Review article

Feast for thought: A comprehensive review of

food allergy 2021-2023
Irene Bartha, MD,a,b Noorah Almulhem, MD,a,c and Alexandra F. Santos, MD, PhDa,b,d London, United Kingdom, and
Dammam, Saudi Arabia

A review of the latest publications in food allergy over the past

couple of years confirmed that food allergy is a major public health Abbreviations used
concern, affecting about 8% of children and 10% of adults in AAF: Amino acid–based formula
developed countries. The prevalence of food allergy varies around AIT: Allergen-specific immunotherapy
the world, with the increase being driven mainly by environmental Ara h: Arapis hypogaea
factors, possibly together with genetic susceptibility to BAT: Basophil activation test
BBEA: Bead-based epitope assay
environmental changes. A precise diagnosis of food allergy is
BTK: Bruton tyrosine kinase
extremely important. Both new tests (eg, the basophil activation CM: Cow’s milk
test) and improved optimization of information provided by CMA: Cow’s milk allergy
existing tests (eg, the skin prick test and measurement of specific CTLA-4: Cytotoxic T lymphocyte-associated protein-4
IgE level) can contribute to improving the accuracy and patients’ DEFASE: Definition of Food Allergy Severity
comfort of food allergy diagnosis. Understanding the underlying EA: Egg allergy
immune mechanisms is fundamental to designing allergen-specific EPIT: Epicutaneous immunotherapy
treatments that can be safe and effective in the long term. New FA: Food allergy
discoveries of the immune response to food allergens, including T- FASS: Food Allergy Severity Score
cell and B-cell responses, have emerged. Novel therapeutic Fc: Fragment crystallizable
JAK: Janus kinase
approaches are being trialed at various stages of development as
LEAP: Learning Early about Peanut Allergy
attempts to allow for more active intervention to treat food allergy. MAT: Mast cell activation test
Prevention is key to reducing the increase in prevalence. Early MC: Mast cell
introduction of allergenic foods seems to be the most effective nsLTP: Nonspecific lipid transfer protein
intervention, but others are being studied, and will, it is hoped, OFC: Oral food challenge
lead to modification of the epidemiologic trajectory of food allergy OIT: Oral immunotherapy
over time. (J Allergy Clin Immunol 2024;153:576-94.) PA: Peanut allergy
RORgt1: Retinoic orphan receptor gamma T-positive
Key words: Food allergy, diagnosis, severity, immunotherapy, oma- sIgE: Specific IgE
lizumab, IgE, skin prick test, basophil activation test SIGLEC: Sialic acid–binding immunoglobulin-like lectin
SLIT: Sublingual immunotherapy
SR: Systematic review
STAL: SIGLEC-engaging tolerance-inducing antigenic liposome
Food allergy (FA) is a major public health issue globally,
Treg: Regulatory T
affecting about 8% of children and 10% of adults (see Fig 11-47 for
VLP: Virus-like particle
global prevalence data). FA has a negative impact on the lives of
patients with allergy and their families, and there is no curative

From athe Children’s Allergy Service, Evelina London Children’s Hospital, Guy’s and St treatment.1,2 Improved understanding of the genetic basis and im-
Thomas’ Hospital, London; bthe Department of Women and Children’s Health (Pedi- mune mechanisms of this condition is important to finding target
atric Allergy), School of Life Course Sciences, Faculty of Life Sciences and Medicine,
therapies that can modify the current epidemiologic context.
and dthe Peter Gorer Department of Immunobiology, School of Immunology and Mi-
crobial Sciences King’s College London; and cthe Department of Otolaryngology Recently, there have been new developments in research and clin-
Head and Neck Surgery, King Fahad Hospital of the University, College of Medicine, ical guidelines in the field that researchers, clinicians and the public
Imam Abdulrahman Bin Faisal University, Dammam. should be aware of. This review highlights the new evidence pub-
Received for publication November 8, 2023; revised November 19, 2023; accepted for lished over the past couple of years on the epidemiology, genetics,
publication November 27, 2023.
Available online December 12, 2023.
immune mechanisms, diagnosis, treatment, and prevention of FA.
Corresponding author: Alexandra F. Santos, MD, PhD, Department of Paediatric Allergy,
2nd floor, South Wing, St Thomas’ Hospital, SE1 7EH London, United Kingdom.
E-mail: [email protected].
The CrossMark symbol notifies online readers when updates have been made to the
article such as errata or minor corrections FA EPIDEMIOLOGY AND GENETICS
0091-6749 Hospital admissions for food-induced anaphylaxis have
Ó 2023 The Authors. Published by Elsevier Inc. on behalf of the American Academy of
Allergy, Asthma & Immunology. This is an open access article under the CC BY li-
increased over recent decades; fortunately, however, fatalities
cense (http://creativecommons.org/licenses/by/4.0/). have not increased.48,49 According to a recent UK study, the most
https://doi.org/10.1016/j.jaci.2023.11.918 affected age groups are children and teenagers and the most

576
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common causes of food-induced anaphylactic deaths are cow’s IMMUNE MECHANISMS OF FA

milk (CM) and nuts.49 Various lessons on the pathologic immune response to food
The prevalence of FA varies in different areas around the allergens have emerged from mouse and in vitro studies of FA and
world, being more common in developed countries and urban from clinical trials of allergen-specific immunotherapy (AIT)
areas (Fig 1). A recent systematic review (SR) estimated a during which blood samples were collected and assessed over
pooled lifetime prevalence and point prevalence of self- time (Fig 2).
reported FA in Europe to be 19.9% and 13.1%, respectively.8
Point prevalence of FA based on specific IgE (slgE) level
was 16.6% as opposed to 5.7% based on a skin prick test, Findings from animal studies
and it was only 0.8% based on oral food challenge (OFC).8 It is worth highlighting an interesting and somehow reversed
Another recent SR and meta-analysis compared estimates of study that tried to mimic a clinical trial, the LEAP study, in an
the 8 most common FAs in Europe between the periods animal model, using BALB/c mice fed commercial peanut butter
2000-2012 and 2012-2021 and concluded that the prevalence in the presence of environmental peanut exposure.61 As expected,
of allergy to these foods has not changed between the 2 time the mice that were fed peanut butter had less peanut sensitization
periods.50 and PA. This seemed to be mediated by human cytotoxic
FA prevalence can be affected by age at diagnosis and the type T lymphocyte–associated antigen-4 (CTLA-4) and the induction
of FA, as certain FAs are more likely to be outgrown than others. of regulatory T (Treg) cells. Another possible target for suppres-
In the HealthNuts study, the prevalence of peanut allergy (PA) sion of allergic responses to food is the programmed death 1 (PD-
was similar at ages 1 and 6 years (3.1%), whereas egg allergy 1)/programmed death ligand 1 (PD-L1) axis. Contrary to the
(EA) had a prevalence of 9% at age 1 year, decreasing markedly to evidence from autoimmune diseases and respiratory allergies,
1.2% by age 6 years. Even though 29% of cases of PA resolved, blocking the PD-1/PD-L1 interaction between T follicular helper
new onset of PA beyond 1 year was observed to occur at a rate of cells and B cells suppressed high-affinity IgE responses and pre-
0.7%, whereas no such new onset was observed for EA.51 Inter- vented anaphylaxis.62 In another model of PA, increased gut
estingly, FA prevalence among Australian children of Asian permeability led to anaphylaxis in response to peanut following
origin was 15% and that among Singaporean children was oral exposure in sensitized mice, highlighting the importance of
1.1%,52 which suggests a possible role of ethnicity, environmental the gut epithelium and barrier integrity in the protection from
factors, and change in environment in the development of FA, developing FA.63 The importance of gut epithelial barrier was
particularly in the early years of life. documented in a separate in vitro study in which dishwasher de-
An accurate estimation of FA prevalence in developing tergents and rinse aids were shown to be cytotoxic and damaging
countries is difficult on account of sparse data. A multicenter to the barrier.64 These studies support the hypothesis that damage
epidemiologic survey done as part of the EuroPrevall study, to the epithelial barrier may be involved in the inception of FA and
conducted in China and India, showed a wide variability in FA the increase in FA incidence over the past few decades.65,66
prevalence between the 2 countries (1.50% in Hong Kong, 0.21%
in Guangzhou, 0.69% in rural Shaoguan, and 0.14% in India) that
could not be explained by the degree of urbanization.53 In Skin and mucosal barriers and allergens
contrast, in the South African Food study (SAFFA), different es- The increased susceptibility to FA in subjects with filaggrin
timates of FAwere found between urban Capetown (2.5%) and ru- mutations due to facilitated allergen skin penetration into a
ral areas (0.5%).54 proinflammatory milieu is well documented. Using samples from
In Southern Europe, nonspecific lipid transfer protein (nsLTP) the German Genetics of Food Allergy Study (GOFA), Kalb et al
allergy is considered the most common cause of primary FA and confirmed this link and established, for the first time, an associ-
food-induced anaphylaxis.55 However, nsLTP allergy has been ation between filaggrin loss-of-function mutations and the
emerging in other countries in Northern Europe, China, Japan, persistence of cow’s milk allergy (CMA) and EA over time.67
and Latin America. Cannabis was recently identified as a primary The biochemical properties of food allergens also have an impor-
sensitizer to nsLTP (namely Cannabis sativa 3) via direct contact tant role in allergen sensitization to foods. Chakrapani et al stud-
or passive inhalation.56 ied the allergenicity of alpha-gal in glycoproteins and glycolipids
Family history of FA and atopic diseases is a recognized risk and found that alpha-gal present in both molecular complexes
factor for FA. Specific human leukocyte antigen (HLA) poly- contributes to the allergic response, but a higher amount of
morphisms have been associated with PA. For instance, in the allergen is present in the protein fraction.68 One of the allergenic
Learning Early about Peanut Allergy (LEAP) study, an associ- foods that has commanded more attention and has accummulated
ation between peanut-specific IgG4 and HLA-DQA1*01:02 was more evidence over the years is peanut. Within peanut, Ara h 2 is
observed in the peanut consumption group across the 38 alleles considered the most important allergen in terms of its ability to
tested. This association, driven by IgG4 specific for Arapis hy- cause effector cell activation and, consequently, allergic reac-
pogaea (Ara h) 2, had a positive correlation with peanut con- tions. Interestingly, immunodominant conformational and linear
sumption.57 Notably, this confirmed the previously reported IgE epitopes lie in a single segment of Ara h 2, as demonstrated
association of HLA-DQA1*01:02, in addition to MALT1 and by structural studies and by an independent study of a cohort of
its single-nucleotide variant rs57265082,58 with risk of PA peanut-sensitized children tested initially on a peanut allergen mi-
development in the peanut avoidance group.59 Other HLA poly- croarray followed by validation of IgE binding measurements us-
morphisms, namely, HLA-DPB1*02:01:02 and the single- ing the ImmunoCAP (Thermo Fisher Scientific, Waltham, Mass)
nucleotide polymorphism rs9277630, were associated with platform.68-71 A previous study published in the Journal of Al-
increased risk of development of wheat-dependent exercise- lergy and Clinical Immunology reported immunologic cross-
induced anaphylaxis in a Japanese study.60 reactivity between the peanut major allergens Ara h 1, Ara h 2,
578 BARTHA, ALMULHEM, AND SANTOS J ALLERGY CLIN IMMUNOL
MARCH 2024

