Introduction
We provide an update from our previous manuscript1covering recent advances in the field with specific focus on biomarkers
of desensitization and tolerance development.
1.1 Food allergy and barrier
function
At the interface between the “exposome” and the human body, epithelial
cells act as the first physical barrier of protection and play an
integral part in maintaining tissue homeostasis. The exposome comprises
external factors including allergens, pollutants, detergents and
microbes, and internal factors namely the microbiota and metabolic
products.2 Maintaining proper barrier function is
crucial for facilitating appropriate immune responses to allergens
(Figure 1). Consequently, epithelial barrier dysfunction and altered
permeability caused by gene mutations or single nucleotide polymorphisms
on key genes including filaggrin, SPINK53, SERPINB7,
KLK7 and Claudin-14,5 are associated with
atopic dermatitis (AD) and food
allergy (FA) development.6–10 Barrier abnormalities
arise from decreases in ceramides, antimicrobial peptides, serine
protease, and skin/gut microbiome dysbiosis through exogenic factors,
namely detergents.4,11,12 A recent review inAllergy explores these concepts further.13
AD is associated with FA development through the dual-allergen exposure
hypothesis, which suggests primary allergen exposure through damaged
skin without prior
gastrointestinal tract (GIT)
exposure favours an inflammatory Th2-type immune response. In contrast,
initial allergen exposure through the GIT promotes regulatory immune
responses and tolerance induction.14,15 Consequently,
food allergen sensitization and FA development is likely linked to skin
barrier dysfunction and potentially microbial
colonization.4,15–17 Commensal bacteria are needed
for skin microbiota protection, maturation of T cells and activation of
antimicrobial peptide production by keratinocytes. Dysbiosis in the skin
microbiome, commonly measured by Staphylococcus aureus abundance,
is positively correlated with AD severity, serving as a promising AD
biomarker.18,19
The use of emollients is the main AD management strategy with the intent
to support barrier function. This concept of preventing barrier
dysfunction in vivo via the provision of moisturizers is a topic
of ongoing investigation. Various formulations of emollients, including
the most common paraffin/petroleum base, and a trilipid base (3:1:1-
ceramides, cholesterol and free fatty acids) are
used.20,21 Emollients may reduce severity and prolong
the time between AD flares22 by reducing skin water
loss21 and improving overall
hydration.23 This is crucial for neonatal skin which
is characterized by a thin stratum corneum layer with reduced lipid
content and moisturizing factors. Emollients, specifically the trilipid
formulation, may promote tolerance with an increased IgG4/IgE ratio and
IL-10, LAP+ T cells and decreased IL-4 producing
CD4+ T cells.20 Additionally, free
fatty acids present in the trilipid formulation may activate peroxisome
proliferator-activated receptors (PPARs), which are generally reduced in
AD, and thereby reduce inflammation.24
Initial pilot studies demonstrated AD could be prevented by regular
emollient use.20,25 However, larger randomized
controlled trials like BEEP26 a multicentre trial with
high-risk-of-allergy newborns concluded daily application of
paraffin/petroleum-based emollient did not prevent eczema at 2 years of
age or reduce incidence of FA despite good treatment
adherence.26 The PreventADALL27trial conducted on newborns, reaffirmed neither intensive emollient use
(paraffin/petroleum-based and emollient bath oil) nor early
complementary feeding reduced AD development.27Allergic sensitization at 6 months was predicted by eczema, dry skin and
impaired skin barrier function at 3 months of age.28However, the emollient formulations may be relevant and additional large
population studies investigating the efficacy of different emollients in
AD treatment are ongoing.25,29–31
1.2 Updates on the humoral
mechanisms of allergen
recognition
Allergen recognition by IgE and receptor crosslinking are central to the
initiation of the acute allergic response. For IgE to elicit its
effector functions, glycosylation in the constant region of the antibody
plays a pivotal role. The presence of an oligomannose glycan at the N394
residue in human IgE is necessary for correct structure and FcɛRI
receptor binding in order to trigger anaphylaxis.32Peanut allergic (PA) individuals
produced IgE antibodies with greater sialylation content compared to
non-allergic individuals, and sialylation enhanced the potency of IgE
crosslinking-induced degranulation in
vivo .33,34 Therefore, sialylation of IgE may provide
an additional diagnostic marker for allergy.
