Local Respiratory Allergy: From Rhinitis Phenotype to Disease Spectrum

foods Review New Insights in Therapy for Food Allergy Cristobalina Mayorga 1,2,*,†, Francisca Palomares 1,† , JoséA. Cañas 1, Natalia Pérez-Sánchez 2, Rafael Núñez 1, María JoséTorres 2,3 and Francisca Gómez 2   Citation: Mayorga, C.; Palomares, F.; Cañas, J.A.; Pérez-Sánchez, N.; Núñez, R.; Torres, M.J.; Gómez, F. New Insights in Therapy for Food Allergy. Foods 2021,10, 1037. https:// doi.org/10.3390/foods10051037 Academic Editor: Christopher John Smith Received: 28 March 2021 Accepted: 5 May 2021 Published: 10 May 2021 Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/). 1Allergy Research Group, Instituto de Investigación Biomédica de Málaga (IBIMA), 29009 Málaga, Spain; [email protected] (F.P.); [email protected] (J.A.C.); [email protected] (R.N.) 2Allergy Clinical Unit, Hospital Regional Universitario de Málaga, 29071 Málaga, Spain; [email protected] (N.P.-S.); [email protected] (M.J.T.); [email protected] (F.G.) 3Medicine Department, Universidad de Málaga-UMA, 29071 Málaga, Spain *Correspondence: lina.mayor[email protected]; Tel.: +34-951-290-224 † C.M. and F.P. contributed equally to this article. Abstract: Food allergy is an increasing problem worldwide, with strict avoidance being classically the only available reliable treatment. The main objective of this review is to cover the latest information about the tools available for the diagnosis and treatment of food allergies. In recent years, many efforts have been made to better understand the humoral and cellular mechanisms involved in food allergy and to improve the strategies for diagnosis and treatment. This review illustrates IgE-mediated food hypersensitivity and provides a current description of the diagnostic strategies and advances in different treatments. Specific immunotherapy, including different routes of administration and new therapeutic approaches, such as hypoallergens and nanoparticles, are discussed in detail. Other treatments, such as biologics and microbiota, are also described. Therefore, we conclude that although important efforts have been made in improving therapies for food allergies, including innovative approaches mainly focusing on efficacy and safety, there is an urgent need to develop a set of basic and clinical results to help in the diagnosis and treatment of food allergies. Keywords: food allergy; specific immunotherapy; non-specific therapy; hypoallergens; nanoparticles; microbiota 1. Introduction Food allergy (FA) is a pathological reaction of the immune system triggered by the ingestion of a food protein antigen. Exposure to very small amounts of allergenic foods can trigger clinical symptoms, such as gastrointestinal disorders, urticaria, and airway inflammation, that range in severity from mild to life-threatening. The FA prevalence is increasing, and the main treatment consists of food allergens avoidance and in the treatment of the systemic reactions induced by them. New concepts considered as co-factors, environment and nutrition, are changing the epidemiology of allergic reactions to food, leading to new food allergy syndromes. To have an effective treatment, an accurate diagnosis of food allergic patients is required. In this sense, advances in diagnosis are directed to the use of in vivo to in vitro tests. Even so, oral food challenge (OFC) is the only test available to confirm the diagnosis. All these diagnostic approaches could help develop specific treatments in which the relevant allergens causing the reaction should be included. However, further research is urgently needed to achieve this purpose. The development of more precise research has contributed to technological advances, allowing us to understand the mechanisms involved at the cellular and molecular levels that are associated with the concept of immunological tolerance. Currently, the tolerance response that is being achieved using specific-allergen and non-specific-allergen approaches can have some limitations in terms of efficacy and safety, such as the fact that the use of food allergenic extracts from natural sources can cause severe reactions during treatment. Foods 2021,10, 1037. https://doi.org/10.3390/foods10051037 https://www.mdpi.com/journal/foods Foods 2021,10, 1037 2 of 23 As a consequence of this, new prevention models and innovative therapeutic strategies are emerging, aimed at a personalized approach for the patient affected by food allergy. This review focuses on specific therapies, new therapeutic approaches, and their practical implications in the management of FA, providing an updated view of this complex pathology. This review is relevant because it broadens the knowledge of approaches for a precise diagnosis, for FA management, and for the different alternatives for treatment of FA in both children and adults. This information collects the reduction in the symptoms associated with food allergies and the modulation of the immunological response caused by different therapeutic approaches. 