Received: 3 September 2020 | Revised: 1 December 2020 | Accepted: 23 December 2020

DOI: 10.1111/pai.13443

REVIEW

Update on food allergy

Rachel L. Peters1,2 | Marta Krawiec3,4,5 | Jennifer J. Koplin1,2,6 |

Alexandra F. Santos3,4,5,7

1
Murdoch Children’s Research Institute
Melbourne, Melbourne, Vic., Australia Abstract
2
Department of Paediatrics, University of Food allergy is a major public health issue with growing prevalence in the urban-
Melbourne, Melbourne, Vic., Australia
ized world and significant impact on the lives of allergic patients and their families.
3
Children’s Allergy Service, Guy’s and St.
Thomas’ NHS Foundation Trust, London, UK
Research into the risk factors that have contributed to this increase and their under-
4
Department of Women and Children’s lying immune mechanisms could lead us to definitive ways for treatment and preven-
Health (Paediatric Allergy), Faculty of Life tion of food allergy. For the time being, introduction of peanut and other allergenic
Sciences and Medicine, School of Life
Course Sciences, King’s College London, foods in the diet at the time of weaning seems to be an effective way to prevent the
London, UK development of food allergy. Improved diagnosis and appropriate management and
5
Peter Gorer Department of Immunobiology,
support of food allergic patients are central to patient care with food immunotherapy
School of Immunology and Microbial
Sciences, King’s College London, London, and biologics making the transition to clinical practice. With the new available treat-
UK
6
ments, it is becoming increasingly important to include patients' and family prefer-
School of Population and Global Health,
University of Melbourne, Melbourne, Vic., ences to provide a management plan tailored to their needs.
Australia
7
Asthma UK Centre for Allergic Mechanisms KEYWORDS
of Asthma, London, UK basophil activation test, biologics, diagnosis, food allergy, IgE, immunotherapy, skin prick test

Correspondence
Alexandra Santos, Department of Pediatric
Allergy, 2nd floor, South Wing, St Thomas’
Hospital, 28 Westminster Bridge Road, SE1
7EH London, UK
Email: [email protected]

Editor: Motohiro Ebisawa

1 | I M PAC T O F FO O D A LLE RG Y epidemic’ after the rise in the prevalence of asthma and respiratory
allergy in previous decades.5-7 Pouessel et al8 have shown that foods
Food allergy (FA) can be classified into IgE- and non–IgE-mediated caused 37% of cases of ICU admissions for anaphylaxis and 79% of
depending on the involvement of IgE in its pathogenesis. In this re- recurrent anaphylaxis. Self-reported FA is even more common with
view, we are focusing on IgE-mediated food allergy. FA affects about an often underappreciated impact.1 Gupta et al1 report that about
8% of children in the Western countries and seems to be rising in 40% of food allergic children report multiple food allergies, often se-
other parts of the world such as in Vietnam and South Africa, and vere food allergies, and carry an adrenaline auto-injector. In Western
other parts of Asia and Africa, particularly in urban rather than rural countries, such as the USA and the UK, FA affects disproportionally
areas.1-4 The prevalence of FA has increased over the recent dec- children from ethnic minorities, such as children of Afro-Caribbean
ades, as has the number of hospitalizations for food-induced ana- descent.1,9,10 Whether this has to do with genetic predisposition
phylaxis, following what seems to be the ‘second wave of the allergy in face of environmental factors related to the modern lifestyle

This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium,
provided the original work is properly cited.
© 2021 The Authors. Pediatric Allergy and Immunology published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.

Pediatr Allergy Immunol. 2021;32:647–657.  wileyonlinelibrary.com/journal/pai | 647

648 | PETERS et al.

