Advances in allergy, asthma, and immunology series 2018
Advances in food allergy in 2017
Corinne A. Keet, MD, MS, PhD,a and Katrina J. Allen, MD, PhDb,c,d
This review highlights research and policy advances in food
allergy that were published in 2017 in the Journal and beyond.
In 2017, many important studies on the treatment of food
allergy were published, bringing us ever closer to a
standardized treatment for food allergy. Other important
advancements included research into other management
strategies, including thresholds for avoidance, management of
food allergies in schools, and development of new guidelines for
prevention of food allergy. There were several important
epidemiologic studies helping us understand the phenotypes of
allergic disease, and new hypotheses were proposed for how best
to prevent food allergy. Finally, there was a welcome increased
attention to non–IgE-mediated food allergies. (J Allergy Clin
Immunol 2018;142:1719-29.)
Key words: Food allergy, atopic dermatitis
This year in review article will summarize research published in
2017 about food allergy in the Journal of Allergy and Clinical
Immunology and beyond. Our goal is to highlight notable advances
in the management, prevention, and epidemiology of food allergy,
including both IgE-mediated and non–IgE-mediated diseases.
EMERGING TREATMENT PARADIGMS FOR FOOD
ALLERGY
New information about treatments for food allergy is emerging
at a rapid pace. After a decade in which rapid progress was made
in oral immunotherapy (OIT) or sublingual immunotherapy as
potential treatments, 2017 saw a number of publications focused
on newer approaches, including alternative immunotherapy
From athe Division of Pediatric Allergy and Immunology, Johns Hopkins University
School of Medicine, Johns Hopkins Hospital, Baltimore; bthe Murdoch Children’s
Research Institute and dthe Department of Allergy and Immunology, Royal Children’s
Hospital, Melbourne; and cthe Department of Pediatrics, University of Melbourne.
Supported in part by 1U01AI125290 from the National Institute of Allergy and Infectious
Diseases (to C.A.K.).
Disclosure of potential conflict of interest: C. A. Keet is on the Board of the American
Board of Allergy and Immunology; is a member of the FDA Scientific Advisory
Committee on Allergenic Products; receives royalties from UpToDate; and holds a
patent on a sublingual immunotherapy delivery method. K. J. Allen is on the Scientific
Advisory Board of Aravax and BeforeBrands and is a Director of Cabrini Health Ltd,
Raising Childrens Network, and the Australian Food Allergy Foundation.
Received for publication August 20, 2018; revised October 1, 2018; accepted for publi-
cation October 19, 2018.
Available online October 25, 2018.
Corresponding author: Corinne A. Keet, MD, MS, PhD, Johns Hopkins School of
Medicine, Pediatric Allergy and Immunology, 1800 Orleans St, Sheikh Zayed Tower,
Baltimore, MD 21287. E-mail: ckeet1@jhmi.edu.
The CrossMark symbol notifies online readers when updates have been made to the
article such as errata or minor corrections
0091-6749/$36.00
Ó 2018 American Academy of Allergy, Asthma & Immunology
https://doi.org/10.1016/j.jaci.2018.10.020
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Baltimore, Md, and Melbourne, Australia
Abbreviations used
BAMSE: Children Allergy Milieu Stockholm Epidemiology
COPSAC2000: Copenhagen Prospective Studies on Asthma in Child-
hood 2000
ED05: Dose the elicits a reaction in 5% of allergic subjects
EPIT: Epicutaneous immunotherapy
FPIES: Food protein–induced enterocolitis
LEAP: Learning Early About Peanut Allergy
NIAID: National Institute of Allergy and Infectious Diseases
OIT: Oral immunotherapy
PAL: Precautionary allergen labeling
PASTURE: Protection Against Allergy Study in Rural
Environments
delivery and adjuvants to optimize oral approaches. In addition to
aiming to increase treatment efficacy, part of the motivation for
these alternative approaches has been ongoing concern about the
safety profile of OIT, including concerns that there is an increased
risk of eosinophilic esophagitis.1 For example, in a review of 104
subjects treated with peanut OIT in 3 studies, Virkud et al2 found
that 87% of OIT-treated subjects experienced adverse events,
including 72% during build-up and 47% during maintenance.