2. Food Allergy Epidemiology There is enough evidence that, over the last decades, food allergy incidence and prevalence have been increasing worldwide, especially in developed countries [ 1 , 2 ]. FA rates have been described to be as high as 10% [ 3 – 5 ], and with the absence of a cure for the majority of the types of FA, prevalence will continue to increase. Determining FA frequency in the general population is challenging due to the fact of its complex methodology and to the fact that the data analyzed in most of the epidemiological studies were obtained from different sources including surveys in subjects with self-reported FA [ 2 – 4 , 6 ]. It is more common in children than in adults. Studies based on OFC indicate that the prevalence of FA amongst preschool children is currently between 5% and 10% in some western countries like Australia, and based upon a combination of clinical history and measurement of specific immunoglobulin E (sIgE), nearly 7% in China and Korea [ 2 , 4 ]. To date, in the United States, FA studies are limited to questionnaire surveys, with an FA estimated rate of 5.7% in children in the 2015 National Health Interview Survey, which included data about food allergy in the past 12 months [ 4 ] and of 7.6% in another US population-based cross-sectional prevalence survey of over 50,000 households performed between 2015 and 2016 [7]. Regarding FA in adults, a prevalence of 0.3–5.6% was determined in the EuroPrevall project, which also referred to probable FA, considered as the combination of self-reported FA and matching IgE-sensitization. Considering OFC in those cases, the researchers suggest a population prevalence of 0.2–4.1% for confirmed FA. According to the EuroPrevall project, the highest prevalence was found in Switzerland (5.6%), followed by Spain, Poland, the Netherlands, Iceland, and, finally, Greece (0.3%) [6]. FA constitutes an important public health burden in developed countries [ 1 ], mainly related to the clinical entities induced by FA, being those induced by an IgE mechanism the most frequent in both children and adults. Although anaphylaxis is a relatively common FA clinical entity, fatal anaphylaxis remains rare, ranging from approximately 0.03 to 0.3 deaths per million persons/year in the general population, and it is most common in young people, with a peak during the second and third decades of life [ 8 – 10 ]. Concerning food allergen triggers, in general there are some main allergenic foods which account for 90% of total FA cases: milk, egg, peanut, tree nuts, soya, wheat, fish, and shellfish [ 6 , 10 – 13 ]; nevertheless, food triggers also differ depending on country-specific consumption patterns [8]. It is clear that published data show that FA prevalence can vary around the world and that the foods responsible for the reactions differ per region and age. These differences could also be attributed to the development of studies with diverse methodologies, FA definition, environmental factors, such as pollen or dust mites, or even endotoxin exposure [14–17]. In this review, we describe the different approaches for FA treatment, taking into account that an efficient treatment requires a precise patient phenotyping by studying the mechanisms and diagnosis. This will help to identify the food or allergenic proteins that are actually involved in the reaction and, therefore, be able to prescribe an accurate therapy according to the patient’s needs. Foods 2021,10, 1037 3 of 23 3. Mechanisms in FA FA is defined as an adverse immune reaction to innocuous ingested food proteins or food allergens, which can be mediated by IgE (immediate hypersensitivity reactions), non-IgE mediated, and mixed (immune reactions mediated by IgE and cells) [18]. Food allergens, commonly derived from the food proteins of plants or animals, trigger the immune response. They enter the organism by ingestion and can be modified during digestion, being processed by antigen-presenting cells (APCs) and presented on the major histocompatibility complex class II (MHCII) to T cells. Depending on the costimulatory signals, the naive helper T (Th) cells differentiate into Th2 cells in the presence of interleukin (IL)-4, producing a plethora of cytokines such as IL-4, IL-5, IL-10, and IL-13, which induced massive production of sIgE by B cells-derived plasma cells [ 19 ]. These allergen-sIgE antibodies bind to the high-affinity IgE receptor (Fc ε RI) placed on mast cells and basophils (Figure 1A). In addition, epithelial cells produce IL-25, IL-33, and thymic stromal lymphopoietin (TSLP), which can affect the Th2 responses [ 20 ]. These cytokines conditioned dendritic cells (DCs) and type 2 innate lymphoid cells (ILC2), leading to expansion and differentiation to Th2 cells [ 21 ], which produces Th2 cytokines [ 22 ], responsible for allergic processes (Figure 1A). During the successive allergen exposure, sIgE antibodies induce mast cell degranulation, release several pro-inflammatory mediators, including histamine, cytokines, and lipid mediators, promoting the Th2 response that is associated with allergic symptoms (Figure 1B). Figure 1. Immunological mechanisms involved in FA: ( A ) Food allergens are taken up by the DC and presented to Th0 cells. ILC2 have been described as IL-5 and IL-13 producers, promoting Th2 response. These cells differentiate into Th2 cells, releasing type-2 cytokines and promoting B cell differentiation into IgE-producing plasma cells. ( B ) Food allergen-sIgE binds to FC ε R placed on mast cells. Re-exposure to specific food