or whether the cultural background, the history of inequality and

different access to health care also play a role is unclear.10,11 The
Key Message
threefold higher risk of peanut and other food allergies in infants
Food allergy is a major health issue in the urbanized world
born in Australia to Asian-born parents compared with the risk of
with increasing prevalence and significant impact on pa-
peanut allergy in infants born to Australian-born parents reinforced
tients' lives. The diagnosis of food allergy is based on clini-
the rapidity with which these changes occur and the importance of
cal history and evidence of allergen-specific IgE, with oral
gene-environment interactions that need to be further explored.12
food challenge being the gold standard and new tests being
There is no curative treatment for FA, and the mainstay of man-
developed. There is no curative treatment for food allergy,
agement is allergen avoidance. Emergency medication needs to be
and allergen avoidance is the mainstay of management,
made available to patients to enable them to treat acute allergic
with allergen immunotherapy and biologicals being tested
reactions that may result from accidental exposure to the culprit
13 currently. The intervention that is widely recommended to
allergens and are unfortunately common. Allergen avoidance im-
prevent food allergy is introduction of peanut and egg at
poses dietary restrictions, with potential nutritional consequences,
the time of weaning, alongside with breastfeeding.
and can lead to food insecurity.14-16 Eighty-six per cent of mothers
of children with suspected FA avoid foods on their own initiative.17
Goldberg et al16 have recently shown that milk-allergic young adults
have reduced bone mineral density and that low calcium intake, mechanism driving this association remains unclear. It has been hy-
asthma and weight constitute independent risk factors. FA can also pothesized that a damaged skin barrier resulting from eczema may
result in an impairment of quality of life and mental health of chil- allow the absorption of food allergens through the skin leading to
dren and their families.17-20 For instance, mothers of children with food sensitization and allergy, in the absence of pre-existing oral
suspected FA have higher state and trait anxiety scores than healthy tolerance to those foods. 29 Alternative explanations include the ex-
17
controls and about 50% of children and teenagers with FA experi- istence of shared genetic or environmental risk factors leading to an
ence bullying.18 FA can also impact negatively on the costs, related increased risk of both eczema and FA.
to not only the healthcare but also the indirect costs, for instance There has been strong interest in identifying factors that can be
related to school and work absences, and the financial burden on the modified to prevent FA. Both observational studies and randomized
families themselves, resulting, for example, from the need to spend controlled trials have investigated the association between FA and
more time shopping and to find alternative foods that are often more factors including vitamin supplements, fish oil, probiotics and tim-
expensive. All these factors account for additional negative impact ing of introduction of allergenic foods. These are described further
on the lives of children with FA and their families that goes beyond below in the FA prevention section. Other factors that have been
the state of hypersensitivity to the culprit allergens, and underscore associated with risk of FA include factors potentially associated with
the importance of an accurate diagnosis and the search for specific increased microbial exposure such as pet dogs and older siblings.30,31
treatments for FA.

3 | M EC H A N I S M S A N D
2 | E PI D E M I O LO G Y PATH O PH YS I O LO G Y

The prevalence of IgE-mediated FA is highest in infancy and early The mechanisms underlying IgE-mediated food allergy is type I hy-
childhood, driven by a relatively high prevalence of egg and cow's persensitivity. Understanding the underlying immune mechanism
milk allergy that often resolves later in childhood. By contrast, pea- can help us identify targets for treatment and other interventions to
nut and tree nut allergies, which also typically present in infancy, are prevent and reduce the impact of FA. T cells are central coordinators
less likely to resolve and therefore predominate in later childhood. 21 of the immune response to food allergens, namely the production
Marked differences in the prevalence of FA between countries have of antibodies by B cells. Using mass cytometry for immunoprofiling
been noted for multiple foods, although data from some countries of infants, Neeland et al32 described cellular fingerprints associated
22-26
remain sparse. More recent studies have shown that large dif- with peanut allergy and tolerance among IgE-sensitized infants.
ferences in FA prevalence can exist even within individual countries, Peanut-allergic infants had increased frequency of CD19hiHLA-
with some of this difference driven by a lower prevalence in rural DRhi–activated B cells and of peanut-specific memory CD4+ T cells,
4,27,28
areas compared with urban areas. Reasons for these differ- as well as overproduction of TNF-alpha, whereas peanut-sensitized
ences are largely speculative, with differences in the prevalence of tolerant infants had reduced frequency of CD4+ naïve T cells and an
the risk factors described below potentially playing a role. increased frequency of plasmacytoid dendritic cells. Following the
The strongest known risk factor for FA is probably eczema, par- description of the new subset of Th2 cells typical of highly allergic
ticularly eczema that starts early in life and is more severe. 27,28 This patients, the TH2A cells, that decreased following allergen-specific
finding has been noted consistently across studies in both popula- immunotherapy by Wambre et al,33 Chiang et al34 found highly
tion-based studies and allergy clinics for many years; however, the differentiated Th2 cells in the peripheral blood of peanut-allergic
PETERS et al. | 649