Forty-two percent experienced systemic reactions, and 20% drop-
ped out, half because of gastrointestinal symptoms. Allergic
rhinitis and larger peanut skin prick test response size before treat-
ment were predictors of higher rates of reactions with OIT but did
not discriminate well between those who experienced adverse ef-
fects and those who do not.
It should be noted that there has been increasing consumer
pressure to access noncommercial options for OIT, and private
practitioners in the United States are now offering OIT in the
nonresearch setting.3 National societies in the United States, Eu-
rope, and Australia have responded to this community expecta-
tion by recommending that OIT only takes place within a
supervised clinical research setting until both safety and efficacy
are more firmly established.4,5
Omalizumab, an anti-IgE mAb, could reduce the risk of these
symptoms, facilitating more rapid dosing or higher retention with
therapy. In a randomized study of omalizumab versus placebo as
an adjuvant to peanut OIT in 37 subjects, 79% of omalizumab-
treated subjects were able to tolerate a 2000-mg peanut dose at the
completion of the trial compared with 12% in the placebo group.6
This study by MacGinnitie et al6 was also unique in the speed of
both initial rush desensitization (which went to a high dose of
250 mg on day 1) and the accelerated weekly escalation to a
dose of 2000 mg over as little as 8 weeks. By comparison, most
initial peanut dose escalation days range from 0.1 to 6 mg3,7-9
and have much longer escalation periods (eg, 4-6 months). The
rush escalation used by MacGinnitie et al6 likely explains the
very poor results in the OIT-only group compared with other
1719
1720 KEET AND ALLEN J ALLERGY CLIN IMMUNOL
DECEMBER 2018

FIG 1. The percentage of subjects receiving AR101 or placebo who were able to successfully tolerate the
indicated dose at the exit double-blind, placebo-controlled food challenge (DBPCFC) is listed on the y-axis
for the primary end point (443 mg cumulative of peanut protein or the 300-mg dose level) and the top chal-
lenge dose tested (1043 mg cumulative of peanut protein or the 600-mg dose level). A, Results for the
intention-to-treat population, in which all subjects withdrawing before the exit DBPCFC are considered
treatment failures. B, Results for the completer population who undertook the exit DBPCFC. Adapted
from Fig 2 from Bird et al.9

OIT studies using slower escalation and might also explain the
overall poorer efficacy and increased rate of reactions and with-
drawls across both groups compared with historical and contem-
porary OIT protocols (eg, Fig 1 shows efficacy results from an
industry-sponsored OIT trial by Bird et al9). A separate report
of 2 cases of eosinophilic esophagitis during a trial of peanut
OIT despite also receiving omalizumab suggests that omalizumab
does not prevent eosinophilic esophagitis,10 as might have been
predicted. Overall, although omalizumab can reduce symptoms
during OIT, effects on efficacy are more mixed and seem relevant
only in rush dosing schemes.
Whether biomarkers can identify a subset of patients receiving
OIT who might most benefit from omalizumab is an open
question. Wood et al11 previously found that there was an
improvement in safety but not efficacy with omalizumab in a non-
rush protocol comparing omalizumab versus placebo as an
adjunct to milk OIT. In a follow-up mechanistic study,
Frischmeyer-Guerrerio et al12 found that measures of basophil
reactivity to milk before treatment, including CD63 activation
to milk and the ratio of this measure to activation to anti-IgE, pre-
dicted a subgroup in which omalizumab appeared to exert a
greater effect on the safety profile. Both the ratio of CD63 activa-
tion to milk to CD63 activation to anti-IgE and the ratio of milk
IgE to total IgE also predicted a differential effect on sustained
unresponsiveness. More work is needed to confirm these bio-
markers of omalizumab.
