
randomly selected 8- to 12-year-old schoolchildren in 21 coun- the conclusions of these studies toward potentially erroneous con-
tries, there was a small increase in the risk of reported eczema clusions of an ill effect from delaying introduction. In a controlled
in association with ever having breast-fed (adjusted OR, 1.11; trial randomizing early exposure to egg in 86 infants at risk for egg
95% CI, 1.0-1.2), and there was no significant association between allergy, a lower but not significant proportion of infants in the egg
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 egg allergy at 12 months of age (33% vs 51%, P 5 .11), possibly
of formula, soy is not considered to have a prevention effect, but suggesting that earlier exposure might not increase egg allergy.
for infants at risk of atopic disease, a hydrolyzed formula with a Taken together, the studies indicate that in an otherwise healthy in-
possibly better advantage of extensively hydrolyzed casein for- fant, there is no rationale to delay introduction of solids and no ratio-
mula (EHCF) might offer protection against eczema over whole nale to defer allergenic foods, although it seems that some
milkbased formulas. However, recent studies on this topic also cautions are warranted, such as using less allergenic foods as initial
remain conflicting, including a single-blind, randomized weaning foods, proceeding gradually, and pursuing more evalua-
controlled trial of a partially hydrolyzed whey-based formula tions, particularly if the infant shows signs of atopy or food-
and a soy or conventional milk-based formula at weaning in induced allergic reactions. A comprehensive approach was recently
high-risk infants, which did not show differences in outcomes outlined.163
for eczema, food reactions, or sensitization.175 In contrast, a An active approach to prevention has focused on prebiotics,
10-year follow-up of a randomized trial of 4 formulas as breast probiotics, synbiotics, and bacterial lysates, essentially
milk substitutes in infants at risk of atopy continued to show a combating the allergy-eliciting nature of a hygienic environment
reduced cumulative relative risk of AD for specific hydrolyzed in- by providing and nurturing nonpathogenic, health-promoting
fant formulas compared with whole cows milk infant formula, bacteria.181 There is some promise, with studies suggesting
with a relative risk of 0.72 (95% CI, 0.58-0.88) for the extensive certain strains, especially when administered both prenatally
hydrolysate of casein. The protection was noted only for AD and postnatally, might at least reduce eczema.182 However,
and not sensitization to foods. In another study of 679 infants studies remain conflicting and inconclusive. For example, Jensen
who were consistently fed the same formula for the first 6 months et al183 presented 5-year follow-up on a randomized postnatal
of life, comparing 345 with hydrolyzed formula with 334 with study of 6 months of treatment with Lactobacillus acidophilus,
cows milk formula, the percentage sensitized to milk protein showing no protective effect for any physician-diagnosed allergic
was significantly lower in the group receiving the hydrolyzed for- disease, but earlier findings of increased risk for sensitization in
mula (12.7% vs 23.4%, P 5 .048).176 Considering these and past treated children were no longer cumulatively significant.
studies,2,171,172 formula selection might provide some atopy pre- A Cochrane database review on prebiotics for prevention of al-
vention, but results for food allergy prevention are weak or lergy in infants, evaluating 4 studies with 1428 infants, concluded
underpowered. that there is some evidence for eczema prevention but also
With regard to the timing and selection of specific complemen- concluded that further research is needed before routine use.184
tary foods, many studies continue to suggest that prolonged A 2012 World Allergy Organization review concluded that probi-
avoidance of solids or specific allergens is not protective and might otics do not have an established role in the prevention or treatment
be a risk factor with regard to atopy or food allergy prevention.163 of allergy.185 Clearly, study results can be affected by strain selec-
For example, Koplin et al39 used a cross-sectional study of 2589 in- tion and other factors. With an increasing number of studies
fants and noted that delayed introduction of egg was associated with that are sensitive to the selection of subjects, timing of treatment,
increased risk of egg allergy compared with introduction at 4 to 6 and strain selection, more definitive conclusions are likely to
months, delaying beyond 12 months carried an adjusted OR of emerge.
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 Future therapies
atopic sensitization, whereas introduction of fish at 9 months or Companion articles in this issue of the Journal8,9 describe ad-
less was inversely associated with allergic rhinitis and atopic sensi- vances in oral, sublingual, and epicutaneous immunotherapies for
tization. Less food diversity already at 3 months of age was associ- foods, as well as a number of approaches under evaluation in murine
ated with a later increase in atopic sensitization. A birth cohort models.186,187 It will be interesting to see whether additional
study in Detroit, Michigan, found that feeding of complementary routes, such as intralymphatic immunotherapy, become viable for
foods before 4 months was associated with a reduced risk of food food immunotherapy.188 Allergen-specific immunotherapeutic
sensitization to peanut and possibly egg by age 2 or 3 years in a sub- approaches include not only oral, sublingual, or epicutaneous
set of the cohort having a parental history of asthma or allergy.179 If immunotherapy with whole allergen but also immunotherapy
there is a period of opportunity in which ingestion is tolerizing, it with modified proteins that were designed to be hypoallergenic to
might vary by food, environmental factors, and genetics. Katz reduce the risk of reactions. Unfortunately, in a pilot safety study
et al40 evaluated a cohort of greater than 13,000 infants and calcu- of heat-killed, Escherichia coliexpressing modified Ara h 1, 2,
lated an OR of 19.3 (95% CI, 6.0-62.1) for development of and 3 as rectal immunotherapy, there were frequent allergic reac-
IgE-mediated CMA among infants exposed after 15 days of age. tions, necessitating a redesign of the study dosing or product.189
Yet another study looking at food allergy outcomes180 found no Additional antigen-specific approaches are under preclinical inves-
difference in the presolids infant diet, but those without food tigation, but combination approaches, such as using allergen
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 has been studied in human subjects, with some promise of
to control for reverse causation, there might be a subtle effect in increased safety.190,191 Although not initially considered an
302 SICHERER AND SAMPSON J ALLERGY CLIN IMMUNOL
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immunotherapeutic approach, a major recent advance in manage- What do we know?