TA B L E 1 Highlights of new discoveries T cells and T follicular •Food allergy involves Th2-skewed response more than a
about immune mechanisms of food allergy helper cells dysregulated regulatory T-cell population.34,35
•The new subset of T follicular helper cells designated Tfh13
induces the sequential class switching from IgG1 to IgE,
leading to the production of high-affinity IgE that can cause
anaphylaxis.37
B cells and antibodies •IgE class switching can happen in the gut-associated lymphoid
tissue.39
•IgA induces tolerance through immune exclusion rather than
active suppression and is generated via a separate mechanism
that is independent of Tfh and germinal centres.38
Basophils and mast cells •IgE glycosylation enhances effector cell degranulation.40
•Basophil response to allergen can distinguish responders from
non-responders as early as 3 months into oral immunotherapy.43

patients who were resistant to the countereffect induced by reg- desialylation of IgE reduced effector cell degranulation and conse-
ulatory T cells, whereas healthy controls did not have detectable quent anaphylaxis, raising a new possibility for intervention to treat
T-cell responses to peanut. A stability of T regulatory response was allergic disease, including FA.
35
reported by Weissler et al in both allergic and non-allergic sub- The differences in T- and B-cell and antibody responses between
jects, with a Th2- and Th1-skewed peanut response detected in allergic and sensitised tolerant individuals modulate the effector
sensitized and non-sensitized individuals, respectively. However, cell response. Hemmings et al41 showed that Ara h 2–specific IgE
Pellerin et al found that Tr1 cells were functionally impaired in pea- induced greater inhibition of IgE binding and greater mast cell de-
36
nut-allergic patients compared with healthy controls. Ruiter et al granulation than Ara h 6, confirming that despite the sequence and
studied the TCR repertoire of CD154+CD4+ memory T cells and structural similarities between Ara h 2 and Ara h 6 and the fact that
found strong convergent selection of peanut-specific clones that both are major allergens in peanut, Ara h 2 is the dominant aller-
were more numerous among effector T cells of peanut-allergic pa- gen. Effector cell response to allergen can support the identification
tients, with an imbalance between effector and regulatory T cells. of phenotypes of food-allergic patients who may deserve different
The more reactive patients had a more diverse and polarized Th2 types of follow-up and may have indication for specific treatments,
effector phenotype with the expression of Th2 cytokines correlating such as allergen-specific immunotherapy or biologics. In a study of
with peanut-specific IgE levels. egg-allergic children, changes in the basophil reactivity but not in the
Recently, new studies have shed light on the role of antibodies T-cell compartment explained the differences in clinical reactivity to
in allergy and tolerance and on the still puzzling discrepancy be- baked egg.42 During peanut oral immunotherapy (OIT), Patil et al43
tween the presence of allergen-specific IgE and clinical reactivity assessed basophil responses to Ara h 2 in peanut-allergic patients at
to foods. For instance, a new subset of T follicular helper cell has baseline and at different time-points. Basophil sensitivity, defined by
37
been identified in the germinal centre and designated Tfh13 cells. the concentration at which basophils reacted, after 3 months of OIT,
Tfh13 cells are characterized by a distinct transcription factor profile could distinguish the patients who responded and had sustained un-
that includes BCL6 and GATA-3, and by the production of IL-4 and responsiveness at the end of the trial from the patients who had
Il-13. Tfh13 result in the production of high-affinity IgE that is able to transient desensitization and whose basophil response to Ara h 2
induce anaphylaxis to allergens. This high-affinity IgE is most likely rebounded after stopping OIT.
a result of indirect isotype switching from IgG1+ to IgE+ B cells. To conclude, understanding the immune mechanisms underly-
Contrary to IgG and IgE that depend on germinal centres and Tfh ing FA and oral tolerance is key to improve diagnostics and the care
cells, IgA seems to follow an independent mechanism that requires for patients and their families and identify targets for a definitive
T cells and CD40 ligand but is independent of germinal centres, Tfh treatment of FA. Table 1 summarizes recent new discoveries about
and T follicular regulatory cells.38 Interestingly, Hoh et al39 have immune mechanisms of FA.
shown that the class switch recombination from IgG to IgE and the
somatic hypermutation that lead to increased affinity for allergens
could develop in the gut of peanut-allergic individuals, underscoring 4 | D I AG N OS I S
the importance of gut-associated lymphoid tissue in FA.
Apart from intrinsic characteristics of IgE, such as affinity for An accurate diagnosis of FA is essential. Correctly identifying FA is
allergens, post-translational modifications such as glycosylation can crucial for providing education and management strategies to miti-
have an impact in the ability of IgE to cause effector cell activation gate the risks of a potentially life-threatening allergic reaction. In
and consequently allergic reactions. In a recent study, Shade et al40 contrast, correctly identifying food tolerance will promote dietary
reported that total IgE from peanut-allergic subjects had higher liberation, which is especially important in the light of the paradigm
sialic acid content compared with non-atopic subjects and that shift encouraging early introduction of allergenic foods to prevent
650 | PETERS et al.