Another possible solution to improve the efficacy and safety of
food OIT might be to start earlier in life when the immune system
could be more responsive to treatment. In a study of peanut OIT in
children aged 9 to 36 months, 81% were desensitized after a
median of 29 months of treatment, and an impressive 78% had
sustained unresponsiveness for 4 weeks after OIT cessation
(Fig 2).13 A larger placebo-controlled trial of peanut OIT in young
children is currently underway, and studies of OIT in infants will
start soon, testing the hypothesis that OIT might work best in a
critical window of immune development.
A potentially safer alternative to OIT might be epicutaneous
immunotherapy (EPIT), but questions remain about efficacy. In a
phase IIb study of epicutaneous patch for peanut allergy, 221
patients were randomized to placebo versus 3 different
epicutaneous doses (range, 50-250 mg) given daily for 12 months
followed by a 2-year open label extension. After 12 months, 50%
of those at the highest dose were labeled ‘‘responders’’ (reacting at
>
_1000 mg of peanut protein or > _10 times the initial dose of peanut
protein) compared with 25% of those treated with placebo.14 The
treatment effect appeared to be limited to 6- to 11-year-old chil-
dren, in whom the response rate was 54% at the highest dose
compared with 20% for the placebo, with no effect noted in ado-
lescents/adults.
In a smaller study of 74 subjects randomized to placebo or
treatment patch at 100 or 250 mg for 52 weeks, treatment success
(defined as passing either a 5044-mg protein food challenge or
consuming > _10-fold increase in dose from baseline) was achieved
by 46% in the 100-mg dose group and 48% in the 250-mg dose
group compared with 12% of placebo-treated subjects. In all
treated subjects the achieved end point was the 10-fold increase,
with no treated subjects passing the full food challenge after
treatment. Notably, if the criteria of success were changed to
consuming at least 1044 mg at food challenge, only 28% of those
treated with the higher dose would have ‘‘succeeded’’ compared
with 12% of placebo-treated subjects (Fig 3).15 Thus, to date,
EPIT provides limited protection to a minority of treated subjects.
At least in mice, the mechanism of EPIT appears to be distinct
from that of OIT. Tordesillas et al16 found in a C3H/HeJ model of
ovalbumin allergy that EPIT induced generation of gastrointes-
tinal homing LAP1FoxP2 regulatory T cells, which suppressed
mast cell activation through a TGF-b–dependent mechanism. In
contrast, oral administration of antigen did not induce regulatory
T cells in this model.
Animal models might suggest other potential future targets for
food allergy. Honjo et al17 reported that inhibition of Notch2-
mediated signaling alleviated both systemic anaphylaxis and
allergic diarrhea in a mouse model of food allergy. Dendritic
cell immunotherapy, as outlined by Dawiciki et al,18 could be
another method to reverse food allergy; in a mouse model they
found that immunotherapy with mature retinoic acid–skewed
dendritic cells induced tolerance to both ovalbumin and peanut.
Altered or recombinant antigen immunotherapy for food
allergy has not been successful thus far,19 but the underlying the-
ory remains compelling. Freidl et al20 report on a mouse model of

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J ALLERGY CLIN IMMUNOL KEET AND ALLEN 1721
VOLUME 142, NUMBER 6

FIG 2. Outcomes of early OIT (E-OIT) and standard-of-care treatment. A, Clinical outcomes of E-OIT. Propor-
tion of overall subjects and those in each treatment arm achieving sustained unresponsiveness are shown
for both intent-to-treat (ITT) and per-protocol (PP) analyses. B, Distributions of peanut-specific IgE among E-
OIT participants and matched control subjects practicing allergen avoidance at baseline and end-of-study
periods (median, 29 and 43 months, respectively). Note that all peanut-specific IgE levels of greater than
100 were transformed to 101 for these analyses because dilutional analysis was not available for all high-
titer samples. C, Proportions of E-OIT and control participants able to reintroduce peanut-containing foods
in the diet at the end of the study period. D, Imputed proportions able to reintroduce peanut-containing
foods in the diet with evidence-based worst-case assumptions. Adapted from Fig 2 from Vickery et al.13

fish allergy in which immunotherapy with recombinant fish al-
lergy induced blocking antibodies that inhibited allergic reactions
on passive transfer. Significant hurdles to translating this into a
safe therapy in the clinic remain.