FIG 1. Prevalence of FA around the world according to clinical diagnosis of FA (represented in bold) and
self-reported FA (indicated between parentheses). Clinical diagnosis of FA is defined as physician-
confirmed FA based on suggestive history and allergen-specific IgE evidenced by skin prick testing and/
or measurement of specific IgE, or based on challenge-proven FA. Different age groups are represented in
different colors (adults in blue; children in red; and all age groups, including adolescents, in green).

and Ara h 3.72 Warmenhoven et al73 recently published evidence suppression of TH2 and TH1 effector cells (but not T follicular
that this cross-inhibition between Ara h 1 or Ara h 3 and Ara h 2 helper subsets) during OIT, and they associated a positive
was due to formation of complexes between the major allergens outcome with the TH2 cell suppression and treatment failure
and contamination of natural Ara h 1 and Ara h 3 with 2S albumin with preexisting TH1 and TH17 subsets that were not suppressed
Ara h 2. For this reason, recombinant allergens are preferred for by OIT. More recently, Calise et al confirmed the existence of 2
diagnostics, as cross-contamination with Ara h 2 could lead to mutually exclusive immunotypes of peanut-specific T cells
overestimation of the clinical relevance of Ara h 1 and Ara h 3 defined by CCR62CRTH21 and CCR61CRTH22, and they
sensitizations. described the immune trajectories for T-cell responses in children
treated with peanut OIT in the IMPACT study, with clinical
response being associated with the elimination of TH2A cells.78
Allergen-specific T-cell responses
Single-cell transcriptomics, together with multiparameter flow
cytometry, have shed light on T-cell responses to food allergens Allergen-specific B-cell responses
and their modulation by AIT.74 Ruiter et al75 identified bio- Exciting findings in B-cell biology in FA have been published
markers that were distinct in more sensitive patients with PA over the past few years. An example is the finding that both central
(ie, those reactive to <
_300 mg of peanut protein) than in patients production of IgE in the bone marrow and IgE production in the
with peanut allergy with a threshold higher than 300 mg of peanut gastrointestinal tract seem to be clinically relevant.79,80 To
protein (so-called hyporreactive patients). Such biomarkers address the discrepancy between IgE sensitization and clinical
include peanut-specific IgE levels, ratio of peanut to total IgE FA, Hemmings et al studied functional characteristics of IgE
level (ie, specific activity), ratio of peanut-specific IgE level to and demonstrated that IgE specificity, specific activity, diversity,
IgG4 level (all higher in patients with PA), and importantly, and clonality all independently influence mast cell (MC) and
higher frequency of peanut-specific effector T cells, with higher basophil activation following allergen stimulation. In the peanut
numbers of peanut-specific T-cell CDR3 sequences (both private IgE model, diversity and specific activity were the major drivers
and public) and greater production of TH2 and TH17 cytokines. of basophil and MC activation. Focusing on epitope specificity,
Berin et al76 corroborated that peanut-specific TH2 cells were Suprun et al and Suarez-Farinas et al81,82 investigated the utility
associated with a lower threshold of reactivity and correlated of peanut peptide–specific IgE to predict later development of
with allergen-specific IgE levels and basophil activation. Further- PA and how this evolved over the course of the LEAP Study.
more, this TH2 cell profile at baseline predicted an adverse They found that levels of peptide-specific IgE at age 3 to 15
response to AIT and decreased over the course of oral immuno- months and age 2 to 3 years, together with peanut-specific IgE
therapy (OIT) to peanut and egg. CCR61 peanut-specific T cells levels, predicted PA outcome after the age of 4. Interestingly, pea-
were inversely correlated with the TH2 cell population but were nut consumption drove an increase in peptide-specific IgG4 early
not directly related to clinical outcomes. Monian et al77 reported in all children, but this increase was more pronounced in peanut
J ALLERGY CLIN IMMUNOL BARTHA, ALMULHEM, AND SANTOS 579
VOLUME 153, NUMBER 3

FIG 2. Highlights on the topics of the novel publications about mechanisms of FA and tolerance mentioned
in the text.

consumers, whereas peptide-specific IgE levels leading to PA understanding of the role of IgA in FA is limited. Zhang et al
(more common in peanut avoiders) increased significantly after have shown that IgE and IgA production are the result of different
age 2.5 years. immune pathways.86 Liu et al87 have tested many plasma and
Trying to target the B-cell pathway to suppress allergen- stool samples from a variety of well-characterized cohorts of
specific antibody production, Bruton et al83 used a combination of food-allergic patients and nonatopic individuals and found that
in vitro and animal models to assess the effect of IL-4Ra blockade individuals with PA have higher levels of peanut-specific IgA
on peanut-specific recall responses. Although IL-4Ra blockade than do individuals without PA. However, gut peanut-specific
significantly abrogated the recall response and protected from IgAs have different epitope specificities from those of plasma
anaphylaxis in the mouse model, in human in vitro studies it peanut-specific IgE and do not predict later development of PA
reduced IgE production and TH2 cytokine production, although or acquisition of tolerance. A similar observation was made for
the terminally differentiated TH2A population resisted indepen- EA. These findings question the protective effect of mucosal
dently of suppression of the pathway downstream the IL-4Ra. IgA in FA. Surprisingly, using established mouse models, Elesela
Another potential therapeutic approach for FA was attempted et al88 found that IgA immunocomplexes applied to gut mucosal
by Hardy et al84; their approach consisted of targeting CD22 on surfaces reduced TH2 cell–driven immune responses, including
memory B cells with sialic acid–binding Ig-like lectin (SI- reduced TH2 cytokine production and enhanced IL-10 and
GLEC)-engaging tolerance-inducing antigenic liposomes TGF-b production and increased Treg cell numbers, following
(STALs) codisplaying peanut allergens (Ara h 1, Ara h 2, or allergen challenge. Interestingly, this regulatory response was
Ara h 3) and high-affinity CD22 ligand (CD22L-STALs). antigen-specific and opened the way for potential new therapeutic
CD22L-STALs significantly suppressed systemic memory to all strategies.
3 major peanut allergens in both mouse models and in human B
cells in vitro.
Effector cells: MCs and basophils
Finally, with regard to effector cells of FA and anaphylaxis, a
Allergen-specific antibodies recent study associated the severity of food allergic reactions with
The physiologic role of IgE-mediated hypersensitivity is the a-tryptase.89 In an EA study, the basophil activation test (BAT)
defense against parasitic infections, and this has generated was the best immune marker to identify severe reactors.90 Inter-
interest in the comparison between antigens from parasites and estingly, no demographic or clinical features and only 1 immune
those from allergenic sources. Hadadianpou et al85 were able to marker in addition to the BAT were statistically significantly
generate naturally occurring helminth-specific mAbs from filarial different between patients with EA who experienced severe reac-
parasiste–infected subjects and demonstrate their ability to induce tions and patients with EA who experienced mild or moderate re-
anaphylaxis in a passive sensitization mouse model. Similarities actions during baked egg challenges. Peanut OIT has been shown
between parasitic antigens and allergens may help us to under- to induce basophil hyporesponsiveness, owing either to a decrease
stand what makes an allergen an allergen and to predict allerge- in IgE-mediated activation and/or to an increase in inhibitory
nicity of new food sources coming into the food chain. Current signaling. In a small peanut OIT study, Kulis et al91 showed
580 BARTHA, ALMULHEM, AND SANTOS J ALLERGY CLIN IMMUNOL
MARCH 2024