Glycosylation on other isotypes including IgG may contribute to the
conferral of early-life atopic predispositions. During healthy
pregnancy, antibodies with di-galactosylated glycans in the Fc domain
are selectively transferred across the placenta and contribute to early
innate immune responses through the induction of natural killer cell
activity.35 In the context of asthma, mice
experiencing exacerbations during pregnancy had higher levels of a
pro-inflammatory glycosylation pattern, as reflected by the absence of
galactose and sialic acid end branches on the Fc part of IgG1. Maternal
glycosylation patterns were correlated with patterns observed in
offspring later developing allergic asthma.36 The
importance of glycosylation for IgG functionality is supported by
discordant IgG Fc glycosylation patterns identified between healthy
children and children with recurrent respiratory
infections.37
An important factor determining IgE’s potency to elicit clinical
reactions is affinity. Affinity maturation in germinal centers is guided
by T-follicular helper (Tfh)
cells, which promote the selection and expansion of B
cells.38 The affinity of IgE may be specifically
affected by Tfh cells. A newly identified IL-13 producing
Tfh13 cell was required to
produce high but not low-affinity IgE and subsequent allergen-induced
anaphylaxis in a murine model. Tfh13 cells display a characteristic
cytokine profile (IL-13hiIL4hiIL-5hiIL-21lo), co-express transcription
factors BCL6 and GATA3 and are more abundant in PA
individuals.39
Characteristics of epitope recognition influence the strength of an
allergic reaction via the diversity of epitopes, their
abundance40, proximity, and overlap with other
isotypes (e.g., IgG4).41,42 Linear epitopes to peanut
allergens Ara h 1-11 were recently compared between PA and sensitized,
non-allergic individuals.43 Seven peptides from the
seed storage proteins Ara h 1, 2 and 3 were preferentially recognized by
IgE from PA individuals, while the IgG4:IgE ratio was higher in peanut
sensitized non-allergics compared to PA individuals, indirectly
suggesting a functional role of IgG4 in tolerance
development.43(Figure 2) Ara h 2 sIgE is known to
enhance diagnostic accuracy and is superior to extract-based
methods.44–47 Machine-learning approaches in early
life (3-15 months) suggested the IgE peanut epitope repertoire was
predictive of the development of PA at 4 years.48Bead-based assays used in the context of egg allergy showed egg allergic
children had higher levels of epitope-specific IgE and IgD and lower IgA
and IgG to Gal d 1 than atopic controls.49,50 Thus,
continued research on linear and conformational IgE epitopes which
includes various isotypes could expand the toolkit to predict the
progression of atopic disease and responses to therapeutic
interventions.
Local antibody production via reservoirs of IgE+ B cell lineages in the
GIT undergoing local class switching may be crucial. Sequential biopsies
in the upper GIT revealed increased numbers for IgE+ B lineage cells in
the mucosa of PA patients, which correlated with systemic peanut sIgE
levels. B cell clonal lineages within biopsies were comprised of both
IgE+ and non-IgE+ isotypes, suggesting class switch recombination can
occur locally.51 Thus, the GIT could serve as an
important reservoir for allergen-specific plasma cells later found in
other tissues.51
1.3 Updates on the cellular network
in food
allergy
The innate immune system is a rapid-onset, non-specific defense
mechanism upstream of adaptive inflammatory allergic responses. The
major effector cells include basophils and mast cells, which release
histamine and other pre-formed inflammatory mediators following allergen
exposure. Basophils are key players in the pathophysiology of
FA.52 They produce large quantities of IL-4,
facilitating mast cell recruitment, activation, proliferation and
isotype switching of B cells to IgE antibody
production.53 Basophils derived from allergic
individuals showed enhanced sensitivity to IL-1β and IL-33 compared to
healthy controls.54 The alarmin IL-33, which mediates
inflammation of mucosal and epithelial surfaces upon exposome
interactions, is a key upstream component of type 2 responses and a
potent activator of mast cells. Recently, the first human mutation in
the IL-33 gene was described, showing a complex phenotype of type 2
inflammation-dominated immune dysregulation.55 IL-33
and IgE-mediated activation of mast cells suppressed
regulatory T cell (Treg)