OPTIMIZING MANAGEMENT OF FOOD ALLERGY
Currently, most practitioners treat all patients given a diagnosis
of peanut allergy as capable of severe reactions with minute
exposure and recommend avoidance of foods with peanut-related
precautionary allergen labeling (PAL),21 although clinical prac-
tice in this regard has been changing.22 Consumer confusion
reigns. Marschiotto et al21 found that almost half of consumers
falsely believed that the law requires PAL. A third believed that
PAL statements were based on amounts of allergen present, and
up to 40% of consumers with food allergy purchased products
with PAL.21
To provide some guidance about exposures likely to trigger
symptoms at the population level, Hourihane et al23 evaluated 378
children with peanut allergy with a single 1.5-mg dose oral food
challenge, with the goal of finding the dose the elicits a reaction in
5% of allergic subjects (ED05). At this dose, 65% of children had
no reaction at all, 18% reported subjective findings without objec-
tive findings, 15% had mild and transient signs that did not meet
the authors’ definition of a reaction, and only 2.1% had objective
signs likely related to the exposure. All reactions were mild. The
single low-dose food challenge approach might ultimately iden-
tify highly sensitive (and less sensitive) populations, allowing
for tailored approaches to avoidance, but the reproducibility of
this measure and its application to real-world exposures need to
be demonstrated before practices change. There has been some
interest in using this screening step in clinical practice to identify
those patients with food allergy who are exquisitely sensitive and
should take extra precautionary steps to avoid allergen of less than
the ED05 threshold level.24
Whether to ban peanuts and tree nuts in schools as allergies to
these foods increase in frequency is controversial. Bartnikas
et al25 surveyed schools in Massachusetts, where there is manda-
tory reporting of epinephrine use, to understand how policies
related to these foods affected the rate of epinephrine use in the
schools. They found that the designation of ‘‘peanut-free’’ did
not decrease the need for epinephrine for peanut/tree nut reac-
tions, whereas the use of peanut/tree nut–free tables was associ-
ated with lower use. In a separate internet survey of parents of
children with peanut allergy, peanut-free schools were not associ-
ated with improved quality of life.26
Anaphylaxis to foods is not restricted to the ‘‘major’’ food
allergens; a case report in the journal Pediatrics presented the first
reported case of anaphylaxis to crocodile meat. The patient, a 13-
year old boy, had a severe IgE-mediated allergy to chicken meat.
The authors identified crocodile a-parvalbumin as the likely
allergen and found that it had extensive homology to chicken a-
parvalbumin.27 This might not be surprising because Crocodilians
are the reptiles most closely related to birds, sharing a common
ancestor with only each other and dinosaurs.28 Perhaps there is
some truth to the cliche ‘‘tastes like chicken.’’
Pursuit of factors that can predict either severity of anaphylaxis
or the risk of a biphasic anaphylaxis reaction remains elusive,
although Lee et al29 found prior anaphylaxis, unknown inciting
trigger, and delayed epinephrine use were risk factors for biphasic
reactions. It should be noted that among 872 anaphylaxis-related
visits to 1 emergency department, only 4% were biphasic.
Part of the difficulty in predicting the severity of anaphylaxis is
because we do not fully understand the cells involved in
anaphylaxis in human subjects. It has been suspected that
basophils might be important, and Korosec et al30 showed in

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1722 KEET AND ALLEN J ALLERGY CLIN IMMUNOL
DECEMBER 2018

FIG 3. Change in successfully consumed peanut dose after EPIT. Adapted from Fig 2 from Jones et al.15

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J ALLERGY CLIN IMMUNOL KEET AND ALLEN 1723
VOLUME 142, NUMBER 6

FIG 4. Effect of early versus late dietary introduction of allergenic food (egg, milk, or peanut) on risk of food
allergy to the same food. Data are from randomized clinical trials. Event refers to allergy to the same food.