that the decrease in CD63 expression was accompanied by a months of age. The BBEA showed similar results at baseline in
decrease in Syk phosphorylation. Whether there is also a decrease both the avoidance and consumption groups. However, peptide-
in phosphorylation of regulatory signaling molecules, such as sIgE expansion occurred mainly in the avoidance group,
SHIP or SHP-2, with treatment remains to be seen. Kanagaratham particularly in patients sensitized at baseline. Interestingly,
et al92 used bone marrow–derived MCs from wild-type and peptide-sIgE expansion was observed primarily after 2.5 years.
FcgRIIb-deficient mice to demonstrate that many IgE-mediated On the other hand, peptide-sIgG4 expansion appeared in all
pathway genes were expressed following IgE receptor cross- groups, but was found earlier in the consumer group (particularly
linking, with a peak at 1 hour, and that antigen-specific IgG could in sensitized children) during the first 30 months.82 Using data
modulate this by activating genes downstream the FcgRIIb, ulti- from the same study, researchers performed BBEA on 74 patients
mately leading to suppression of the Syk signaling pathway. from among the LEAP participants in combination with specific
IgE of peanuts and its components to assess its ability to predict
the outcome of OFC at age 5 years. An algorithm combining
FA DIAGNOSIS peptide-sIgE and IgE to Ara h 1, Ara h 2, Ara h 3, and Ara h 9 pro-
OFC is the criterion standard for definitive diagnosis of FA. teins gave 64% validation accuracy at baseline and 83% accuracy
Recently, EAACI guidelines on the diagnosis of IgE-mediated of samples taken at 1 year to predict the OFC outcome at
FA recommend open OFC for most clinical situations, with 5 years.102
double-blind placebo-controlled food challenge being reserved The BAT and the MAT are flow cytometry–based tests that
for cases in which open OFCs are equivocal and for research.93 involve all components of the allergic reaction, including effector
The PRACTALL guidelines on how to perform OFC are widely cells, sIgE, and allergen-specific antibodies of other isotypes.
used. The Consortium for Food Allergy Research, version 3 (Co- When compared with sIgE assays, they provide a result that is
FAR, v3), which uses less-objective symptoms and less-rigid closer to the patient’s allergic status. In a recent publication of the
challenge stop criteria, was recently proposed.94 This proposed BAT2 study (National Clinical Trials [NCT] no. 03309488), the
approach can potentially compromise the reproducibility of BAT proved to be the best diagnostic utility for EA from the
the OFC and overestimate FA, and it did not seem to reduce standpoint of diagnostic accuracy.103 An approach of applying
the anaphylaxis rate much.95 Importantly, allergen thresholds 100% sensitive and 100% specific cutoffs to select patients who
can vary even in the absence of any intervention; Turner et al96 are without allergy and tolerant, respectively, followed by addi-
and Patel et al97 have recently shown that thresholds can vary tional tests or OFC in equivocal cases, was proposed and provided
within half a log (equivalent to 1 PRACTALL dosing interval) 100% diagnostic accuracy. The BAT provided the greatest reduc-
in peanut and CM allergic patients. tion in OFC in all age groups when used as a single test. Using
OFCs are time-consuming and costly, and they involve the risk BAT as a second step after testing for sIgE to egg white or oval-
of potentially severe allergic reactions. Thus, there has been a bumin reduced the number of BATs required, providing a similar
constant search for better diagnostic tools. A comprehensive SR reduction in OFC use and 100% diagnostic accuracy, thus empha-
and meta-analyses of studies on the utility of tests to support the sizing its role as a second test to improve diagnostic accuracy. In
diagnosis of FA, in which at least a proportion of patients the same study, the BAT was the best predictor of severity and
underwent OFC, has recently generated useful indicative cut- threshold of allergic reaction, providing 76% sensitivity, 74%
offs with sensitivity and specificity that can be used to guide specificity, and 75% accuracy to identify severe reactors to baked
interpretation of allergy test results.98 Novel diagnostic in vitro egg. As for identification of patients who react to low doses of
tests with promising results include cellular tests, namely, the allergen, the BAT showed 70% sensitivity, 72% specificity, and
BAT and MC activation test (MAT), and serologic tests such as 71% accuracy.90 In a PA study, the BAT demonstrated a high
measurement of epitope-specific IgE level. These tests are prom- reproducibility and reliability when tested in different
ising future diagnostic tools for FA, with the BAT having an laboratories.104
advantage over epitope-specific IgE testing for being a functional Compared with the BAT, the MAT has shown similar
assay that combines all IgE characteristics.99 specificity but lower sensitivity in the diagnosis of PA.99,105 How-
IgE to epitope-containing peptides reduces the possibility of ever, in the 10% to 15% of individuals who have nonresponding
cross-reactivity and has higher specificity than does IgE to whole basophils, the MAT can provide conclusive results.100,105
allergen. It may, however, produce false-negative results owing to A proposed novel MAT assay uses conditional Hoxb8-
a smaller IgE-binding region and the possibility of missing the immortalized progenitor-derived mouse MCs transgenic to hu-
conformational epitopes, which play an important role in man high-affinity IgE receptor (FcεRIa) passively sensitized
antibody binding. To minimize false-negative results, testing for with patient’s serum and analyzed by flow cytometry following
specific IgE (sIgE) to allergen components can be done in allergen stimulation, as in the original MAT.106 Recently, the
addition.99,100 Using peptide microarray, testing for Ara h BAT was, for the first time, included as a recommended test to
2 peptide–specific IgE added diagnostic value to Ara h 2–specific support the diagnosis of IgE-mediated FA in clinical guidelines.93
IgE in diagnosis of PA, and the best was to consider IgE to Ara h 2 However, it was decided that the MAT and peptide-sIgE required
and to 4 of its peptides simultaneously.70 Of those 4 Ara h 2 pep- more research before being used clinically.
tides, 3 shared amino acid motifs, with sequences identified as im- Following a definitive diagnosis, delineating the severity of FA
munodominant in separate studies done using the bead-based is important to identify patients who need a more intense follow-
epitope assay (BBEA),71,101 up and may have an indication for selective treatments. However,
In a subset from the LEAP study cohort, BBEA to test for IgE doing so can be difficult because the severity of allergic reactions
binding to 64 informative epitopes was used to compare peptide- is multifactorial and many factors depend on the circumstances in
sIgE and peptide-sIgG4 at baseline and again at 12, 30, and 60 which the allergic reaction occurs, which are in turn
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TABLE I. Summary of the diagnostic performance of reported optimal cutoffs for different tests for specific food allergies based
on recent meta-analyses of studies including children and/or adults
CM (allergy
to fresh EA (allergy Cashew Sesame
Diagnostic pasteurized to whole Hazelnut nut seed Wheat Shrimp
test CM) cooked egg) PA allergy allergy allergy allergy allergy

SPT Cutoffs 4 (3-8) 5 (3-8) 4 (3-8) 5 (3-7) 5 (4-6) 8 (4-10) 3 (3-5) 3 (3-5)
(mm)
Sensitivity 0.52 (0.24-0.79) 0.68 (0.37-0.88) 0.84 (0.69-0.92) 0.82 0.93 0.70 0.53 0.62
(0.68-0.91) (0.89-0.96) (0.55-0.82) (0.23-0.81) (0.44-0.77)
Specificity 0.80 (0.65-0.90) 0.77 (0.64-0.86) 0.86 (0.79-0.91) 0.78 0.92 0.89 0.72 0.90
(0.44-0.94) (0.82-0.96) (0.76-0.95) (0.57-0.84) (0.31-0.99)
sIgE to Cutoffs 3.5 (0.9-10.5) 3.5 (1.7-5.5) 4.3 (0.35-10) 2.34 1.1 7.5 0.6 1.2
allergen (KU/L) (0.6-6.3) (0.6-3.1) (0.9-50) (0.35-5.6) (0.5-3.1)
extracts
Sensitivity 0.82 (0.59-0.94) 0.85 (0.77-0.90) 0.81 (0.71-0.88) 0.79 0.94 0.70 0.72 0.96
(0.71-0.85) (0.89-0.97) (0.23-0.95) (0.54-0.84) (0.42-1.00)
Specificity 0.92 (0.80-0.97) 0.73 (0.63-0.80) 0.83 (0.71-0.90) 0.62 0.64 0.83 0.79 0.63
(0.38-0.81) (0.54-0.74) (0.26-0.99) (0.68-0.86) (0.46-0.78)
sIgE to Cutoffs Casein Ovomucoid Ara h 2 Cor a 14 Ana o 3 Omega- Pen a 1
allergen (KU/L) 2.6 (1.0-5.3) 0.8 (0.35-3.7) 0.44 (0.3-1.3) 0.64 (0.35-3.5) 0.4 (0.2-0.6) 5-gliadin 1.1 (0.6-4.4)
components 0.3 (0.1-0.6)
Sensitivity 0.67 (0.53-0.78) 0.74 (0.54-0.87) 0.82 (0.77-0.86) 0.73 0.96 0.79 0.62
(0.53-0.87) (0.91-0.98) (0.68-0.88) (0.45-0.76)
Specificity 0.93 (0.85-0.97) 0.91 (0.87-0.93) 0.92 (0.87-0.95) 0.95 0.94 0.78 0.89
(0.90-0.98) (0.88-0.97) (0.66-0.86) (0.75-0.95)
BAT Cutoffs (% 5.0 (4.7-7.1) 10.9
CD631 (8.2-11.6)
basophils)
Sensitivity 0.84 (0.76-0.90) 0.89
(0.80-0.94)
Specificity 0.90 (0.83-0.94) 0.93
(0.76-0.98)

All ranges in parentheses are 95% CIs.

Data from Santos et al93 and Riggioni et al.98
Ana o, Anacardium occidentale; Cor a, Corylus avellana; Pen a, Penaeus aztecus; SPT, skin prick test.

unpredictable. Risk factors for severity have been defined from FA TREATMENT
reviewing cohorts with fatal and near-fatal reactions. However, Food allergen immunotherapy
large longitudinal population-based studies are needed to be able AIT for FA has gained adepts, both among clinicians and
to accurately risk-stratify patients with FA. In addition, patients among patients. Recent studies have addressed important remain-
might still develop severe reactions in the absence of risk ing questions that concern clinicians, researchers, and patients
factors.107 Nevertheless, having a way to more holistically cate- alike; these concerns include the heterogeneity of study design,
gorize both severity of allergic reactions and disease severity in protocol, outcomes and risk of bias, the ideal patient profile, the
an objective and unified manner would be helpful. Fern
andez-Ri- best route of administration, duration of treatment, and associated
vas et al developed the Food Allergy Severity Score (FASS) based management of FA in terms of food avoidance and need for
on multidisciplinary expert consensus and mathematic modeling epinephrine autoinjectors. Table II shows recent and ongoing
of data from the EuroPrevall study. Versions of the FASS include studies in this area.
the oFASS-3 (which uses 3 grades [mild, moderate, and severe]), Baked milk OIT showed desensitization and a good safety
the oFASS-5 (which uses 5 grades, scored 1-5), and the nFASS profile after 12 months of treatment in children aged 3 to 18 years,
(which uses a numeric scale). Its internal validation was followed with improvement in proxy-reported FA quality of life.110 OIT is
by external validation using 5 cohorts.108 The Definition of Food more effective in preschool children, with higher rates of sustained
Allergy Severity (DEFASE) scoring system was proposed unresponsiveness, desensitization, and even ad lib consumption
following an international expert consensus using the Delphi following treatment, although whether these effects are long
method. The DEFASE consists of 5 domains, including signs term is still unknown.78,111 Interestingly, in children with PA,
and symptoms of the most severe reaction, the minimum therapy remission was associated with both younger age and lower base-
to treat the most severe reaction, individual eliciting dose, current line peanut-sIgE levels.78 The superior efficacy could be due to
FA-related quality of life, and economic impact of FA severity. the greater plasticity of the immune response in the preschool
Each domain is scored as mild (1 point), moderate (2 points), or years; better adherence to treatment thanks to greater parental
severe (3 points), and the overall DEFASE score is the sum of and caregiver supervision; milder phenotypes of PA; and lower
the scores of all 5 domains.109 For a summary of the diagnostic likelihood of aversion, dislike, and/or anxiety around food.111
performance of the reported optimal cutoffs for several of the Epicutaneous immunotherapy (EPIT) has a good safety profile.
aforementioned tests, see Table I. The peanut patch VP250, which contains a dose of 250 mg of
582 BARTHA, ALMULHEM, AND SANTOS J ALLERGY CLIN IMMUNOL
MARCH 2024