FA.44 Double-blind placebo-controlled food challenges remain the CI 87-100) and 96% (95% CI 86-100), respectively. BAT performed
gold standard for FA diagnosis. Updated guidance on performing similarly well when validated in an independent sample (83% sen-
oral food challenges has recently been published, with additional sitivity and 100% specificity).56 For other allergens, BAT performed
focus on safety, psychosocial considerations, and baked egg and milk well but not necessarily superior to other measures. In a prospective
challenges, to name a few.45 However, due to the inherent risks and study of 83 children with suspected tree nut allergy, SPT demon-
intensive resource requirements, their feasibility is limited in some strated greater sensitivity to BAT, while BAT demonstrated greater
clinical and research settings. The utility of traditional tests of sen- specificity compared with SPT; AUC was similar for both measures
sitization (SPT and sIgE), as well as development of new molecular with the exception of hazelnut where BAT had greater AUC than
techniques that are able to diagnose food allergy without the need SPT.57 While the performance of BAT appears promising, its clini-
for oral food challenges, remains an active area of research. This sec- cal utility may be limited because it requires live cells and flow cy-
tion highlights recent advances in this area. tometry equipment. BAT may therefore be more feasible in settings
Skin prick tests (SPT) and serum-specific IgE (sIgE) are rou- where it can be used in combination with conventional diagnostic
tinely used in clinical practice and are relatively safe and inex- tests. For example, performing peanut BAT as a second step fol-
pensive to perform. However, the conventional positive results lowing equivocal SPT or sIgE to Ara h 2 reduced the need for OFC
(SPT ≥ 3 mm or sIgE ≥ 0.35 kU/L) have poor specificity to clinical by 97% compared with the combination of SPT and sIgE to whole
FA, with approximately half of sensitized individuals able to toler- peanut.56
ate the food without reaction. As increasing magnitude of these The mast cell activation test (MAT) offers another promising
tests correlates with a higher risk of reaction, many studies have approach and has the advantage over BAT that it uses stored
defined thresholds for these tests with 95% positive predictive plasma rather than fresh whole blood. In the same sample as de-
value (PPV) to FA (reviewed in 46-51). Although SPT and sIgE thresh- scribed previously for peanut BAT, 56 MAT performed equally well
olds with 95% PPV to FA are routinely used to minimize the need to BAT in terms of specificity; however, the sensitivity of MAT was
for diagnostic food challenges, a proportion of children remain in lower than BAT. 58 Importantly, MAT provided definitive results
the immunologic grey area; that is, they are food-sensitized but in all cases where basophils were non-responsive. 58 In a smaller
below the 95% PPV threshold. New approaches that can accu- study, MAT performed better than BAT based on AUC for the
rately diagnose FA while reducing the need for food challenges diagnosis of peanut allergy; however, confidence intervals over-
are urgently needed. lapped. 59 The utility of these tests has been assessed for some
Allergen component-resolved diagnostics (CRD) are proposed other common allergens and performs similarly well but further
as a more accurate method of diagnosis, because instead of using research is needed. 60 Additionally, these cellular tests may offer
crude allergen extracts, which consist of both allergenic and non-al- additional clinical utility as the results are correlated with reac-
lergenic components, CRD measures sIgE to individual allergen pro- tion severity, 59,60 whereas SPT and sIgE are not always predic-
teins. A systematic review comparing SPT and sIgE to whole peanut tive of reaction severity. 61,62 However, further work is required
and its components concluded that sIgE to Ara h 2 had greater di- to inform standardization of laboratory procedures, optimal test
agnostic accuracy compared with the other tests.49 Furthermore, a parameters and thresholds, and cost-effectiveness in different
meta-analysis of 19 studies found that while sIgE to Ara h 1, Ara h settings before these novel approaches are ready for routine clin-
2 and Ara h 3 had high specificity to peanut allergy, sensitivity was ical practice. 55
highest in Ara h 2. The pooled sensitivity and specificity of Ara h Despite continued advances and development of novel molecu-
2 ≥ 0.35 kU/L to peanut allergy were 83% (95% CI 76%-89%) and lar techniques, identifying a definitive diagnostic test to negate the
84% (95% CI 77%-88%).52 Likewise, further studies support that need for oral food challenges remains elusive. The optimal thresh-
CRD offer greater accuracy compared with sIgE to whole allergens old requires a trade-off between false negatives and false positives,
for hazelnut53 and it is plausible that this increased accuracy applies and this varies in the published literature due to heterogeneity in
to other foods. The major allergen components for most common study sample, design, methods, regional characteristics, allergen ex-
food allergens have been isolated, and research continues to identify tracts and laboratory procedures. Figure 1 represents a suggested
the optimal cut-off points.54 approach to the sequential use of diagnostic tests to improve the
Approaches to the diagnosis of FA using cellular tests also appear diagnosis of food allergy without the need for OFC, as proposed by
to offer greater sensitivity and specificity than traditional tests. The several studies.63 This approach involves first-line tests of traditional
basophil activation test (BAT) measures the expression of activation SPT and/or sIgE using established 95% PPVs. If results are equivocal,
markers on the surface of basophils, stimulated with food allergens a second-line test of CRD, BAT or MAT may be ordered and this ap-
and controls, by flow cytometry.55 In a study of 104 children, BAT proach has been shown to substantially reduce the need for OFC.63
demonstrated superior ability to discriminate between peanut-aller- However, OFC remain the gold standard and may be required to con-
gic and peanut-sensitized tolerant children compared with SPT, sIgE firm the diagnosis if all tests are equivocal. Identification, validation
and sIgE to Ara h 2. The optimal diagnostic parameter and threshold and cost-effectiveness of the optimal diagnostic approach for FA
demonstrated an impressive sensitivity and specificity of 98% (95% continue to be an active area of research.
PETERS et al. | 651