The size of the data markers is proportional to study weights in the meta-analysis. Adapted from Fig 1 from
Ierodiakonou et al.39

patients presenting to the emergency department with anaphy-
laxis or undergoing food challenge that basophil markers increase
and basophil numbers decrease, suggesting migration to the tis-
sues and implicating the basophil in human anaphylaxis.
The improved early identification of food allergy has now led to
increased clinical awareness of the equal importance in timely
identification of tolerance development among children with food
allergy.31 This is particularly so with the emergence of novel ther-
apies that can be costly to the individual and the health care sys-
tem. Following the new National Institute of Allergy and
Infectious Diseases (NIAID) guidelines for peanut allergy pre-
vention, Bird et al32 have updated recommendations for safely un-
dertaking peanut challenge protocols in young infants. Data
comparing the prevalence and types of food-induced allergic re-
actions in the community compared with challenge clinic reac-
tions in young children are also now available,33 as are data on
the safety of food exposure after a negative challenge result.34
PREVENTION OF FOOD ALLERGY
Given the current limitations of food allergy treatments,
prevention of food allergy remains a priority to help contain a
condition that is overwhelming some allergy services. In our
current post–Learning Early About Peanut Allergy (LEAP) study
era, the tide has shifted from delayed introduction of foods to
prevent allergy to encouragement of earlier introduction. In 2017,
at least 4 randomized controlled trials extended the evidence
beyond early introduction of peanut to evaluate egg introduc-
tion.35-38 Taken together,39 these studies suggest that early egg
introduction can also protect against egg allergy but also raise
concerns about the use of uncooked egg powder for early intro-
duction because many infants were reactive to this form of egg.
Of the 4 studies, the best results for both efficacy and safety
came with cooked egg in a protocol that further incorporated
skin care into treatment.35
Further reassurance about the safety of early introduction of
solid foods was provided in 2017 by 2 studies that indicated that
autoimmune diseases were not triggered by early introduction to
specific foods. In a randomized double-blind trial of infants at
high risk of celiac disease, Hyytinen et al40 found that casein hy-
drolysate formula did not prevent celiac disease compared with
cow’s milk formula. Similarly, a meta-analysis published in the
Journal of the American Medical Association found no relation-
ship between the timing of food introduction and autoimmune
disease (Fig 4).39 These findings were reassuring that early intro-
duction to prevent allergy will not adversely affect the prevalence
of autoimmune diseases.
In 2017, expert societies began releasing updated infant
feeding guidelines in response to these data.41 In the United
States, the NIAID-sponsored guidelines were based on the spe-
cific inclusion criteria and screening schema of the LEAP study,
recommending introduction of peanut-containing foods as early
as 4 to 6 months for infants with severe eczema or egg allergy
and at about 6 months for infants with milder eczema, and further
recommending screening for the highest-risk infants before intro-
duction (Fig 5).42
Other countries have taken a different approach.43,44 For
example, Australia released guidelines after a 2016 Infant
Feeding Summit recommending that infants begin introducing
solid foods at around 6 months (but not before 4 months) and

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1724 KEET AND ALLEN
FIG 5. Summary of the 3 addendum guidelines to be used as a quick reference. Used with permission from
Togias et al.42
that all infants should be given allergenic solid foods including
peanut butter, cooked egg, dairy, and wheat products in the first
year of life, irrespective of risk category. In addition, they do
not recommend hydrolyzed infant formula for the prevention of
allergenic disease. These recommendations were subsequently
entirely accepted by the US National Academy of Sciences
Expert Committee and outlined in the publication ‘‘Pathways to
food safety.’’45 A joint statement from the Scientific Advisory
Committee on Nutrition and the Committee on Toxicity of Chem-
icals in Food, Consumer Products and the Environment also rec-
ommended that the United Kingdom government adopt very
similar guidelines to Australia.46 Movement toward consistent,
evidence-based, and standardized infant feeding guidelines will
help settle the confusion felt by parents as they navigate the
myriad recommendations available for infant feeding.