TABLE II. Current and ongoing research studies examining treatment of FA

Study name Estimated Target age
(NCT or ACTRN no.) Study description enrollment groups Main Outcomes

OIT
Using Commonly Available Food Multicenter, randomized, parallel N 5 216 3-23 y Proportion of participants in intervention arms
Products to Treat assignment, phase III of OIT to (combined) vs in control arm (by allergen) who,
Food Allergy (NATASHA Study; peanut or CM, with crossover for following 9-12 mo of OIT, tolerate > _1 g of food
NCT05503446) those allocated to control group protein (discrete dose, ;4-6 peanuts or 30 mL of
after primary outcome (;24 mo) CM) AND demonstration of a minimum 10-fold
increase in the MTD (defined as the highest dose
not causing dose-limiting symptoms) at DBPCFC
at the end of updosing vs at baseline DBPCFC
Multifood OIT
ADP101 for Oral Immunotherapy in Phase I and II, multicenter, N 5 73 4-55 y Proportion of subjects who tolerate a dose of > _600
Food-Allergic Children and Adults randomized, double-blind, mg of protein of the relevant allergen or allergens
(the Harmony Study; placebo-controlled study (average with no more than mild symptoms at the exit
NCT04856865) of 1 y) of ADP101, an active DBPCFC
powder formulation for OIT
Open-label Extension Study of Phase I and II, open-label, safety N 5 45 4-57 y Long-term safety and tolerability of ADP101,
ADP101 (NCT05243719) extension study for participants including the incidence of adverse events during
who participated in the Harmony the study period
study (protocol ADP101-MA-01;
;4-6 y)
Low-Dose Multi-OIT for Food Phase II, single-center, single-arm, N 5 18 6 mo-15 y Change in MTD in a dichotomous manner and
Allergy (LoMo) (LoMO Study; open-label study (;18 mo) of immunologic change in IgG4 level over 18 mo
NCT03799328) multifood OIT
EPIT
Follow-up of the EPITOPE Study to Phase III, multicenter, open-label, N 5 330 2-5 y Proportion of subjects reaching an ED of >
_1000 mg
Evaluate Long-term Efficacy and follow-up study for subjects who at ages 12, 24, and 36 mo
Safety of DBV712 in Young completed the EPITOPE study
Children (EPOPEX Study; (24-36 mo)
NCT03859700)
Safety and Efficacy Study of Viaskin Phase III, multicenter, randomized, N 5 600 4-7 years Proportion of responders in active treatment vs in
Peanut in Peanut-Allergic double-blind and placebo- the placebo group. A participant is defined as a
Children 4-7 Years of Age controlled study (;58 wk) of daily treatment responder if the initial ED was <
_30 mg
(VITESSE Study; NCT05741476) DBV712 250 mg of peanut protein and the ED was > _300 mg of
peanut protein at the posttreatment DBPCFC at
mo 12 OR the initial ED was > 30 mg of peanut
protein and the ED is >_600 mg of peanut protein
at the posttreatment DBPCFC at mo 12
Efficacy and Safety of Viaskin Milk Phase I and II, multicenter, N 5 198 2 to 17 Proportion of subjects who are treatment responders
in Children with IgE-Mediated randomized, double-blind and after 12 mo of EPIT treatment. Treatment
Cow’s Milk Allergy (MILES placebo-controlled study (12 mo) responder is defined as a subject who meets >
_1 of
Study; NCT02223182) the following criteria:

d A> _10-fold increase in the CRD of CM proteins

at the mo 12 DBPCFC vs value at baseline and
reaching >
_144 mg of CM proteins;
d A CRD of CM proteins of >
_1444 mg at the 12-mo
DBPCFC
Oral mucosal immunotherapy
OMEGA Study: A Study of the Phase I, multicenter, randomized, N 5 32 18-55 y
Safety and Feasibility of double-blind, placebo-controlled d Proportion of participants able to consistently
Uptitration with INT301 in Adults study (48 wk) of INT301, a fully tolerate the protocol-specified highest dose
with Sensitivity to Peanut (the functional peanut toothpaste
d Incidence of systemic and nonsystemic adverse
OMEGA Study; NCT04603300) containing immunotherapy agents
reactions will be evaluated
able to deliver >
_50 mg of peanut
product per dose vs 2-3.7 mg per
dose in SLIT
(Continued)
J ALLERGY CLIN IMMUNOL BARTHA, ALMULHEM, AND SANTOS 583
VOLUME 153, NUMBER 3

TABLE II. (Continued)

Study name Estimated Target age
(NCT or ACTRN no.) Study description enrollment groups Main Outcomes

SCIT
HAL-MPE1 Safety and Tolerability Phase I, multicenter, randomized, N 5 42 5-50 y Local and systemic reactions (immediate [< _1 h]),
Study (NCT02991885) double-blind, placebo-controlled early [within 1-4 h], and late [>4 h]) and the
study (an average of 16 wk) of occurrence of treatment-emergent adverse events
HAL-MPE1, an off-white to white To confirm its safety and tolerability of HAL-MPE1
liquid suspension containing in adults with PA and subsequently assess its
modified peanut extract delivered safety and tolerability in adolescents and children
as SCIT with PA
Combination of immunotherapies
Improving the Safety of Oral Phase II and III, a 2-center, parallel N 5 68 6-17 y Proportion of participants experiencing adverse
Immunotherapy for Cow’s Milk group, 3-arm, randomized events (excluding mild, nontransient symptoms)
Allergy (SOCMA Study; placebo- conventional OIT for CM in phase 2, in those who
NCT02216175) controlled trial (;15 mo) of CM have received SLIT before treatment vs placebo
SLIT 1 OIT vs OIT
3 study arms:
- SLIT followed by conventional
OIT
- Conventional OIT
- Placebo followed by conventional
OIT
mAbs
Study to Evaluate Dupilumab Phase II, multicenter, open-label, N 5 25 6-17 y Proportion of participants treated with dupilumab
Monotherapy in Pediatric Patients single-group assignment study who tolerate >
_444 mg (cumulative) of peanut
with Peanut Allergy (;36 wk) of dupilumab as protein during DBPCFC at wk 24
(NCT03793608) monotherapy in children with PA
Study in Pediatric Subjects with Phase 2, multicenter, randomized, N 5 149 6-17 y Proportion of participants treated with dupilumab 1
Peanut Allergy to Evaluate double-blind, placebo-controlled AR101 vs placebo 1 AR101 who tolerate 2044
Efficacy and Safety of Dupilumab study (;76 wk) of dupilumab with mg (cumulative) of peanut protein in DBPCFC
as Adjunct to AR101 (Peanut Oral peanut OIT in children with PA (time frame: <_40 wk)
Immunotherapy; NCT03682770)
Dupilumab and Milk OIT for the Phase II, multicenter, randomized, N 5 40 4-50 y Proportion of subjects treated with dupilumab 1
Treatment of Cow’s Milk Allergy double-blind, parallel group, 2- milk protein OIT vs placebo 1 milk protein OIT
(NCT04148352) arm study (44 wk) of dupilumab who tolerate >_2040 mg (cumulative) of CM
with milk OIT in children and protein during DBPCFC to milk at wk 18
adults with CMA
Clinical Study Using Biologics to Phase II, multicenter, randomized, N 5 110 4-55 y Proportion of subjects able to tolerate peanut,
Improve Multi-OIT Outcomes double-blind multiallergen OIT peanut and >_1 other food allergen, or peanut and
(COMBINE Study; study of combination of biologics 2 other food allergens at 44 wk
NCT03679676) (omalizumab and dupilumab) and
multifood OIT
(;44 wk)
Food allergens evaluated include
CM, almond, shellfish, fish,
cashew, hazelnut, egg, walnut,
sesame seeds, soy, and wheat
Omalizumab as Monotherapy and as Phase III, multicenter, randomized, N 5 471 1-55 y
Adjunct Therapy to Multiallergen double-blind, placebo-controlled d Proportion of participants who successfully
OIT in Food-Allergic Participants study (;56 mo) of omaliumab as consume a single dose of >_600 mg of peanut
(OUtMATCH Study; monotherapy and omalizumab protein without dose-limiting symptoms during
NCT03881696) with multifood OIT the DBPCFC at the end of stage I of treatment
Food allergens evaluated include
d Proportion of participants who consume foods
milk, egg, wheat, cashew,
without dose-limiting symptoms during a
hazelnut, and walnut
DBPCFC after treatment with either omalizumab
or placebo for omalizumab
(Continued)
584 BARTHA, ALMULHEM, AND SANTOS J ALLERGY CLIN IMMUNOL
MARCH 2024

TABLE II. (Continued)

Study name Estimated Target age
(NCT or ACTRN no.) Study description enrollment groups Main Outcomes