F I G U R E 1 Proposed use of
component-resolved diagnostics (CRD),
basophil and mast cell activation tests
(BAT and MAT) in combination with
conventional tests, skin prick test (SPT)
and specific IgE (sIgE), to reduce the need
for oral food challenges (OFC)

5 | TR E ATM E NT 5.2 | Food immunotherapy

5.1 | Allergen avoidance Just over twenty years since the first RCT demonstrated its effi-
cacy,74 food immunotherapy (FIT) has become the first established
In the absence of effective treatment, allergen avoidance and treatment modality for FA, which is now recognised by national and
providing appropriate emergency medication used to be the only international guidelines.75-77 The efficacy of oral FIT has been docu-
64
approach to management of FA. Avoidance of food allergen is on- mented in RCT in children with milk, egg and peanut allergy,78 with
erous for patients and families and often fails with ten per cent of lower desensitization rates being achieved in wheat allergy.79 In the
patients on average experiencing an allergic reaction per year. 65­-67 largest oral FIT study so far, the PALISADE study, which investigated
Additionally, allergen avoidance inflicts multiple pressures on al- efficacy of 300-mg dose of peanut protein in inducing tolerance
lergic individuals and their families, food manufacturers, and to peanut in almost 500 children ≥ 4 years, 67.2% of participants
restaurants and public spaces such as schools and aircrafts. 68,69 achieved the primary end-point of passing 600-mg dose at the exit
Precautionary allergen labelling is in general voluntary and used DBPCFC.80 It has also been confirmed recently in a placebo-con-
inconsistently across industry which can be misleading for patients trolled study that peanut oral IT (POIT) significantly reduces the risk
and caregivers. 65 of reaction after accidental exposure to peanut (placebo group, 24
Providing adrenaline auto-injectors (AAI) to patients at risk of reactions in 14 patients; active group, eight reactions in five patients;
anaphylaxis encounters challenges related to their availability, which P < .001).81 Nevertheless, the recent safety meta-analysis, which
is mostly limited to high-income countries, varied national regula- looked into 12 POIT studies, estimated that the risk of anaphylaxis
tions in prescribing and high cost.70 When prescribed, AAI are only while on POIT is over three times higher compared with peanut
carried at all times by half of the patients71 and mistakes in use are avoidance (RR, 3.12, 95% CI 1.76-5.55) and the risk of adrenaline
frequent among both patients72 and medical staff.73 use is over twice as high (RR, 2.21; 95% CI 1.27-3.83). 82 Therefore,
Meeting the needs of both food-allergic children undergoing the current focus of FIT research is orientated towards answering
immunotherapy and those continuing strict avoidance in the same crucial questions about increasing safety of FIT by choosing well-
environment, for example school or household with two allergic sib- tolerated and effective formulation,83 route and dose, adding adju-
lings managed differently, is an arising challenge. vants at the initial stage of the treatment and identifying patients
652 | PETERS et al.

