Update on food allergy

Abstract Food allergy is a major public health issue with growing prevalence in the urbanized world and significant impact on the lives of allergic patients and their families. Research into the risk factors that have contributed to this increase and their underlying immune mechanisms could lead us to definitive ways for treatment and prevention of food allergy. For the time being, introduction of peanut and other allergenic foods in the diet at the time of weaning seems to be an effective way to prevent the development of food allergy. Improved diagnosis and appropriate management and support of food allergic patients are central to patient care with food immunotherapy and biologics making the transition to clinical practice. With the new available treatments, it is becoming increasingly important to include patients' and family preferences to provide a management plan tailored to their needs.

or whether the cultural background, the history of inequality and different access to health care also play a role is unclear. 10,11 The threefold higher risk of peanut and other food allergies in infants born in Australia to Asian-born parents compared with the risk of peanut allergy in infants born to Australian-born parents reinforced the rapidity with which these changes occur and the importance of gene-environment interactions that need to be further explored. 12 There is no curative treatment for FA, and the mainstay of management is allergen avoidance. Emergency medication needs to be made available to patients to enable them to treat acute allergic reactions that may result from accidental exposure to the culprit allergens and are unfortunately common. 13 Allergen avoidance imposes dietary restrictions, with potential nutritional consequences, and can lead to food insecurity. [14][15][16] Eighty-six per cent of mothers of children with suspected FA avoid foods on their own initiative. 17 Goldberg et al 16 have recently shown that milk-allergic young adults have reduced bone mineral density and that low calcium intake, asthma and weight constitute independent risk factors. FA can also result in an impairment of quality of life and mental health of children and their families. [17][18][19][20] For instance, mothers of children with suspected FA have higher state and trait anxiety scores than healthy controls 17 and about 50% of children and teenagers with FA experience bullying. 18 FA can also impact negatively on the costs, related to not only the healthcare but also the indirect costs, for instance related to school and work absences, and the financial burden on the families themselves, resulting, for example, from the need to spend more time shopping and to find alternative foods that are often more expensive. All these factors account for additional negative impact on the lives of children with FA and their families that goes beyond the state of hypersensitivity to the culprit allergens, and underscore the importance of an accurate diagnosis and the search for specific treatments for FA.

| EPIDEMI OLOGY
The prevalence of IgE-mediated FA is highest in infancy and early childhood, driven by a relatively high prevalence of egg and cow's milk allergy that often resolves later in childhood. By contrast, peanut and tree nut allergies, which also typically present in infancy, are less likely to resolve and therefore predominate in later childhood. 21 Marked differences in the prevalence of FA between countries have been noted for multiple foods, although data from some countries remain sparse. [22][23][24][25][26] More recent studies have shown that large differences in FA prevalence can exist even within individual countries, with some of this difference driven by a lower prevalence in rural areas compared with urban areas. 4,27,28 Reasons for these differences are largely speculative, with differences in the prevalence of the risk factors described below potentially playing a role.
The strongest known risk factor for FA is probably eczema, particularly eczema that starts early in life and is more severe. 27,28 This finding has been noted consistently across studies in both population-based studies and allergy clinics for many years; however, the mechanism driving this association remains unclear. It has been hypothesized that a damaged skin barrier resulting from eczema may allow the absorption of food allergens through the skin leading to food sensitization and allergy, in the absence of pre-existing oral tolerance to those foods. 29 Alternative explanations include the existence of shared genetic or environmental risk factors leading to an increased risk of both eczema and FA.
There has been strong interest in identifying factors that can be modified to prevent FA. Both observational studies and randomized controlled trials have investigated the association between FA and factors including vitamin supplements, fish oil, probiotics and timing of introduction of allergenic foods. These are described further below in the FA prevention section. Other factors that have been associated with risk of FA include factors potentially associated with increased microbial exposure such as pet dogs and older siblings. 30,31