Omalizumab to Accelerate a Phase IIb, multicenter randomized N 5 90 6-25 y Time from initial food escalation to target multifood
Symptom-driven Multi-food OIT double-blind and placebo- protein maintenance dose of 1500 mg of total
(BOOM Study; NCT04045301) controlled study (15 mo) of food protein assessed <_52 wk after initial food
omalizumab at decreasing times to escalation
maintenance during a symptom-
driven multifood OIT
Food allergens evaluated include
peanut, milk, egg, wheat, oat, soy,
barley, rye, buckwheat, hazelnut,
pecan, cashew, pistachio, almond,
walnut, and sesame
E-B-FAHF-2, Multi-OIT and Phase II, multicenter randomized N 5 33 6-40 y To evaluate sustained unresponsiveness by the
Omalizumab for Food Allergy double-blind and placebo- absence of dose-limiting symptoms to a
(NCT02879006) controlled study (;26 mo) of cumulative dose of 4444 mg of food allergen
Chinese herbal formula, multifood protein at mo 29
OIT, and omalizumab Food allergens evaluated include milk, egg, peanut,
almond, cashew, hazelnut, walnut, sesame, and/or
wheat
Efficacy and Safety of QGE031 Phase III multicenter, randomized, N 5 486 6-55 y Proportion of participants who can tolerate a single
(Ligelizumab) in Patients double-blind, placebo-controlled dose of >
_ 600 mg (1044 mg cumulative tolerated
with Peanut Allergy study (52-wk) of 2 regimens for dose) of peanut protein without dose-limiting
(NCT04984876) dosing ligelizumab (240 mg and symptoms at wk 12
120 mg) via subcutaneous Responder status is defined as tolerating a single
injection every 4 wk in dose of >
_ 600 mg (1044 mg cumulative tolerated
participants with a medically dose) of peanut protein without dose-limiting
confirmed diagnosis of IgE- symptoms during the DBPCFC conducted at wk
mediated PA 12
JAK Inhibition in Food Allergy Phase I single-center, randomized, N 5 40 18-50 y Change in basophil activation and in SPT result after
(NCT05069831) double-blind pilot study (4 mo) of 4 mo of treatment vs at baseline
abrocitinib
Food allergens evaluated include
peanut, cashew, walnut, hazelnut,
sesame, cod, and/or shrimp
Adjuvant Treatment with Abatacept Phase IIa, multicenter, randomized, N 5 14 14-50 y Change in peanut-specific/total IgE at wk 24 vs at
to Promote Remission during double-blind placebo-controlled baseline
Peanut Oral Immunotherapy trial of 24 wk of abatacept, a
(ATARI Study, NCT04872218) fusion protein of the extracellular
domain of the CTLA-4 linked to
the Fc domain of human
immunoglobulin, vs placebo used
as an adjuvant to OIT (;48 wk
overall)
Study of Efficacy, Safety and Phase II, multicenter, randomized, N 5 110 18-55 y Proportion of participants who can tolerate a single
Tolerability of Remibrutinib in investigator- and participant- dose of >
_600 mg of peanut protein without dose-
Adult Participants with an Allergy blinded, placebo-controlled study limiting symptoms during DBPCFC at baseline
to Peanuts (NCT05432388) of oral remibrutinib (LOU064) in and d 26
3 doses of oral tablet twice a day Responder status defined as tolerating a single dose
compared with placebo (;1 mo or of >
_600 mg of peanut protein without dose-
up to 5 wk) limiting symptoms during the DBPCFC
Microbiome-modulating agents
A Randomized, Controlled Trial of 3-Arm, randomized (4:4:1), stratified N 5 90 1-17 y Proportion of participants with an 8-wk sustained
Probiotic and Peanut Oral (by age), blinded, placebo- unresponsiveness (passed T1 and T2 challenges)
Immunotherapy in Inducing controlled, parallel-group, in probiotic and peanut OIT vs placebo (T2 5 8
Tolerance in Hong Kong Children superiority trial of probiotic and wk after final day of maintenance treatment)
with Peanut Allergy Compared peanut OIT (;130 wk) T1, 18 mo; T2, 8 wk; and T3, 12 mo
with Oral Immunotherapy (OIT)
Alone and with Placebo
(NCT05165329)
(Continued)
J ALLERGY CLIN IMMUNOL BARTHA, ALMULHEM, AND SANTOS 585
VOLUME 153, NUMBER 3

TABLE II. (Continued)

Study name Estimated Target age
(NCT or ACTRN no.) Study description enrollment groups Main Outcomes

Probiotic Egg Allergen Phase II, dual-center, N 5 80 5-30 y Proportion of participants who attain an 8-wk
Oral Immunotherapy for Treatment randomized, double-blind placebo- sustained unresponsiveness (remission) (passed
of Egg Allergy: The PEAT Study controlled study of egg OIT T1 and T2 challenges) in active and placebo-
(;21 mo) treated groups
T1, 18 mo from baseline; T2, 20 mo from baseline
Pinpoint Trial: Prebiotics in Peanut Phase I and II, randomized, single- N 5 30 4-17 y
Oral Immunotherapy group assignment double-blind d Proportion of subjects who tolerate > _1043 mg
(NCT05138757) placebo-controlled study of (cumulative) of peanut protein with no more
prebiotics (dietary fiber) and than mild symptoms at the 12-mo DBPCFC (time
peanut OIT (4 y) frame: <
_4 y)
d Reduction of side effects of OIT
d Changes in the gut microbiota
Oral Peanut Immunotherapy with a Randomized, blinded, parallel group, N 5 65 10-16 y Proportion of participants who tolerate >
_1400 mg of
Modified Dietary Starch Adjuvant 3-arm, placebo-controlled trial of roasted peanut at a DBPCFC after 12 mo of
for Treatment of Peanut Allergy in dietary fiber supplement that is treatment followed by 6 wk of interruption of
Children Aged 10-16 years high in a key short-chain fatty acid treatment
(ACTRN12617000914369) (butyrate) in combination with
peanut OIT (;25.5 mo)
Study arm A: peanut OIT and a
supplement control group
(receiving LAMS, a low-amylose
maize)
Study arm B: peanut OIT and a
supplement group (HAMSB, a
butyrylated high-amylase maize
starch)
Study arm C: peanut OIT control
(peanut avoidance)
Evaluating the Safety and Efficacy of Phase I, nonrandomized, single- N 5 15 18-40 y Presence of FMT-related adverse events grade >
_2
Oral Encapsulated Fecal group assignment, treatment study (time frame: 12 mo)
Microbiota Transplant in Peanut of oral encapsulated FMT in PA
Allergic Patients (NCT02960074) (;1 y)
Evaluating the Safety and Efficacy of Phase II randomized, double-blind, N 5 24 12-17 y Change in threshold of peanut reactivity during a
Oral Encapsulated Microbiota placebo-controlled study of oral DBPCFC from < _100 mg of peanut protein to 300
Transplantation Therapy in Peanut encapsulated fecal MTT with mg after 28 days of MTT vs placebo therapy and
Allergic Patients (NCT05695261) antibiotic pretreatment 4 mo after therapy initiation
VE416 for Treatment of Food Phase I/II, single-center, randomized, N 5 60 12-55 y Primary end point for phase Ib: no. of participants
Allergy (NCT03936998) double-blind placebo-controlled with treatment-related adverse events, as assessed
study of oral encapsulated fecal by CTCAE, v4.0, by 7 wk
MTT with antibiotic pretreatment Primary end point for phase II: geometric mean of
(;54 wk) the MTD of peanut protein at DBPCFC at 23 wk
VE416 is a consortium of
commensal, or "friendly", dormant
(inactive) bacteria given in a
capsule. The bacteria are
reactivated once they reach
participants’ intestines
Study arms:
- Combination Product: vancomycin
1 VE416 before peanut OIT
- Combination Product: vancomycin
1 VE416 with peanut OIT
- Combination product: placebo
1 VE416 with peanut OIT
- Combination product: placebo
1 placebo with peanut OIT
(Continued)
586 BARTHA, ALMULHEM, AND SANTOS J ALLERGY CLIN IMMUNOL
MARCH 2024

TABLE II. (Continued)

Study name Estimated Target age
(NCT or ACTRN no.) Study description enrollment groups Main Outcomes

Other molecules
Phase I Trial to Evaluate VLP Peanut Phase I, randomized, sequential N 5 58 18-50 y No. and severity of adverse events, including local
in Healthy and Peanut Allergic assignment, interventional, 2-part and systemic (time frame: group A1, 18 wk; part
Subjects (PROTECT Study, clinical trial of SCIT to Ara h 2 B, 64 wk (part B); group A2, 3 d)
NCT05476497) using peanut VLPs (;34 wk) No. of subjects discontinuing prematurely from
2-part clinical trial: treatment owing to adverse events (time frame:
Part A: open-label with 2 groups group A1, 11 wk; part B, 15 wk)
(A1 and A2):
A1 (healthy subjects): subcutaneous
(SC) dosing with ascending
concentrations of peanut VLPs
A2 (subjects with PA): SPT
performed with ascending
concentrations of peanut VLPs.
Part B: double-blind, placebo-
controlled part that will enroll
subjects with PA: subcutaneous
dosing with ascending
concentrations of peanut VLPs
A Safety and Efficacy Study of Phase II, multicenter, randomized, N 5 90 4-17 y
PVX108 in Children and double-blind placebo-controlled d Ratio of MTD of peanut protein at the wk 46
Adolescents with Peanut Allergy study of PVX108 immunotherapy DBPCFC relative to baseline in children aged
(NCT05621317) (;74 wk) 4-11 y treated with PVX108 vs placebo
A Study to Evaluate Safety, Phase 1, randomized, parallel N 5 20 12-17 y
Tolerability and Immune Response assignment, double blind, placebo- d _d 576)
Treatment-emergent adverse events (<
in Adolescents Allergic to Peanut controlled study of intradermal
d _d 50). Systemic
Local reactogenicity reactions (<
after Receiving Intradermal administration of ASP0892
_d 50) anti–LAMP-1
reactogenicity reactions (<
Administration of ASP0892 (;576 d [18 mo and 28 d])
antibody formation (<_d 576)
(ARA-LAMP-vax), a Single
Multivalent Peanut (Ara h1, h2, d ASP0892 (ARA-LAMP-vax): a d No. of participants with vital signs abnormalities
h3) Lysosomal Associated single multivalent peanut (Ara and/or with laboratory value abnormalities and/or
Membrane Protein DNA Plasmid h1, h2, h3) lysosomal-associated _d 576)
adverse events (<
Vaccine (NCT03755713) membrane protein DNA plasmid
vaccine applied by intradermal
administration
Cohort A: experimental ASP0892, low
dose
Cohort B: experimental ASP0892, high
dose
Placebo comparator: placebo
CNP-201 in Subjects with Peanut Phase I and II, multicenter, N 5 58 16-55 y Safe and tolerable dose level determined by
Allergy (NCT05250856) randomized, quadruple blind, evaluating the frequency of adverse events and
multiple ascending dose study of serious adverse events (through study completion,
CNP-201: a comprised purified an average of 67 d) and serum cytokine levels (an
peanut extract substance dispersed average of 52 d)
within a special matrix. (;67 d)