most likely to benefit from FIT. The two most studied alternative are possible during the treatment, the long-term effect remains un-
routes to oral FIT are sublingual (SLIT) and epicutaneous IT (EPIT). predictable with up to 70 per cent successfully desensitized individ-
Their safety profile is favourable with few systemic allergic reactions uals losing tolerance after a short period of avoidance.43 Why the
84-87
reported; it comes, however, at the cost of lower efficacy. The post-IT tolerance is lost despite apparent similarities in immunologic
modest level of desensitization predisposes SLIT and EPIT for use in response with FA resolution (e.g. decrease in specific IgE concentra-
87
individuals not tolerating OIT. It may also be the case that longer tion and raise in specific IgG4) remains unclear.90
treatment duration is necessary to achieve results comparable with As sustained unresponsiveness is not achieved by at least
OIT.84 The other main need is understanding long-term outcomes half of the patients, the question about the necessary frequency
of the treatment.88,89 Table 2 summarizes recent developments in of consumption of the food after completion of FIT remains.
FIT, and Figure 2 illustrates phenotypes of food allergy and possible Reassuringly, consumption of an egg twice a week has proven
outcomes of FIT. sufficient to sustain tolerance in the Spanish SEICAP study.91 In
Despite the efficacy in inducing desensitization to the culprit the large long-term follow-up Finnish cohort of children who com-
food, the outcome of FIT differs from natural outgrowing of FA. pleted milk OIT, only a quarter of the children returned to milk
While the benefits of a margin of protection in case of accidental avoidance diet during the median 6.5-year-long observation pe-
exposure and introducing certain amount of the food in regular diet riod.92 Regarding ongoing peanut consumption, 64% of previous

Route In the large phase 3 study on epicutaneous IT to peanut, 35.3% of TA B L E 2 Recent developments in food
participants achieved predefined response rate compared with 13.6% immunotherapy (FIT)
of children in placebo group; despite the difference being statistically
significant, the 95% CI exceeded pre-specified lower cut-off, which
means the study did not meet its primary end-point.102
Dose Daily dose equivalent of one peanut and ten peanuts exert similar
clinical and immunologic effects in peanut IT in young children.103
No use of adrenaline related to treatment was reported in the recent
peanut OIT study in which maintenance peanut protein dose was
established at a low dose (between 125 mg and 250 mg).81
In the group of Japanese children with history of anaphylaxis to
wheat, 31% of subjects developed mild anaphylaxis despite low-dose
protocol (53 mg of wheat protein).104
Age FIT tends to be associated with reassuring safety profile and higher
rates of sustained unresponsiveness if started early.103
In the Italian cohort of 73 infants with IgE-mediated milk allergy who
underwent milk OIT, 97% reached the target 150-mL dose of milk. No
patient required use of AAI at home.105
Formulation The BOPI study looked into effectiveness and safety of boiled peanut
IT. 28% of participants presented with 1.9 episodes of anaphylaxis
during treatment, which is comparable to average rate of severe
adverse events reported in other studies.
Small proof-of-concept study confirmed that baked egg IT led to
desensitization to lightly cooked egg with no moderate or severe
adverse events noted.Eg
Egg IT is more effective in inducing sustained unresponsiveness than
baked egg consumption.107
Adjuvants Multiple adjuvant agents have been tested in the context of improving
benefit-risk ratio in FIT, from probiotics and Chinese herb medicine
through montelukast and antihistamines to biologic treatments.108
Omalizumab allows quicker up-dosing with fewer adverse events
without affecting immunologic desensitization processes.108
Omalizumab may potentially mask early symptoms of gastrointestinal
disease related to FIT.110
Adverse events may start occurring after discontinuation of anti-IgE
during the maintenance phase.111,112
Sustained The baseline epitope-specific antibody binding models can achieve
unresponsiveness even 87% accuracy in predicting SU in milk OIT.113
In peanut oral IT, early decrease in basophil sensitivity to Ara h 2
correlates with SU.43
Higher baseline peanut-specific IgG4-to-IgE ratio and lower Ara h 2
IgE and basophil activation responses were associated with sustained
unresponsiveness in the POISED study.
PETERS et al. | 653