One controversy is whether certain infants should be screened
before peanut. The NIAID-sponsored guidelines do suggest
screening certain children before peanut introduction, whereas
other countries, such as Australia and the United Kingdom, do
not. The arguments against screening include resources required
for screening because screening a segment of the population
might be costly and stress the health care system47,48 but also
include the idea that screening can have other unintended conse-
quences, such as false-positives and ‘‘screening creep.’’ Further-
more, there is concern about a paradoxical delay in introduction
in the very infants most likely to benefit from early introduction
because of delays related to the need for screening by medical
practitioners who already have long waiting lists.49 In the absence
of pragmatic trials of different approaches, this question is likely
to remain controversial in the United States, although the
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J ALLERGY CLIN IMMUNOL
DECEMBER 2018
controversy appears mostly resolved in Australia and the United
Kingdom.
Another major difference between guidelines from the United
States and other countries is the inclusion of advice about other
foods. In the United States the updated guidelines only mention
peanut, which is in line with evidence generated by the LEAP
study, whereas in the United Kingdom guidance is for peanut and
egg. By contrast, Australia provides recommendations for all of
the major allergenic solid foods, but these are only loosely
prescriptive. The separation of a recommendation in the Austra-
lian guidelines around commencement of solids (‘‘around
6 months and not before 4 months’’) and timing of allergenic
solids (‘‘in the first year of life’’) is expected to be future proof,
even if evidence for more specific windows of opportunity for
individual allergenic solids comes to light.
It is highly unlikely that alterations to infant feeding timing will
completely prevent food allergy, even with perfect uptake by the
population. Czarnowicki et al50 reviewed emerging theories about
the role of skincare interventions along with early introduction to
prevent food allergy. Thus far, data from human trials to support
skin barrier interventions for food allergy prevention are sparse,
but a number of clinical trials are underway and might provide
a path to prevent both food allergy and atopic dermatitis.
Based on observations that the gastrointestinal microbiome
plays an important role in immune modulation, another theoret-
ical approach to prevent and/or treat food allergy is to manipulate
the gut commensal flora.51 Berni Canani et al52 performed a ran-
domized controlled trial of extensively hydrolyzed casein for-
mula with or without the probiotic Lactobacillus rhamnosus
GG in infants with IgE-mediated milk allergy to determine
J ALLERGY CLIN IMMUNOL KEET AND ALLEN 1725
VOLUME 142, NUMBER 6

FIG 6. Dietary advanced glycation end-products (AGEs) influence the pattern of microbiota, their produc-
tion of AGEs, or glyoxalase enzyme activity. Low vitamin D levels are associated with epithelial injury
and risk of infection and expression of receptor for advanced glycation end-products (RAGE). Dietary sugars
bind to endogenous proteins and bacterial proteins to further add to the AGE pool. Soluble RAGE and the
amount of endogenous glyoxalase enzymes will reduce the effect of the total AGE pool. RAGE activation
influences multiple immune cells and multiple proallergic mediators. ILC2, Type 2 innate lymphoid cells;
TSLP, thymic stromal lymphopoietin. Used with permission from Smith et al.71

whether Lactobacillus rhamnosus GG resulted in decreased
manifestation of other allergic diseases and more rapid resolution
of cow’s milk allergy. They found that milk allergy did resolve
faster in the treatment group and that allergic manifestations
were less frequent,52 but this needs to be replicated in other
studies.
There has been some concern on social media that vaccines
might contain food allergens, causing food sensitization. Hoyt
et al53 analyzed common pediatric vaccines with highly specific
antibody assays for peanut, egg, and cow’s milk allergens and
did not find any evidence that these allergens were present.
EPIDEMIOLOGY OF FOOD ALLERGY
In trying to understand how allergies, including food allergy,
can be prevented, several groups have examined longitudinal
data to find phenotypes of allergic disease development, an
approach first used by Peters et al54 in the HealthNuts study. Ro-
duit et al55 used the Protection Against Allergy Study in Rural
Environments (PASTURE) study to identify subclasses of atopic
dermatitis. Early atopic dermatitis (onset <2 years of age) was
strongly associated with physician-diagnosed food allergy,
even in those with early transient disease, whereas later-onset
atopic dermatitis was only associated with allergic rhinitis but
not food allergy,55 confirming previous challenge-proved
findings of the HealthNuts cohort.56 Using the PASTURE cohort
plus the Multizentrische Allergiestudie (MAS) cohort, Hose
et al57 used latent class analysis to identify phenotypes of
allergic sensitization (but not challenge-proved food allergy).