Details of the studies, including recruitment status, are as of October 2023 (https://clinicaltrials.gov/).
ACTRN, Australian New Zealand Clinical Trials Registry number; CRD, cumulative reactive dose; CTCAE, Common Terminology Criteria for Adverse Events; DBPCFC, double-
blind placebo-controlled food challenge; ED, Eliciting dose; FMT, fecal microbiota transplantation; JAK, Janus kinase; MTD, maximum tolerated dose; MTT, microbial
transplantation therapy; NCT, National Clinical Trial; SCIT, subcutaneous immunotherapy; SPT, skin prick test.

peanut protein, was safe and well tolerated in children with PA.112 Sublingual immunotherapy (SLIT) has shown an intermediate
Subjects with atopic dermatitis at baseline showed a higher trend safety profile between OIT and EPIT, likely related to the dose of
of responder rates but also higher rates of local reactions.113 The allergen administered and possibly to the route of administration.
desensitization effects of EPIT to peanut have improved with SLIT has been studied for PA and compared with OIT. Younger
longer duration of treatments,114 so follow-up studies are currently age groups and longer duration of SLIT were associated with
ongoing to evaluate this in the long term. Other EPIT studies, higher dose of peanut protein tolerated; hence, as is the case with
namely, examining the effects of EPIT to CM, are ongoing. OIT, implementing this therapy earlier in life may be beneficial.
J ALLERGY CLIN IMMUNOL BARTHA, ALMULHEM, AND SANTOS 587
VOLUME 153, NUMBER 3

Recently, an open-label prospective study in children with PA Microbiome-modulating agents

who were aged 1 to 11 years showed that peanut SLIT induced Gut microbial composition, diversity, and metabolic activity
desensitization in 70% of the participants and 36% successfully are factors that can influence the balance between allergy and
consumed a dose of 5000 mg of peanut protein.115 Combination tolerance to certain foods. For instance, Chun et al120 followed
of SLIT and OIT is currently being trialed for CMA in the high-risk infants with no PA up until about 9 years of age and
Improving the Safety of Oral Immunotherapy for Cow’s Milk Al- found that 28.7% of the children developed PA over time. Chil-
lergy (SOCMA) study. dren with PA had lower gut microbiome diversity and different
A new delivery platform for AIT called oral mucosal immu- abundances of Clostridium and Bifidobacterium species, with
notherapy has been developed; it enables the delivery of higher butyrate and isovalerate decreasing and histidine metabolites,
allergen doses (compared with those used in SLIT) to areas in the like histamine, increasing over time.
oral mucosa with higher concentrations of Langerhans cells. Oral In terms of clinical trials of probiotic supplementation, Bifi-
mucosal immunotherapy aims to improve safety, adherence, and dobacterium bifidum TMC3115 improved safety outcomes in
efficacy versus with SLIT and is being tested in a phase I study of children with CMA,121 and in another study,122 Lactobacillus
INT301 in adults with PA (the OMEGA study).116 SCIT is a route rhamnosus GG facilitated recovery from gastrointestinal symp-
of administration that is also currently being trialed (eg, for treat- toms and improved fecal occult blood in children with
ment of PA). CMA.122 Probiotics may improve the safety of AIT when given
as an adjunct treatment. Lactobacillus rhamnosus GG ATCC
53103 reduced systemic reactions, gastrointestinal symptoms,
Biologics and moderate-to-severe adverse events but did not affect the ef-
An SR of the literature with meta-analyses has compiled ficacy of peanut OIT in children, particularly those aged 1 to 5
evidence on the use of omalizumab to treat FA.117 Most such years.123 A similar study in a Chinese population is currently
studies focus on the use of omalizumab as an adjuvant of OIT, ongoing (NCT05165329). However, neither study included a
with fewer studies assessing its efficacy as monotherapy. The probiotic-only arm, thus preventing a proper measure of effect.
SR concluded that omalizumab increased the dose of food toler- Probiotics are also currently being studied in combination with
ated compared to before treatment, reduced allergic reactions, and egg OIT.123
improved quality of life. As an adjunct of OIT, omalizumab facil- Prebiotics (eg, dietary fiber [NCT05138757] or modified
itated dose escalation and higher maintenance doses. The results dietary starch [Australian and New Zealand Clinical Trial
of the Outmatch study, the primary outcome of which is the effi- Registry number (ACTRN) 12617000914369]) are being evalu-
cacy of omalizumab as monotherapy for multiple FAs, are eagerly ated as adjuvants of peanut OIT. The combination of synbiotics
awaited. The safety and efficacy of pretreatment with omalizu- (prebiotics oligosaccharides and probiotic Bifidobacterium breve
mab to use a lower maintenance dose in a multifood OIT regimen M-16V) and an amino acid–based formula (AAF) in infants aged
have been evaluated recently. The study compared 2 dose regi- 13 months or younger who have IgE-mediated CMA did not show
mens, 300 and 1200 mg of total protein, including total doses any difference from AAF alone.124 However, stool samples
of at least 2 and up to a maximum of 5 foods. On both study collected in this study for analysis of fecal microbiota showed a
arms, 70% of the participants showed changes in the sIgG4/IgE higher percentage to bifidobacteria in AAF-plus-synbiotic group
ratio of at least 2 allergens, and no differences were found in terms at both 6 and 12 months than in the AAF group.
of adverse events.118 Dosing studies of omalizumab to accelerate Transplantation of healthy fecal microbiota or defined
multifood OIT, either on its own (eg, the BOOM study) or commensal bacterial taxa can potentially modify intestinal
together with E-B-FAHF-2 Chinese herbal therapy, are ongoing. immune responses through restoration of gut immune regula-
Another anti-IgE mAb, ligelizumab, which has an approxi- tory checkpoints, mainly related to retinoic orphan receptor
mately 88-fold higher affinity for human IgE than omalizumab, is gamma T-positive (RORgt1) Treg cells, the epithelial barrier,
currently being trialed for PA in phase III multicenter study and IgA response to gut commensals.125 Initial in vitro and an-
(NCT04984876). Dupilumab, a mAb against the a-chain of the imal studies have led to clinical trials evaluating the efficacy of
IL-4 receptor inhibiting the signal for both IL-4 and IL-13, is be- fecal microbiota transplantation in FA (eg, a phase II study to
ing studied in combination with peanut OIT (NCT03793608 and evaluate the safety and tolerability of oral encapsulated fecal
NCT03682770), milk OIT (NCT04148352), and omalizumab and microbial transplantation therapy for patients with PA
multifood OIT (NCT03679676). [NCT05695261] is ongoing). A recent SR showed that fecal
Other pharmacologic agents being trialed in FA include the microbiota transplantation is a promising strategy to prevent
following: abrocitinib, an oral Janus kinase (JAK) inhibitor that allergic symptoms, but further investigation is still required.126
is being tested in a phase I study for peanut, cashew, walnut, Further studies are needed to evaluate which microorganism
hazelnut, sesame, cod, and/or shrimp allergies in patients aged are best, which is the optimal dose, whether treatment needs
18 to 50 years (NCT05069831); abatacept, a fusion protein of to be continued, and whether the effects are maintained over
the extracellular domain of the human CTLA-4 that links to the the long term. Another approach being tested is the administra-
fragment crystallizable (Fc) domain of human immunoglobulin tion of antibiotics before or during peanut OIT (Table II).
and is being tested as an adjuvant to OIT in a phase II study of
adolescents and adults with PA (NCT04872218); and remi-
brutinib, a Bruton tyrosine kinase (BTK) inhibitor that is being Allergen-specific vaccines
tested in a phase II study of adults with PA (NCT05432388). Peanut virus-like particles (VLPs) have shown, in a mouse
Acalabrutinib, another BTK inhibitor, has been shown to model of PA, that the fusion vaccine using Ara h 2 is highly
increase patients’ threshold dose of peanut protein in adults immunogenic and confers protection against local and systemic
with PA.119 reactions to peanut. As the concentration of Ara h 2 is relatively
588 BARTHA, ALMULHEM, AND SANTOS J ALLERGY CLIN IMMUNOL
MARCH 2024