conversion from naïve T cells in a murine co-culture
model.56 Similarly, a murine knockout of CD300f, an
inhibitory receptor on mast cells, exhibited reduced Treg numbers and
exacerbated allergic responses.57 These studies
suggest blocking IL-33 and IgE during OIT may be beneficial in reducing
allergic responses by downregulating mast cell activation and promoting
the generation of Tregs.56 Correspondingly, a small
clinical study reported a single dose of the anti-IL-33 biologic
Etokimab was shown to elevate the threshold to peanuts in allergic
patients, reduce allergen specific type 2 cell frequencies or cytokine
production (IL-4, 5, 9 and 13) and peanut-specific
IgE.58
Mast cell contribution to the development of allergic diseases is traced
back to early life. In rodents, fetal mast cells can be sensitized with
maternal allergen-specific IgE and showed allergen sensitivity during
postnatal exposure.59 A human ex vivo placental
perfusion model demonstrated functional peanut allergen could also be
transferred across the placenta. However, evidence for the transfer of
IgE even with omalizumab treatment could not be provided, despite the
potential for IgG-mediated transport.60 The relevance
of these findings for the human system remains to be established since
they challenge the concept IgE is not transferred to the
fetus.59,60
Rare subsets such as innate
lymphoid cells (ILCs) are enriched at mucosal sites and are crucial in
initiating and regulating allergic responses. ILC2s are capable of
rapidly secreting pro-allergenic cytokines such as IL-5, -4, -13 and -9
upon activation by alarmins (IL-33, IL-25 and TSLP). ILC2-derived IL-13
contributes to Tfh cell development and allergen-specific IgE
generation.61,62 Recently, the regulatory capacity of
ILC2 cells in controlling inflammation was recognized. It is not clear
whether there is a distinct group of
regulatory ILCs (ILCregs) or a
subset of ILC2s producing tolerogenic IL-10. These ILCreg cells were
identified in human intestines and kidneys suppressing inflammation and
activation of ILC1/3 cells via IL-10 and TGF-β1
production.63,64 Following
allergen immunotherapy (AIT),
IL-10+ ILC2 cells were upregulated in the allergic
group, suggesting these cells may be involved in tolerance
development.65
T and B cells are drivers of the adaptive immune system responsible for
the generation of allergen-specific memory. The Generation R cohort
reported children with atopic diseases had a higher proportion of Th2,
Th17, Treg, memory Treg, and
CD27+IgA+ memory B cells compared to
non-atopic children, which may point toward important regulatory
processes initiated during allergic disease.66 PA
patients with a lower tolerance and high clinical sensitivity have a
larger, more diversified allergen-specific CD4+ T cell repertoire
compared to hyporeactive patients. This repertoire is enriched with
Th2-skewed effector T cells and more responsive to
allergen-stimulation.67 Highly reactive patients also
have a higher frequency of peanut-specific Th2a
cells.67 This pro-inflammatory subset is characterized
by CRTH2, CD161 and CD49d expression and co-secretion of type-2
cytokines.68 Th2a cells are linked to the pathogenesis
of atopic disease, and decreased significantly in allergic patients
treated with AIT.68 Suppression of Th2a-like cells was
associated with better treatment outcomes post-OIT.69In a Phase 2 clinical trial (NCT02626611) of multi-food-OIT under
omalizumab protection, there was a significant decrease in Th2a and Th17
cells in participants >10-years-old. DCreg markers STAB1
and FcγRIIIa were also significantly altered. Therefore, Th2a and Th17
cell frequencies and DCreg markers could expand the toolkit of
biomarkers to monitor successful OIT.70
Tregs are proposed to be key cellular mediators of tolerance
induction.71,72 Lower proportions of naïve Tregs at
birth and in cord blood are predictors of FA development in
infancy.73,74 There are several Treg subtypes involved
in tolerance: FoxP3+ Tregs, TGF-β secreting Th3 cells
and IL-10 secreting type 1
regulatory T (Tr1) cells. Tr1 cell populations were found to be
significantly higher in younger (<6-years-old), non-allergic
children compared to food allergic children. These Tr1 cells expressed
higher levels of CCR6, a gut-homing marker, indicating a role in
promoting local tolerance.75 Adaptive immune cells
play a fundamental role in the development of FA, but also in the
induction of desensitization and tolerance.