| MECHANIS MS AND PATHOPHYS IOLOGY
The mechanisms underlying IgE-mediated food allergy is type I hypersensitivity. Understanding the underlying immune mechanism can help us identify targets for treatment and other interventions to prevent and reduce the impact of FA. T cells are central coordinators of the immune response to food allergens, namely the production of antibodies by B cells. Using mass cytometry for immunoprofiling of infants, Neeland et al 32 described cellular fingerprints associated with peanut allergy and tolerance among IgE-sensitized infants.
Peanut-allergic infants had increased frequency of CD19 hi HLA-DR hi -activated B cells and of peanut-specific memory CD4+ T cells, as well as overproduction of TNF-alpha, whereas peanut-sensitized tolerant infants had reduced frequency of CD4+ naïve T cells and an increased frequency of plasmacytoid dendritic cells. Following the description of the new subset of Th2 cells typical of highly allergic patients, the TH2A cells, that decreased following allergen-specific immunotherapy by Wambre et al, 33 Chiang et al 34  Tfh13 cells are characterized by a distinct transcription factor profile that includes BCL6 and GATA-3, and by the production of IL-4 and Il-13. Tfh13 result in the production of high-affinity IgE that is able to induce anaphylaxis to allergens. This high-affinity IgE is most likely a result of indirect isotype switching from IgG1+ to IgE+ B cells.
Contrary to IgG and IgE that depend on germinal centres and Tfh cells, IgA seems to follow an independent mechanism that requires T cells and CD40 ligand but is independent of germinal centres, Tfh and T follicular regulatory cells. 38 Interestingly, Hoh et al 39  To conclude, understanding the immune mechanisms underlying FA and oral tolerance is key to improve diagnostics and the care for patients and their families and identify targets for a definitive treatment of FA. Table 1 summarizes recent new discoveries about immune mechanisms of FA.

| D IAG NOS IS
An accurate diagnosis of FA is essential. Correctly identifying FA is crucial for providing education and management strategies to mitigate the risks of a potentially life-threatening allergic reaction. In contrast, correctly identifying food tolerance will promote dietary liberation, which is especially important in the light of the paradigm shift encouraging early introduction of allergenic foods to prevent T cells and T follicular helper cells •Food allergy involves Th2-skewed response more than a 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 The mast cell activation test (MAT) offers another promising approach and has the advantage over BAT that it uses stored plasma rather than fresh whole blood. In the same sample as described previously for peanut BAT, 56 MAT performed equally well to BAT in terms of specificity; however, the sensitivity of MAT was lower than BAT. 58 Importantly, MAT provided definitive results in all cases where basophils were non-responsive. 58 In a smaller study, MAT performed better than BAT based on AUC for the diagnosis of peanut allergy; however, confidence intervals overlapped. 59 The utility of these tests has been assessed for some other common allergens and performs similarly well but further research is needed. 60 Additionally, these cellular tests may offer additional clinical utility as the results are correlated with reaction severity, 59,60 whereas SPT and sIgE are not always predictive of reaction severity. 61,62 However, further work is required to inform standardization of laboratory procedures, optimal test parameters and thresholds, and cost-effectiveness in different settings before these novel approaches are ready for routine clinical practice. 55 Despite continued advances and development of novel molecular techniques, identifying a definitive diagnostic test to negate the need for oral food challenges remains elusive. The optimal threshold requires a trade-off between false negatives and false positives, and this varies in the published literature due to heterogeneity in study sample, design, methods, regional characteristics, allergen extracts and laboratory procedures. Figure 1 represents a suggested approach to the sequential use of diagnostic tests to improve the diagnosis of food allergy without the need for OFC, as proposed by several studies. 63 This approach involves first-line tests of traditional SPT and/or sIgE using established 95% PPVs. If results are equivocal, a second-line test of CRD, BAT or MAT may be ordered and this approach has been shown to substantially reduce the need for OFC. 63 However, OFC remain the gold standard and may be required to confirm the diagnosis if all tests are equivocal. Identification, validation and cost-effectiveness of the optimal diagnostic approach for FA continue to be an active area of research.

| Allergen avoidance
In the absence of effective treatment, allergen avoidance and providing appropriate emergency medication used to be the only approach to management of FA. 64 Avoidance of food allergen is onerous for patients and families and often fails with ten per cent of patients on average experiencing an allergic reaction per year. 65 -67 Additionally, allergen avoidance inflicts multiple pressures on allergic individuals and their families, food manufacturers, and restaurants and public spaces such as schools and aircrafts. 68,69 Precautionary allergen labelling is in general voluntary and used inconsistently across industry which can be misleading for patients and caregivers. 65 Providing adrenaline auto-injectors (AAI) to patients at risk of anaphylaxis encounters challenges related to their availability, which is mostly limited to high-income countries, varied national regulations in prescribing and high cost. 70 When prescribed, AAI are only carried at all times by half of the patients 71 and mistakes in use are frequent among both patients 72 and medical staff. 73 Meeting the needs of both food-allergic children undergoing immunotherapy and those continuing strict avoidance in the same environment, for example school or household with two allergic siblings managed differently, is an arising challenge.