low, the potential interaction and activation of MCs and basophils Skin interventions in infancy
is reduced.127,128 Peanut VLPs are currently being evaluated in The dual allergen exposure hypothesis proposes that FA risk
humans in a phase I study (Table II). Prunus persica 3 VLPs results from the balance between dose, timing, and route of
have also been evaluated in a mouse model with promising exposure to food allergens in infancy, with high-dose exposure
results.129 through the oral route being tolerogenic and low-dose exposure
Peptide-based AIT is another approach that may minimize the through the skin, particularly inflamed skin affected with eczema,
risk of IgE-mediated reactions, as peptides may be too small to being proallergenic.137 This hypothesis was supported by the
bind and cross-link IgE.130,131 PVX108, a mixture of short, syn- LEAP study findings a few years ago138,139 and has motivated tri-
thetic peptides derived from peanut allergens administered als of skin interventions to prevent sensitization and development
intradermally has shown a favorable profile, with changes in of FA. However, the findings have been somewhat surprising,
allergen-specific T cells and skin prick test response persisting af- with the BEEP study showing negative results for the preventative
ter dosing. Currently, a phase II study in children and adolescents effects of emollients on FA risk and the PreventADALL study
with PA is ongoing (NCT05621317). showing that emollients and early food introduction did not pre-
Additional approaches being studied in individuals with PA are vent eczema at age 12 months but did prevent FA at age 36
as follows: ASP0892 (ARA-LAMP-vax), a single multivalent months.140-142 In the Enquiring about Tolerance (EAT) study, reg-
peanut (Ara h 1, Ara h 2, and Ara h 3) lysosomal-associated ular application of moisturizers to the skin of young infants was
membrane protein DNA plasmid vaccine administered intrader- associated with increased transcutaneous sensitization and
mally (NCT03755713), and nanoparticles coated with peanut FA.143 Specifically, moisturization frequency showed a dose-
protein (CNP-201) administered by intravenous infusion response relationship with the development of FA in children
(NCT05250856). mRNA vaccines encoding allergens may be with and without visible eczema at enrollment.143 Two possible
the next approach to be tried, given the success of this mode of explanations have emerged for these findings: either moisturizers
delivery in the coronavirus disease 2019 (COVID-19) pandemic, facilitate the penetration of food allergens across the skin barrier
which was worthy of the Nobel Prize in Physiology and Medicine and/or allergenic proteins are transferred to the babies’ skin by
2023. parents’ hands. A Cochrane review concluded that skin care inter-
ventions in infancy did not prevent eczema and may increase the
risk of skin infection and FA.144
FA PREVENTION Given that eczema is a risk factor for FA, the question of
Important research in FA development in early childhood over whether early proactive treatment or reactive treatment of eczema
the past 15 to 20 years has motivated the transition from passive is best for FA prevention has been addressed. For example, in the
allergen avoidance to active management based on prompt Prevention of Allergy via cutaneous Intervention (PACI) study,
interventions on eczema-affected skin and early introduction of infants were randomized to proactively apply emollients and
allergenic foods. Maternal interventions during pregnancy and topical corticosteroids to both lesional and nonlesional skin
lactation have had more controversial results (Table III). (enhanced treatment) or to use topical corticosteroids on lesional
skin reactively when needed (conventional treatment). The
incidence of EA was significantly reduced with use of enhanced
Maternal interventions during pregnancy and treatment (31.4%) versus conventional treatment (41.9%). How-
lactation ever, the enhanced treatment lowered body weight and height;
Healthy diet diversity during pregnancy and in the first year of thus, lower potency topical corticosteroids or other topical
life, which can result in changes in the gut microbiome, has been therapies should be considered.145 Along a similar line, the Stop-
associated with lower odds of FA. Venter et al created the ping Eczema and Allergy (SEAL) study aims to compare the ef-
maternal diet index using data from the Healthy Start, a prebirth fect of proactive sequential skin care or moisturizer with proactive
cohort of mother-offspring dyads.132,133 The index considered the use of fluticasone propionate cream to reduce the occurrence,
consumption of vegetables, yogurt, fried potatoes, rice and grains, exacerbation, and severity of atopic dermatitis, and therefore, to
red meats, pure fruit juice, and cold cereals. Vegetables and prevent FA (NCT03742414).
yogurt were associated with the prevention of allergic disease.
In adjusted models, a 1-unit increase in the maternal diet index
was associated with a decreased risk of atopic diseases, except Dietary interventions in infancy
for FA. A variety of prevention studies have examined early introduc-
An important intervention to study is the consumption of tion of allergenic foods, in both the general population and high-
allergenic foods during pregnancy and whether this changes the risk infants. The main allergenic foods studied were peanut, egg,
FA risk in the offspring. As an example, the PrEggNut study is and CM. The landmark LEAP study showed the effectiveness of
evaluating the effect that a maternal diet rich in eggs and peanuts early peanut introduction in high-risk children aged 4 to 11
has on egg and PA outcomes in their toddlers at 12 months of months, with those with severe eczema and/or EA considered
age.134 A recent mouse study suggests that application of high-risk individuals.138,139 The EAT study focused on the gen-
Bifidobacterium bifidum TMC3115 during pregnancy shapes eral population, and a significant reduction in PA and EA was
offspring gut microbiota, which may induce tolerance to aller- seen only in the per-protocol analyses for children in the interven-
gens.135 Preliminary results suggest protective and anti- tion arm.146 In a recent pooled analyses of the LEAP and EAT
inflammatory properties of Bifidobacterium infantis136 and data, a significant reduction was seen with early introduction in
motivated a new trial assessing its effect on symptoms at the all risk subgroups,147 highlighting the need to intervene at the
fourth week in infants with allergy to 1 of the following foods: level of the whole population, especially in countries in which
cow’s milk, egg, soya, and wheat (NCT05965063). peanut is an important food.148 The efficacy of the intervention
J ALLERGY CLIN IMMUNOL BARTHA, ALMULHEM, AND SANTOS 589
VOLUME 153, NUMBER 3

TABLE III. Current and ongoing research studies in FA prevention

Target
Estimated age
Study name (NCT or ACTRN no.) Study description enrollment group Main outcomes

Maternal interventions during pregnancy and lactation

Can Vitamin D Supplementation in Phase 4, randomized, parallel N 5 2739 6-12 wk Prevalence of challenge-proven FA at age 12
the First Year of Life Prevent assignment, quadruple masking, mo.
Food Allergy in Infants? The prevention study (;6 years) Occurrence of definite FA or tolerance at age 6 y
VITALITY Trial: Parts 1 & 2 (the by combining data from an OFC, an SPT, and/
VITALITY Study; or serum specific IgE test, and/or parent- or
NCT02112734) self-reported ingestion history, and reactions
to the index food
The Role of Bifidobacterium Randomized, parallel assignment, open- N 5 300 0-12 mo Clinical symptoms of infants at the fourth wk by
Intervention in Food-Allergic label, treatment study with milk-related symptom score (0-33 [higher
Infants (NCT05965063) Bifidobacterium intervention scores means worse outcomes])
(;12 wk)
Food allergies include CM, egg, soy, and
wheat
Maternal Diet Rich in Eggs and Randomized, multicenter, parallel, N 5 2136 Pregnant Food challenge–proven IgE-mediated EA and/or
Peanuts to Reduce Food Allergies: 2-arm women PA in the infants at age 12 mo
A Randomized (1:1 allocation), at <
_wk IgE-mediated EA and/or PA is defined as an
Controlled Trial (the PrEggNut single-blinded, controlled study of a diet 23 of allergic reaction to egg with sensitization to
Study; ACTRN12618000937213) rich in egg and peanut during gestation egg and/or an allergic reaction to peanut with
pregnancy sensitization to peanut. Sensitization is
defined as >_3-mm weal size based on an SPT.
Infants with a positive SPT who do not
proceed with the corresponding food
challenge because of previous anaphylaxis or
allergic reaction will be considered positive
for IgE-mediated EA and/or PA; otherwise,
the allergic reaction will be established
according to an OFC
Skin barrier: Emollients, steroids and microbiome
Moisturizer-Mediated Prevention of Phase III, multicenter, randomized, non– N 5 360 < 3 wk Cumulative incidence of children with AD in the
Symptoms of Atopic Dermatitis in treatment-controlled, investigator- treatment group at age 6 mo is significantly
Early Childhood (the MOPAD blinded study of SanaCutan lower than in the control group without
Study; NCT04398758) Basiscreme (;12 mo) predetermined treatment (P <.05)
Bathing Babies and Allergy (the Prospective, observational cohort study N 5 144 <
_72 h Change in skin TEWL at 18-36 hours after the
BBA study; NCT03050658) of impact of a baby’s first bath on his/ of life baby’s first bath in the hospital vs baseline
her TEWL and skin microflora (;2 y)
Seal, Stopping Eczema and Allergy Phase II, randomized, controlled, parallel N 5 875 1-12 wk
Study (the SEAL; NCT03742414) design, open-label clinical study of d Occurrence and severity of AD in early
proactive sequential skin care, infancy
including the twice-daily use of a
trilipid skin barrier cream (Epiceram) d Per-participant cumulative no. of challenge-
or moisturizer and proactive use of proven FAs at 3 y Food allergens included
fluticasone propionate cream, against are egg, CM, peanut, sesame, fish, wheat, and
reactive AD therapy (;3 y) 9 tree nuts
Allergic Disease Onset Prevention Phase Ib and II, multicenter, randomized, N 5 264 0-14 d Parts A1 and A2:
Study (the ADORED Study; double-blind, placebo-controlled study Neonate AEs, SAEs, and AESIs (at < _d 56 of study)
NCT05003804) of STMC-103H (;672 d [22 mo and and infants Part B:
3 d]) subjects at
STMC-103H is a combination of risk for d AEs, SAEs, AESI, physical examination find-
bacterial species that have been found development ings, and clinical safety laboratory test results
to be depleted in the gut microbiota of of atopic (at <
_d 672 of study)
infants who go on to develop allergic disease
d incidence of physician-diagnosed AD at
sensitization and allergic diseases in
d 336
childhood
Secondary outcomes:

d Proportion of subjects who develop any

atopic disease (AD, FA, allergic rhinitis/
conjunctivitis, asthma),
d Incidence of sensitization to food and aeroal-
lergen and incidence of physician-diagnosed
FA, allergic rhinitis/conjunctivitis, urticaria,
and wheezing illnesses/asthma

(Continued)
590 BARTHA, ALMULHEM, AND SANTOS J ALLERGY CLIN IMMUNOL
MARCH 2024

TABLE III. (Continued)

Target
Estimated age
Study name (NCT or ACTRN no.) Study description enrollment group Main outcomes
Restoration of Microbiota in Randomized, single-center, parallel N 5 300 Newborns of Cumulative incidence of IgE-associated allergic
Neonates (RoMaNs Study; assignment, triple-masking, placebo- mothers aged disease at age 2 y in infants delivered by
NCT03928431) controlled study of exposure to the 18-40 y cesarean section vs in nontreated infants
maternal vaginal and fecal microbiota delivered by cesarean section
directly after birth (;2 y) SPTs will be performed in infancy (at age 6 mo
and age 12 mo) and childhood (at age 24 mo)
Early introduction and natural tolerance development
Preterm Infants on Early Solid Randomized, parallel assignment, N 5 177 1 wk-3 mo o Height difference at age 1 year, corrected for
Foods (PIES-Project; prospective 2-arm intervention study prematurity
NCT01809548) (;5 y) o Height will be measured under standardized
conditions in cm at defined times during the
first year of life until age 1 y, corrected for
prematurity. Measurements will be done
before, within, and after intervention to
demonstrate the changes due to all interven-
tion tools
Secondary outcomes:
- FX5 (specific IgE levels of food allergens at
age 5 y)
- SCORAD
The TreEat Study: Can Early Phase III, randomized, 2-arm, open- N 5 200 4-11 mo Difference between the 2 treatment arms in the
Introduction of Tree Nuts Prevent label, controlled study of a supervised proportion of participants with clinically
Tree Nut Allergy in Infants with hospital based multitree nut (almond, confirmed tree nut allergy at age 18 mo
Peanut Allergy (the TreEat Study; cashew, hazelnut, and walnut) OFC Tree nut allergy outcomes at 18 mo will be
NCT04801823) and then home introduction of the defined as
remaining tree nuts vs standard care - Having an allergy (has evidence of tree nut
(home introduction of all 8 tree nuts) sensitization [SPT result > _ 3 mm] and having
in infants with PA to reduce the risk of had a reaction consistent with IgE-mediated
developing tree nut allergy (;18 mo) FA OR positive formal OFC)
- Tolerant of tree nuts (successfully tolerated 1
tsp of the tree nut per occasion at home on
>3 occasions OR has had a negative formal
OFC result)
- Inconclusive (has an unknown outcome, as
ingestion has not occurred and participant
has declined OFC)