1.4 Lessons from Rodent Data on Food
Allergy
Recent murine studies revealed novel mechanisms employed by the
microbiome to promote immune tolerance to food antigens or drive
allergic responses resulting in anaphylaxis.
Fecal microbiota transplant (FMT)
from healthy or food allergic children into germ-free mice
was performed by several
investigators. Germ-free mice colonized with bacteria from healthy, but
not cow’s milk allergic infants were protected against anaphylactic
responses to a milk allergen, which correlated with distinct
transcriptome signatures in the ileal epithelium. One clostridial
species, Anaerostipes caccae , was associated with protection from
an allergic response to food.76 An independent study
replicated these FMT findings and further demonstrated transfer of an
infant microbiota with a low bifidobacteria/lachnospiraceae ratio
orients the murine immune system toward a Th2 atopic profile with
enhanced symptoms of allergy in the murine
recipient.77
Secretion of metabolites by the microbiome mediate many of the observed
functional effects on immune cells within the intestine. Several recent
studies have focused on
short-chain fatty acids (SCFAs),
including butyrate, propionate and acetate. SCFAs were shown to support
Treg polarization and expansion.78 Recently, SCFAs
triggering G-protein-coupled
receptors (GPCR) were shown to synergize with cytokine receptor
signaling to provide key signals to expand tissue populations of ILC1,
ILC2 and ILC3.79 Propionate and butyrate, but not
acetate, inhibited IgE- and non–IgE-mediated mast cell degranulation.
These effects were independent of the stimulation of SCFA receptors
GPR41, GPR43, or PPAR, but instead were associated with inhibition of
histone deacetylases.80,81 Additionally, pre-treatment
of mice with butyrate significantly reduced allergic response in three
different animal models of FA. This was associated with induction of
tolerogenic cytokines, inhibition of Th2 cytokine production and
modulation of oxidative stress.82 GPR109A, which is a
receptor for butyrate and niacin, was also shown to be important for
maintenance of epithelial function and as a negative regulator of type 2
immune responses.83 Lastly, a wide range of
immunomodulatory bacterial-derived metabolites that activate GPCRs, aryl
hydrocarbon receptor and nuclear receptors have recently been described
and are currently being examined in murine models of
FA.84
Murine studies are helping us to better understand the contribution of
novel immune cell subsets to FA. In the small intestine, ILC3s, the
dominant cellular source of IL-2, are essential for maintaining Tregs,
immunological homeostasis, and oral tolerance to dietary antigens. IL-2
is induced selectively by IL-1β, which is produced by macrophages in an
MYD88- and NOD2-dependent mechanism.85 The role of Tfh
cells in the induction of peanut-specific IgA was clarified. While IgG1
and IgE responses to peanut require Tfh cells, IgA responses were
Tfh-independent suggesting the cellular mechanisms for induction of IgA
to food antigens is different to those culminating in IgE or
IgG1.86 Interestingly, mice sensitized to peanut in
the absence of an adjuvant were characterized by the presence of
increased numbers of Tfh cells in the mesenteric lymph nodes, reduced
fecal IgA levels, altered gut permeability and a distinct microbiome
composition.87 Further studies in genetically
susceptible mouse strains indicated genetic loci outside of Tlr4 and
Dock8 are responsible for the oral anaphylactic susceptibility of
C3H/HeJ mice to peanut.88 The mechanisms via which
SCFAs support connective tissue mast cell maturation from immature mouse
bone marrow-derived mast cells was demonstrated to involve the
transcriptional upregulation of heparin sulfate biosynthesis enzymes,
certain mast cell-specific proteases, MAS-related GPCR family members,
and transcription factors required for mast cell lineage
determination.89
2 Mechanisms and potential
biomarkers of food allergy
immunotherapy
AIT is currently the most promising and researched FA treatment.
However, depending on the approach, limitations regarding safety,
efficacy, time of up-dosing, costs and the extent of protection arise.
Data on sustained unresponsiveness, considered a surrogate of tolerance
development, is challenging to obtain. Despite significant improvements
in the therapeutic concepts, alternative strategies with better safety
profiles capable of inducing tolerance are needed. A variety of
different administration routes and doses are being explored:
oral (OIT), epicutaneous (EPIT),
sublingual (SLIT) and subcutaneous (SCIT). AIT is mechanistically
proposed to have its effects when a relevant allergen either in its
native or modified form is introduced starting at a subthreshold level
then at incremental doses to induce desensitization and increase the
threshold of tolerance. (Figure 3)
OIT is the most common form of AIT (typical maintenance dose
125mg–4g).90 Via the ingestion of subthreshold
amounts of allergen, reduction in allergen-induced basophil and mast
cell activation are among the first immunological changes observed.