ment is the observation that a majority of children with egg or
CMA can tolerate extensively heated forms of these allergens, d The prevalence of food allergy is high, up to 10% of the
such as in bakery goods, and that ingesting these products might population, and likely increased in the past decades.
speed recovery. In a long-term follow up of children who were d Numerous genetic and environmental risk factors have
able to add baked milk products (eg, muffins) to their diet, tolerance been identified.
of regular milk was 16 times more likely compared with a group
treated with standard-of-care avoidance.192 The treated group d Insights on route of sensitization, allergen characteriza-
showed an increase in milk-specific IgG4 levels. Similarly, Leonard tion, and immune response provide insights for diagnosis
et al193 performed a follow-up study in children with egg allergy and treatment.
who were successfully challenged with baked egg products and d There is a wide spectrum of disease caused by food allergy
ate them routinely. These children were 14.6 times more likely related to different immune mechanisms and the target
than comparison control subjects (P < .0001) to have tolerance to organs affected. Diagnosis depends on combining a
unheated egg. However, these were not randomized trials, and not knowledge of pathophysiology and epidemiology with the
all studies suggest an immunotherapeutic response.194 A study is patients history and test results. It is clearly possible to
underway in COFAR evaluating baked egg versus egg oral have sensitization without clinical reactivity and vice versa.
immunotherapy. d The use of CRD is entering clinical practice.
Therapies that are not allergen specific are especially attractive
d Management currently requires attention to allergen avoid-
because many patients have multiple food allergies. These
ance and emergency treatment, and numerous resources are
approaches include various mAbs, traditional Chinese medicine,
available to patients and physicians to promote education
probiotics, and others.195,196 A trial of omalizumab for peanut al-
and counseling to improve safety and quality of life.
lergy was stopped early for a safety concern related to the food
challenge approach but showed some trend toward efficacy in d Numerous clinical trials are underway for more definitive
increasing the threshold of reactivity.197 An herbal formula to therapies.
treat food allergy was evaluated in a safety trial for 6 months
with no significant side effects and a trend toward decreasing What is still unknown?
eosinophil and basophil numbers, and in vitro tests showed a d The cause for an increase in food allergy
decrease in basophil activation.198 Individual studies are looking
at probiotics for treatment. For example, in one study199 other- d Translation of environmental and genetic risk factors into
wise healthy infants with CMA were given EHCFs (n 5 55), improved prevention
EHCF with Lactobacillus rhamnosus GG (n 5 71), hydrolyzed d The best diagnostic approaches
rice formula (n 5 46), soy formula (n 5 55), or amino acidbased d How to maximize safety and quality of life during
formula (n 5 33), and OFCs were performed after 12 months to management
assess acquisition of tolerance. The rate of tolerance after 12 d The best novel therapeutic options
months was significantly higher (P < .05) in the groups receiving
EHCF (43.6%) or EHCF plus Lactobacillus rhamnosus GG d A personalized medicine approach to diagnosis and
(78.9%) compared with the other groups: hydrolyzed rice formula treatment of food allergy is likely required but remains
(32.6%), soy formula (23.6%), and amino acidbased formula elusive.
(18.2%). More studies are needed to evaluate the safety and
efficacy of all of these approaches, as well as combination Key concepts and therapeutic implications
approaches, by using allergen-specific and nonspecific modalities
or combining approaches serially (sublingual immunotherapy d Identification of food-specific IgE by means of testing in-
leading to oral immunotherapy) or concomitantly. Table E2 dicates sensitization but is not, in isolation, diagnostic.
in this articles Online Repository at www.jacionline.org lists d Knowledge of the epidemiology, natural course, patho-
examples of therapies under preclinical and clinical studies.
physiology, and clinical manifestations of food allergies
and other adverse reactions to foods is required to
approach diagnosis and management. The medical history
SUMMARY is key, noninvasive tests are supportive and possibly diag-
In the 3 years since our last review, remarkable advances have nostic, and the OFC is the most definitive test.
occurred in understanding and managing food allergies. Unfortu-
nately, the intense efforts to improve diagnosis, treatment, and d Management requires attention to education about avoid-
prevention are partly the result of an unexplained significant increase ance and prompt appropriate treatment of anaphylaxis.
in prevalence. Although conflicting studies and disappointing results d Various approaches to treatment are under investigation,
in some clinical treatment trials are frustrating, remarkable advances and patients should be alerted to clinical trials.
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
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307.e1 SICHERER AND SAMPSON J ALLERGY CLIN IMMUNOL
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REFERENCES
E1. Sicherer SH, Sampson HA. Food allergy. J Allergy Clin Immunol 2010;
125(Suppl 2):S116-25.
E2. Boyce JA, Assaad A, Burks AW, Jones SM, Sampson HA, Wood RA, et al.
Guidelines for the diagnosis and management of food allergy in the United
States: report of the NIAID-sponsored expert panel. J Allergy Clin Immunol
2010;126(Suppl):S1-58.
TABLE E1. Food-induced allergic disorders (also see text)E1,E2

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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 J ALLERGY CLIN IMMUNOL
FEBRUARY 2014

TABLE E2. Selected immunotherapeutic strategies


Therapy Immune rationale Benefits Observations to date

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

Revised from Sicherer and Sampson.E1