They identified a severe atopy phenotype characterized by
high levels of specific IgE to seasonal allergens; a high risk for
asthma, hay fever, eczema, and lung impairments; and an
increased Ig-5/IFN-g ratio.57 A similar cluster analysis of the
Copenhagen Prospective Studies on Asthma in Childhood
2000 (COPSAC2000) and validated in the Children Allergy
Milieu Stockholm Epidemiology (BAMSE) cohort found 7 phe-
notypes of sensitizations: (1) dog/cat/horse, (2) timothy grass/
birch, (3) molds, (4) house dust mites, (5) peanut/wheat flour/
mugwort, (6) peanut/soybean, and (7) egg/milk/wheat flour.
The first sensitization pattern was associated with asthma, and
all except dust mite were associated with eczema.58 It is not clear
whether such phenotypes would be found in other geographies
with different exposure patterns or whether these factors are
critical for the risk of development or resolution of challenge-
proved food allergy,59 highlighting the complex nature of inves-
tigating allergic outcomes in longitudinal cohorts in the absence
of gold standard testing for food allergy.
Another analysis of the BAMSE cohort by Johansson et al,60
examined longitudinal relationships between preschool eczema,
filaggrin mutations, and IgE sensitization. As has been previously

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1726 KEET AND ALLEN
FIG 7. Showing immune changes with an FPIES reaction. Adapted from the graphic abstract from Goswami
et al.76
TABLE I. Key advances in food allergy in 2017
Evidence-based changes in practice introduced in the past year
d Most vaccines, including the flu shot, are safe to give to all
children with food allergy.
d Peanut introduction in the first year of life helps prevent
peanut allergy.
d In Europe and Australia, introduction of other allergenic
foods is also recommended in the first year of life; US
guidelines have not been developed for other foods.
d Food avoidance should not be used to prevent autoimmune
diseases.
reported in many cohorts, preschool eczema was associated with
sensitization to both food and aeroallergens, with persistent
eczema a stronger predictor.61 Filaggrin mutations were found
to be associated only with peanut sensitization and not other foods
or aeroallergens, but appeared to be a risk factor for peanut al-
lergy, even without preschool eczema.60
Another publication from the COPSAC2000 cohort found that
preeclampsia was associated with asthma, allergic rhinitis, sensi-
tization to aeroallergens, and food allergy,62 suggesting that pre-
natal exposure to systemic inflammation might increase the risk
of allergy.
Also important for designing rational prevention and popula-
tion management strategies is understanding the overall epide-
miology of food allergy and how it changes over time. Most
previous epidemiologic information about specific food allergies
has been self-reported allergy from surveys. Acker et al63 used
detailed electronic health records in Boston to examine the prev-
alence of food allergies. They found an overall prevalence of food
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J ALLERGY CLIN IMMUNOL
DECEMBER 2018
Changes to practice that need further evidence before adoption
Treatment
d OIT appears to effectively desensitize but carries significant risks of reactions.
d Omalizumab can increase the speed at which OIT is given but does not prevent
OIT-induced eosinophilic esophagitis and might not improve efficacy.
d EPIT can partially desensitize a portion of children with food allergy.
d Earlier use of OIT can increase efficacy.
d Novel treatment targets for food allergy can start to be translated from animal
models to human trials.
d A high proportion of patients with peanut allergy can tolerate small amounts of
peanut protein.
d Peanut-free schools might not improve quality of life or the safety of children
with peanut allergy.
d Probiotic supplementation can speed the resolution of milk allergy.