F I G U R E 2 Clinical phenotypes of food-sensitized and food-allergic children and possible outcomes of food immunotherapy. Although the
largest evidence comes from peanut studies, the concepts highlighted here are applicable to other food allergies

peanut IT participants continued to ingest peanut daily and an- 6 | PR E V E NTI O N

other 25% less frequently. Unfortunately, allergic reactions includ-
ing airway involvement were still noted even in this late stage of Despite significant progress in identifying risk factors for FA,
93
desensitization. With the first commercial product for peanut there is still little that can be recommended to prevent FA. Few
OIT approved by FDA in January 2020, FIT is likely to become of the known risk factors described above are easily modifiable.
more widely available and uniform in the coming years. Furthermore, of the potentially modifiable factors tested in clini-
cal trials to date, most have not been effective in preventing FA.
A recent systematic review by the European Academy of Allergy
5.3 | Biologicals and Clinical Immunology FA and Anaphylaxis Guidelines Group100
identified 41 randomized controlled trials of potential FA pre-
In FA, biologic treatments have been mostly investigated in the con- vention strategies in infancy and childhood. The vast majority of
text of facilitating FIT. In addition to the above-mentioned FIT/anti- these trials showed little to no effect on preventing FA, including
IgE studies, which have already been completed, there are ongoing trials of dietary avoidance of food allergens, vitamin supplements
projects looking at use of dupilumab in combination with peanut OIT (maternal and infant), fish oil, probiotics, prebiotics, symbiotics
(Clinicaltrials.gov NCT03793608, Clinicaltrials.gov NCT03682770), and hydrolysed formulas. However, the authors also concluded
combination of dupilumab and omalizumab in multi-food OIT that the evidence around most of these interventions remains
(Clinicaltrials.gov NCT03679676), and anti-IL-33 in peanut OIT very uncertain. Many of the trials were at risk of bias due to lack
(Clinicaltrials.gov NCT02920021).94 of robust diagnostic criteria, high loss to follow-up, potential con-
Due to its pathomechanism, eosinophilic pathway inhibition has founding, and lack of blinding, and were underpowered for the
95
been extensively studied in the treatment of EoE. The use of anti-IL-5, outcome of interest.
anti-IL-13 and anti-IL-4 has been associated with significant reduction Although some of the risk of FA is likely to be already established
in histologic features of EoE in three RCTs.96,97 However, there have at birth, to date there are no known effective preventative strat-
been no clear clinical improvement noted. Therefore, the treatments egies that can be applied during pregnancy. The only intervention
98
are currently not routinely recommended in EoE management. that is currently widely recommended to reduce the risk of FA is
Recently, inhibition of alarmins (IL-25, IL-33 and TSLP) in a timely introduction of peanut into the infant's diet. This recommen-
mouse model was effective in preventing FA,99 which may suggest dation is primarily based on the results of a large, high-quality ran-
future promising direction of biologic use in FA. domized controlled trial in high-risk infants conducted in the United
654 | PETERS et al.

Kingdom9—a country with a relatively high prevalence of FA. The ORCID

relevance of these findings to countries with a low peanut allergy Alexandra F. Santos https://orcid.org/0000-0002-7805-1436
prevalence is less clear.101 There is also evidence from meta-analyses
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