During the initial up-dosing, an upregulation of sIgE production and a
transient increase in allergen-specific type 2 effector cells are
observed in concurrence with desensitization.90–93 A
transient increase in TGF-β producing CD4+ T cells is also associated
with successful desensitization. In adult patients undergoing peanut
OIT, transient esophageal eosinophilia and gastrointestinal eosinophilia
may occur.94 As
immunotherapy continues, Th2 cell activity and frequency decreases while
IL-10 producing regulatory cells (Tregs and Bregs) become more
prominent.70,95 This later phase is associated with an
increase in sIgG, sIgG4 and sIgA, and lower sIgE/total IgE
ratios.90,93,96 However, measurement of sIgA as a
surrogate for mucosal response does not seem to predict sustained
tolerance or successful desensitization.97 Initiation
of OIT before 4 years of age and lower sIgE at baseline are correlated
with increased chances of desensitization and remission following
OIT.98 Tissue-specific effects of OIT in humans are
under-researched and may play an important role.99,100
SLIT utilizes a hundred-fold lower dose of allergen (maintenance dose
2-5mg/day). It takes advantage of local oral tolerance mechanisms as
reported for inhalant allergen SLIT.101,102 Such
mechanisms include the uptake of allergens by oral
antigen presenting cells (APCs)
from the sublingual mucosa. In murine models,
CD103-CD11b+ DC were implicated in
the transfer of antigens to submandibular lymph nodes, which supported
Treg differentiation through the production of retinoic
acid.103,104 During the early stages of SLIT
treatment, the transient increase in sIgE was attributed to the
induction of class switching of IgG+ memory B cells into short-lived
IgE+ plasmablasts.105 Importantly, increases in sIgE
from allergen exposure due to SLIT were not associated with a
diversification of the IgE repertoire.105 SLIT was
recently investigated for the treatment of birch pollen-related FA using
recombinant Mal d 1, which reduced Th2 cell frequency and IL-4
production106 and increased IgG with functional
blocking activity.107 Additional biomarkers for SLIT
include salivary sIgA, which is thought to inhibit allergen uptake at
the mucosal surface and demonstrated alignment with treatment outcomes
following peanut SLIT.108 A long-term, five-year
peanut SLIT trial reported treatment was associated with decreased sIgE
and SPT wheal size, increased IgG4/IgE ratio, and reduced basophil
activation.109
EPIT directly targets immune cells in the skin. Desensitization is
induced through the application of a skin patch with very low doses of
allergen in the microgram range (50-250μg).102,110 The
allergen is taken up through the stratum corneum by Langerhans cells,
which migrate to lymph nodes and induce Foxp3+ Treg
differentiation.111 Additionally, gut-homing
LAP+FoxP3- Tregs are induced and
decrease the risk of anaphylaxis via TGF-β-dependent inhibition of mast
cell activation.112 Even though EPIT is shown to be
tolerable and safe, its success in provoking desensitisation remains
unclear. The phase 3 PEPITES trial for PA successfully demonstrated
safety, but did not meet its pre-specified efficacy
outcome.113 The follow-up PEOPLE trial, a 2-year open
label extension of the PEPITES study, reported continued EPIT therapy
remained clinically beneficial and tolerable, with an increase in
eliciting dose from baseline.114 EPIT continues to be
investigated for various allergens including cashew, where EPIT recently
demonstrated efficacy in reducing mast cell reactivity and anaphylactic
symptoms in mouse models.115 A range of different
types of biomarkers are being utilized to mark the success of the
various AIT administration routes. (Table 1)
3 Updates on clinical treatment
approaches
The management of FA during the last three years was influenced by the
COVID-19 pandemic116–119 with a shift to
telemedicine120 which will continue to influence
practice. OIT has continued to gain momentum as an alternative to food
avoidance in the management of FA. The USA121 and
Europe recently approved the first pharmaceutical product for the
treatment of PA in children aged 4-17 years. Approaches in other
countries122,123 support the use of foods for OIT.