Details of the studies, including recruitment status, are as of October 2023 (https://clinicaltrials.gov/).
ACTRN, Australian New Zealand Clinical Trials Registry number; AD, atopic dermatitis; AE, adverse event; AESI, adverse event of special interest; NCT, National Clinical Trial; SAE,
serious adverse events; SCORAD, Scoring Atopic Dermatitis; SPT, skin prick test; TEWL, transepidermal water loss.

increased with earlier age of introduction147,148 and was reduced nuts. The TreEAT Study will evaluate whether early introduction
if delayed until age 12 months.148 In a recent meta-analysis, early of nuts can prevent allergy development in aged 4 to 11 months
introduction of peanut from age 3 months to age 10 months was who have PA (NCT04801823).
associated with a reduced risk of PA.149 The evidence that early introduction of CM can prevent CMA
Following the modification of the early introduction guidelines is conflicting.149 For instance, in the EAT and PreventADALL
in Australia, there has been a preliminary indication of a reduction studies, no difference between the early introduction and standard
in food anaphylaxis admission rates in 1- to 14-year-olds. introduction groups was found in the development of
However, it seems that an increase in FA rate was seen in those CMA.141,143,146 The ABC trial noted higher rates of sensitization
younger than 1 year, which may be explained by earlier presen- to CM and CMA in those who had been receiving CM formula
tation of pre-existing FA with the introduction of allergenic solids since their first day of life. However, these results should be inter-
in the first year of life.150 Specifically for PA, cross-sectional an- preted with caution, as the time before discontinuation differed
alyses did not reveal changes in prevalence of PA across the pop- broadly among infants. In the SPADE study, in which infants
ulation.151 There are a variety of factors that could lead to this; were randomized to introduction of CM at age 1 month or avoid-
they include not enough time for implementation of guidelines ance during the first and second months of life, a reduction of
and follow-up of infants affected, no strict adherence to the appro- CMA was observed in the group with daily ingestion of CM for-
priate amount and frequency of consumption, lifestyle choices, mula during the first and second months of life.152 Interestingly, in
influence of cultural practices, and access to accurate information infants with exposure to CM in the first 3 days of life, CMA devel-
about weaning strategies. Many children with PA also avoid tree opment was associated with CM formula discontinuation.153
J ALLERGY CLIN IMMUNOL BARTHA, ALMULHEM, AND SANTOS 591
VOLUME 153, NUMBER 3

Introduction of solid foods in the diet can have benefits other 4. Aramburo-Galvez JG, Figueroa-Salcido OG, Ramirez-Torres GI, Teran-Cabanillas
than exposure to the allergen via the tolerogenic gastrointestinal E, Gracia-Valenzuela MH, Arvizu-Flores AA, et al. Prevalence of parent-reported
food allergy in a Mexican pre-school population. J Clin Med 2023;12:5095.
tract. In the EAT study, introduction of allergenic foods from the 5. Beltran-Cardenas CE, Granda-Restrepo DM, Franco-Aguilar A, Lopez-Teros V,
age of 3 months promoted a significant increase in gut micro- Arvizu-Flores AA, Cardenas-Torres FI, et al. Prevalence of food-hypersensitivity
biome diversity, specific microbes in the gut, and differential and food-dependent anaphylaxis in Colombian schoolchildren by parent-report.
dynamics of maturation of the gut microbial communities versus Medicina (Kaunas) 2021;57:146.
6. Goncalves LC, Guimaraes TC, Silva RM, Cheik MF, de Ramos Napolis AC, Bar-
in infants to whom solid foods were introduced only after age 6 bosa ESG, Segundo GR. Prevalence of food allergy in infants and pre-schoolers
months.154 A recent prospective study showed that infants with in Brazil. Allergol Immunopathol (Madr) 2016;44:497-503.
high diet diversity scores had lower gene expression of IL-4, 7. Cabrera-Chavez F, Rodriguez-Bellegarrigue CI, Figueroa-Salcido OG, Lopez-
IL5, IL-6, IL-8, and IL-13 and greater microbial diversity than Gallardo JA, Aramburo-Galvez JG, Vergara-Jimenez MJ, et al. Food allergy prev-
alence in Salvadoran schoolchildren estimated by parent-report. Int J Environ Res
observed in the group with lower diet diversity. The same study
Public Health 2018;15:2446.
associated these changes with achieving oral tolerance and 8. Spolidoro GCI, Amera YT, Ali MM, Nyassi S, Lisik D, Ioannidou A, et al. Fre-
reducing the possibility of developing EA in high-risk infants.155 quency of food allergy in Europe: an updated systematic review and meta-anal-
ysis. Allergy 2023;78:351-68.
9. Lyons SA, Clausen M, Knulst AC, Ballmer-Weber BK, Fern
andez-Rivas M, Bar-
reales L, et al. Prevalence of food sensitization and food allergy in children across
CONCLUSIONS Europe. J Allergy Clin Immunol Pract 2020;8:2736-46.e9.
We are living exciting times in FA research, with many 10. Lyons SA, Burney PGJ, Ballmer-Weber BK, Fern
andez-Rivas M, Barreales L,
promising fundamental and translational studies in the pipeline. Clausen M, et al. Food allergy in adults: substantial variation in prevalence and
causative foods across Europe. J Allergy Clin Immunol Pract 2019;7:1920-8.e11.
The dissection of the immune mechanisms of FA and the
11. Tamazouzt S, Adel-Patient K, Deschildre A, Roduit C, Charles MA, de Lauzon-
identification of new targets for a definitive treatment should be Guillain B, Divaret-Chauveau A. Prevalence of food allergy in France up to 5.5
a priority. A curative treatment is much needed, and the years of age: results from the ELFE Cohort. Nutrients 2022;14:3624.
identification of specific targets in the aberrant allergic response 12. McBride D, Keil T, Grabenhenrich L, Dubakiene R, Drasutiene G, Fiocchi A,
are the key to unlock a true modification of this condition. An et al. The EuroPrevall birth cohort study on food allergy: baseline characteristics
of 12,000 newborns and their families from nine European countries. Pediatr Al-
improved understanding of the epidemiologic and genetic lergy Immunol 2012;23:230-9.
changes in FA can help design specific interventions. It is hoped 13. Roehr CC, Edenharter G, Reimann S, Ehlers I, Worm M, Zuberbier T, Nigge-
that ongoing clinical trials will lead us to more precise diagnostics mann B. Food allergy and non-allergic food hypersensitivity in children and ad-
and more active management of FA. Overall, such therapeutic olescents. Clin Exp Allergy 2004;34:1534-41.
interventions, and particularly preventive measures, can reduce 14. Venkataraman D, Erlewyn-Lajeunesse M, Kurukulaaratchy RJ, Potter S, Roberts
G, Matthews S, Arshad SH. Prevalence and longitudinal trends of food allergy
the prevalence of FA and reduce its burden on patients’ lives and during childhood and adolescence: results of the Isle of Wight Birth Cohort study.
the society. Clin Exp Allergy 2018;48:394-402.
15. Kaya A, Erkocoglu M, Civelek E, Cakir B, Kocabas CN. Prevalence of confirmed
IgE-mediated food allergy among adolescents in Turkey. Pediatr Allergy Immu-
nol 2013;24:456-62.
DISCLOSURE STATEMENT 16. Mohamed MF, Zakaraya DN, Abd-El Wahab HE, Ashour ZA. Prevalence of
Supported by the Medical Research Council (grants MR/ confirmed immunoglobulin E-mediated food allergy among adult Egyptian pa-
M008517/1, MC/PC/18052, and MR/T032081/1 [to A.F.S.]); tients. Egypt J Immunol 2021;28:23-32.
17. Hassan A, Alsaihati A, Al Shammari M, Alaithan H, Al-Johani W, AlShamlan N,
Food Allergy Research and Education (to A.F.S.); the Immune
Aljubran S. Food allergy among university students: uncharted territory. Allergy
Tolerance Network/National Institute of Allergy and Infectious Asthma Clin Immunol 2020;16:17.
Diseases, National Institutes of Health (to A.F.S.); Asthma UK 18. Ziyab AH. Prevalence of food allergy among schoolchildren in Kuwait and its as-
(grant AUK-BC-2015-01 [to A.F.S.]); the Biotechnology and sociation with the coexistence and severity of asthma, rhinitis, and eczema: a
Biological Sciences Research Council (to A.F.S.), the Rosetrees cross-sectional study. World Allergy Organ J 2019;12:100024.
19. Ali F. A Survey of self-reported food allergy and food-related anaphylaxis among
Trust (to A.F.S.) and the National Institute for Health Research young adult students at Kuwait University, Kuwait. Med Princ Pract 2017;26:
through the Biomedical Research Centre Award to Guy’s and 229-34.
St. Thomas’ NHS Foundation Trust (to A.F.S.) during the conduct 20. AbdulAal N, Alalwan TA. The reported prevalence of food allergy among school-
of the study. aged children in Bahrain. Allergol Immunopathol (Madr) 2023;51:90-8.
21. Sakakini J, Irani C, Bikai R, Sahyoun G, Hallit S, Salameh P, Dano D. Prevalence
Disclosure of potential conflict of interest: A. F. Santos reports
of food allergy among schoolchildren in Lebanon. Int Arch Allergy Immunol
personal fees from Thermo Scientific, Nutricia, Infomed, Novar- 2022;183:611-6.
tis, Allergy Therapeutics, and Buhlmann, as well as research sup- 22. Irani C, Maalouly G. Prevalence of self-reported food allergy in Lebanon:
port from Buhlmann and Thermo Fisher Scientific through a A middle-Eastern taste. Int Sch Res Notices 2015;2015:639796.
collaboration agreement with King’s College London. The rest 23. Garkaby J, Epov L, Musallam N, Almog M, Bamberger E, Mandelberg A, et al.
The sesame-peanut conundrum in Israel: reevaluation of food allergy prevalence
of the authors declare that they have no relevant conflicts of in young children. J Allergy Clin Immunol Pract 2021;9:200-5.
interest. 24. Nachshon L, Schwartz N, Elizur A, Schon Y, Cheryomukhin M, Katz Y, Goldberg
MR. The prevalence of food allergy in young Israeli adults. J Allergy Clin Immu-
nol Pract 2019;7:2782-9.e4.
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