| Food immunotherapy
Just over twenty years since the first RCT demonstrated its efficacy, 74 food immunotherapy (FIT) has become the first established treatment modality for FA, which is now recognised by national and international guidelines. [75][76][77] The efficacy of oral FIT has been documented in RCT in children with milk, egg and peanut allergy, 78 with lower desensitization rates being achieved in wheat allergy. 79 In the largest oral FIT study so far, the PALISADE study, which investigated efficacy of 300-mg dose of peanut protein in inducing tolerance to peanut in almost 500 children ≥ 4 years, 67.2% of participants achieved the primary end-point of passing 600-mg dose at the exit DBPCFC. 80 It has also been confirmed recently in a placebo-con- most likely to benefit from FIT. The two most studied alternative routes to oral FIT are sublingual (SLIT) and epicutaneous IT (EPIT).
Their safety profile is favourable with few systemic allergic reactions reported; it comes, however, at the cost of lower efficacy. [84][85][86][87] The modest level of desensitization predisposes SLIT and EPIT for use in individuals not tolerating OIT. 87 It may also be the case that longer treatment duration is necessary to achieve results comparable with OIT. 84 The other main need is understanding long-term outcomes of the treatment. 88,89 Table 2 summarizes recent developments in FIT, and Figure 2 illustrates phenotypes of food allergy and possible outcomes of FIT.
Despite the efficacy in inducing desensitization to the culprit food, the outcome of FIT differs from natural outgrowing of FA.
While the benefits of a margin of protection in case of accidental exposure and introducing certain amount of the food in regular diet are possible during the treatment, the long-term effect remains unpredictable with up to 70 per cent successfully desensitized individuals losing tolerance after a short period of avoidance. 43 Why the post-IT tolerance is lost despite apparent similarities in immunologic response with FA resolution (e.g. decrease in specific IgE concentration and raise in specific IgG4) remains unclear. 90 As sustained unresponsiveness is not achieved by at least half of the patients, the question about the necessary frequency of consumption of the food after completion of FIT remains.
Reassuringly, consumption of an egg twice a week has proven sufficient to sustain tolerance in the Spanish SEICAP study. 91 In the large long-term follow-up Finnish cohort of children who completed milk OIT, only a quarter of the children returned to milk avoidance diet during the median 6.5-year-long observation period. 92 Regarding ongoing peanut consumption, 64% of previous

Route
In the large phase 3 study on epicutaneous IT to peanut, 35.3% of participants achieved predefined response rate compared with 13.6% 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 unresponsiveness The baseline epitope-specific antibody binding models can achieve 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.

TA B L E 2 Recent developments in food immunotherapy (FIT)
peanut IT participants continued to ingest peanut daily and another 25% less frequently. Unfortunately, allergic reactions including airway involvement were still noted even in this late stage of desensitization. 93 With the first commercial product for peanut OIT approved by FDA in January 2020, FIT is likely to become more widely available and uniform in the coming years.

| Biologicals
In FA, biologic treatments have been mostly investigated in the con- Due to its pathomechanism, eosinophilic pathway inhibition has been extensively studied in the treatment of EoE. 95 The use of anti-IL-5, anti-IL-13 and anti-IL-4 has been associated with significant reduction in histologic features of EoE in three RCTs. 96

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 Kingdom 9 -a country with a relatively high prevalence of FA. The relevance of these findings to countries with a low peanut allergy prevalence is less clear. 101 There is also evidence from meta-analyses of multiple trials that early introduction of egg into the infant diet reduces the risk of egg allergy, although the extent of the reduction in risk appears lower than for peanut. 44  Writing-review & editing (equal).

PE E R R E V I E W
The peer review history for this article is available at https://publo ns.com/publo n/10.1111/pai.13443.