Debate about the best application of OIT continues, with concerns about
the risk of severe allergic reactions due to OIT itself needing to be
balanced against possible reduction in reactions from accidental
exposure (Figure 4). Mathematical modeling suggests food desensitization
is expected to have some benefit in reducing accidental
exposure,124,125 which will vary depending on the
increase in threshold achieved. A recent meta-analysis concluded there
were less severe allergic reactions in OIT as compared to
placebo.126
It is increasingly clear OIT must be continued in most patients to
maintain its effect, as illustrated in the POISED127,
POIMD128 and IMPACT98 studies. After
achieving a maintenance dose of 4g/day of peanut protein, 120 children
and adults in the POISED study were randomized to no peanut or 300mg
peanut and followed over time.127 Most lost their
desensitization and even the ongoing ingestion of 300mg resulted in a
lower threshold than when ingesting 4g a day.127 In
the POIMD study, one month of peanut avoidance after peanut OIT lowered
the maximum tolerated amount of peanut by an average of more than
7g.128 Similarly, in the IMPACT study, 26 weeks of
peanut avoidance after peanut OIT resulted in only 21% of the treatment
group maintaining remission to peanut.98
Since OIT is needed long-term for most food allergic individuals, there
is significant interest in the dose and the dosing schedule which
balances risks and benefits. Slow up-dosing regimens, meaning less
frequently than every 2 weeks, appear to reduce adverse events versus
quicker regimens.129 There are now multiple clinical
studies aiming to directly assess safety and efficacy of lower doses. In
nut allergy for example, NCT04415593, NCT03799328, NCT03532360, and
NCT03907397 will focus on dose. Another important aspect is cross
protection in tree nut OIT. In a recent study, desensitization to cashew
resulted in cross-desensitization to pistachio in patients with a
co-allergy, indicating co-treatment of multiple nut allergies with one
nut may also be possible.130
An even simpler implementation of OIT may be with no up-dosing. Miura et
al. reported the outcome of fixed dosing for milk OIT at 1,2,3
years.131 Children with severe milk allergy received a
fixed dose of only 3ml daily with OFC to 25ml each year with 27%, 52%,
and 61% achieving this goal. Baseline sIgE levels predicted this
success and participants showed significant reduction in sIgE to casein
with increased milk and casein specific IgG4. There was no placebo
group, but historical controls showed no significant laboratory changes
over the same period. Less intensive regimens have the potential benefit
of making FA treatment far more accessible and
equitable.132
For some patients, food desensitization may benefit from the addition of
biologicals as adjunctive therapy.133–135 Currently,
multiple studies are using omalizumab or dupilumab either alone or in
combination with OIT (NCT04045301, NCT03679676, NCT03881696, and
NCT04037176). Although there was interest in the effect of probiotic
adjuvants on OIT, the effectiveness of these additions remains to be
seen.136
Alternative routes to oral food desensitization continue to be studied.
SLIT is showing significant efficacy with minimal serious side effects.
However, this approach resulted in a high dropout
rate.137,138 The significant reduction in risk and
potential to be implemented on a larger scale requires further research.
While EPIT has shown favorable safety and tolerability, its
desensitization effect is uncertain.110 EPIT in
4–12-year-old children found no episodes of severe anaphylaxis and only
4/294 drop-outs.139 Long-term follow-up showed a
stable desensitization effect from 52 weeks to 130 weeks but with no
additional desensitization after the one year of
treatment.140 Sub-analysis suggesting a better effect
in younger children (1-3 years-old) may provide more insight
(NCT03211247, NCT03859700).
There is an emerging change in the clinical management of FA beyond
immunotherapy to include non-complete avoidance of the food. For
example, the 2020 Japanese Food Allergy Guidelines141state the purpose of the OFCs is not only diagnosis of FA, but for
determination of the safe quantity for ongoing ingestion. When patients
are not highly allergic (e.g., food pollen syndrome, exercise-induced
anaphylaxis, baked milk/egg diets) it is widely accepted clinical
practice to allow low amounts of the allergenic food in the
diet.142 Overall, these approaches are based in the
appreciation that most food allergic individuals do not have an
exquisitely severe allergy and can tolerate small amounts of allergen.