Prevention
d Early introduction of egg can prevent egg allergy, but introduction of cooked
forms first is probably the safest way to do this.
allergies or intolerances of 3.6%, with higher rates in female and
Asian subjects. The foods most implicated were shellfish (0.9%
prevalence), fruits or vegetables (0.7%), milk (0.5%), and peanut
(0.5%).
In a prospective cohort with comprehensive food allergy
phenotyping, the HealthNuts study in Australia, Peters et al64
found the prevalence of challenge-proved food allergy at 4 years
was 3.8%, down from 11% at 1 year, suggesting a high rate of
transient allergy in infancy. The prevalence of peanut allergy
was 1.9%, that of egg was 1.2%, and that of sesame was 0.4%.
Peanut allergy arising between the first and fourth years was un-
common. The overall rate of any childhood allergic disease dur-
ing the first 4 years of life was 40% to 50%.
In terms of time trends in food allergy and food-related
anaphylaxis, data from Olmstead County, Minnesota, are a
valuable resource in the United State because they represent a
relatively stable and circumscribed population that has been
followed for decades. Lee et al65 reported on data from 2001-2010
J ALLERGY CLIN IMMUNOL
VOLUME 142, NUMBER 6
on anaphylaxis trends in this community. They found that the
overall rate of anaphylaxis during this time was 42 per 100,000
person-years, with a significant increase over time. The most
marked change was in food-related anaphylaxis. Similarly, Moto-
sue et al66 looked at trends in anaphylaxis by using claims data in
the United States and found that there was an increase overall in
anaphylaxis between 2005 and 2014, with the biggest increase in
children aged 5 to 17 years, and for anaphylaxis to foods and med-
ications. Although self-reported and claims data show increases
in food allergy in recent decades, a study from Australia
comparing 2 Melbourne cohorts across more than a decade did
not find any change in sensitization to foods.67 This is in keeping
with a previous US study using the national survey National
Health and Nutrition Examination Survey68 and suggests that
an environmental factor that has altered the conversion step
from sensitization to food allergy might be at play, such as altered
infant feeding patterns over the same time period.69,70 A further
contributor to changing prevalence could be an increase in recog-
nition of the condition by the community.
A different hypothesis to explain the increase in food allergy
was proposed by Smith et al71 in 2017. Their theory, which they
call the ‘‘false alarm hypothesis,’’ posits that Western diets
include and produce advanced glycation end-products that are
alarmins. They suggest that these advanced glycation end-
products prime innate signaling, leading to development of food
allergy and other allergic phenotypes. This theory could explain
repeated epidemiologic findings that Western diets predispose
to allergic disease (Fig 6).
GASTROINTESTINAL FOOD ALLERGIES
Gastrointestinal food allergies (non–IgE-mediated food al-
lergy) continue to perplex clinicians72 and are often caught be-
tween different specialty areas, especially allergy and
gastroenterology. In an attempt to define and provide a
consensus approach to this important but poorly delineated
group of conditions, the American Academy of Allergy, Asthma
& Immunology published an important and thorough review of
the literature.73 This review provides expert consensus opinion
on the diagnosis and management of acute food protein-
induced enterocolitis syndrome (FPIES), which is a relatively
rare condition occurring at an estimated rate of 15/100,000/y
over the first year of life.74 The mechanism of FPIES is poorly
understood; IgE is not thought to play a role, specific IgG re-
sponses to the culprit food are lower than in children without
the condition, and T-cell responses do not seem to differ from
those in healthy children.75 Instead, positive food challenge re-
sults are associated with profound activation of the innate im-
mune system (Fig 7),76 but the mechanism of antigen
specificity remains elusive. Resolution of acute FPIES typically
occurs in the first few years of life, with some foods (fish and
egg) potentially resolving more slowly.77,78
Finally, another consensus document that crosses the discipline
of allergy and gastroenterology has been recently published for
eosinophilic esophagitis, another condition that benefits from
multidisciplinary care.79
CONCLUSIONS
Although many advances in our understanding of food allergy
were made in 2017 (Table I), many questions about the optimal
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KEET AND ALLEN 1727
treatment and prevention of food allergy remain. We anticipate
that the coming years will continue to bring major advances in
this field.
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