However, further understanding of dose
thresholds143–146 along with product labeling is
needed. Sub-threshold amounts of the allergic food in the diet is
encountered in the use of baked milk/egg ladders147,
although it is not yet clear if incorporating baked milk/egg into the
diet of milk and egg allergic individuals is preferred to OIT. Children
allergic to unbaked egg but tolerant to baked egg treated with egg OIT
were significantly more likely to achieve sustained unresponsiveness in
a two-year time frame than children ingesting baked
egg.148 Children allergic to the baked forms can have
severe allergic reactions and patients must be chosen carefully for the
introduction of baked foods based on negative OFCs.
Matching the patient to the right treatment requires consideration of
their risks and benefits in a patient-centered manner. The assessment of
risk is hindered by many factors, including inconsistencies in the
definition of FA severity (Figure 4). The Consensus on DEfinition of
Food Allergy SEverity (DEFACE) initiative149 aims to
standardize severity. The recognition of knowledge gaps in FA management
increased focus on shared decision-making to have bi-directional
discussions on patients’ values, goals, risks, benefits and
preferences.121,150–153
Prognostic factors for success influence risk-benefit discussions of
immunotherapy. Lower age, such as preschool children may be more
successful and allow for completion before significant
anxiety.154 However, lower age will result in many
children undergoing OIT, and the risks it entails, who may naturally
outgrow the FA.155 Baseline clinical laboratory
analysis repeatedly demonstrates individuals with lower laboratory tests
(lower sIgE, lower SPT) have the most success with
desensitization,129 and yet the ones who may stand to
benefit most from desensitization may be the ones with the highest
numbers. Threshold and severity assessments may also be assisted by
biomarkers. The cumulative tolerated dose of allergic reaction was
associated with sequential (linear) epitope-specific IgE
profiling.156 The severity of allergic reactions of
children was shown to inversely associate with platelet activating
factor acetylhydrolase, a stable enzyme that plays a central role in
degrading the lipid mediator platelet activating
factor.157 The management of FA has an ongoing need
for refinement of patient selection, dose, regimen, and duration.
Options to improve immunotherapy must integrate cellular, humoral, and
functional biomarkers with clinical history to further understand
treatment response.158 Paramount markers were defined
and linked to clinical outcome. (Figure 5)
In summary, the clinical management of FA continues to evolve. The
recognized need for long-term treatment will continue to spur fewer
intensive approaches to desensitization including fixed dosing, low-dose
maintenance targets, alternative routes, and biological adjuvants or
monotherapy. Improved ability to risk-phenotype and a patient-centered
lens will continue to refine immunotherapy and drive alternative
approaches.
Conclusion
Further refinement of potential biomarkers for immunotherapy will
contribute to the progressing FA clinical management and facilitate
implementation as a clinical routine. Continuous research in rodent
models exploring the microbiome and its metabolites’ roles can help
elucidate their functional effects and novel immune cell subsets.
Ongoing trials for FA will reveal additional insights into how best to
modify therapies and enhance the safety profile of current treatment
strategies.
Conflicts of
interest
AL, LH, and JH have nothing to disclose. JEMU reports grants/research
support from DBV Technologies, Regeneron, CIHR, ALK-Abelló, SickKids
Food Allergy and Anaphylaxis Program, Advisory board for Pfizer, Bausch
Health, Food Allergy Canada; in-kind drug donation from Novartis, other
for Astra-Zeneca, all outside the current work. LOM reports personal
fees from PrecisionBiotics, grants from GSK and Chiesi, outside the
submitted work. He has contributed to company sponsored symposia for
Nestle, Nutricia, Reckitt and Abbott. TE reports to act as local PI for
company sponsored trials by DBV Therapeutics, Greer Stallergens, and
sub-investigator for Regeneron and ALK-Abelló. He is Co-Investigator or
scientific lead in three investigator-initiated oral immunotherapy
trials supported by the SickKids Food Allergy and Anaphylaxis Program
and serves as an associate editor for Allergy. He/his lab received
unconditional/in-kind contributions from Macro Array Diagnostics and an
unrestricted grant from ALK-Abelló. He holds advisory board roles for
ALK-Abelló, VAMED, Nutricia/Danone and Aimmune. TE reports lecture fees
from Novartis, ThermoFisher, Nutricia/Danone, Aimmune, ALK-Abelló.