allergen induces mast cell degranulation and promotes Th2 immune response. Foods 2021,10, 1037 4 of 23 4. Approaches for a Precise Diagnosis One of the most challenging issues is the achievement of a precise diagnosis, discriminating between sensitization and real clinically relevant response to foods. Expert panels, practice parameters, systematic reviews, and guidelines have identified several recommended diagnostic modalities [ 23 – 25 ]. These tests include medical history, physical examination, elimination diets, skin prick tests (SPTs), sIgE tests, and OFC. 4.1. Related to the In Vivo Diagnosis The most important single “test” for diagnosing an FA is clinical history. This must be reviewed in the context of the clinical manifestations that must be compatible with an allergic reaction, the onset of the appearance of symptoms (time after food intake), the risk factors associated with the patient, the epidemiology of the FA, and keeping in mind disorders with similar clinical manifestations that might be misconstrued. After a well-structured clinical history, testing is probably unnecessary and would likely be confirmatory. Additional diagnostic information is obtained by appropriately selecting and interpreting tests, such as SPTs, sIgE measurements, and OFCs, which must be interpreted within the context of the epidemiology and the pathophysiology [3]. 4.2. Related to the In Vitro Diagnosis Classically, the diagnosis of an FA has been performed using allergen extracts containing a mixture of allergenic and non-allergenic molecules that are difficult to standardize. The use of allergen-specific serum IgE (RAST) permits restricting the number of allergen extracts, according to the patient’s clinical history. Thus, diagnosis defines the source but not the allergenic molecule(s) eliciting the disease. In the last decade, advances in molecular allergology have enabled cloning and producing the allergens of major allergenic sources as foods in a recombinant form. This new strategy was deeply integrated in the new precision medicine approach due to the very accurate characterization of the patient’s phenotype [26]. (a) Molecular or component-resolved diagnostic (CRD) tests have been considered promising, and studies regarding their utility continue to emerge. The general premise is that IgE binding to specific proteins in a food might provide more specific diagnostic information than tests that report IgE binding to extracts composed of mixtures of proteins. For example, Ara h 2 is a major peanut protein, a 2S albumin associated with clinical reactions, whereas Ara h 8 is a birch pollen Bet v 1 homolog and is labile and unlikely to be attributable to severe clinical reactions or to be clinically relevant. It is also useful to distinguish different patterns of sensitization related to the geographical area. A Spanish study that included a well-defined group of adult patients allergic to peanut, hazelnut, and walnut concluded that the lipid transfer protein (LTP) was the main allergen in nut allergy [ 27 ]. One interesting point related to the CRD is that, for example, an isolated positive result to Ara h 8 would usually suggest general tolerance, since detection of Ara h 2 is related to severe reactions [28,29]. The allergological work up could include the in vitro CRD singleplex tests with extractbased analytes, which are commonly prescribed as a sort of confirmatory evaluation of the in vivo testing, and the single components are performed for an in-depth analysis. Several multiplex systems have recently been developed, such as the ISAC, allowing the evaluation of hundreds of distinct components at the same time and in the same patient. Such an in vitro test could detect a comprehensive profile of IgE sensitization [ 30 ]. This tool detects IgE-related sensitization to panels of allergens and gives a more precise and comprehensive evaluation for an IgE-based epidemiology. This insight brings data for a better understanding of the sensitization process. (b) Basophil activation test (BAT): In recent years, BAT has emerged as a functional assay to differentiate between sensitization and clinically relevant allergy and has proved to be superior to other diagnostic tests in discriminating between peanut allergy and tolerance, particularly in difficult cases, reducing the need for OFCs. Moreover, different parameters, Foods 2021,10, 1037 5 of 23 such as basophil reactivity (percentage of activated basophils) or basophil sensitivity (dose at which basophils can react), reflect the severity of allergic symptoms at which patients react during OFC [ 31 , 32 ]. Currently, it is also considered promising [ 24 ], although there are challenges related to its use outside the research setting [33]. For now, the OFC is the only test available to confirm the diagnosis, and it is considered the gold standard; however, the tests described above can be used judiciously as previous screening steps to reduce the need for OFCs. The main advantage of this type of test is that it is able to differentiate sensitization profiles, predicting patients with more severe allergies such as peanut allergy due the fact of Ara h 2 sensitization [ 31 , 32 ]. However, these tests can be misleading, due to the broad sensitization profiles that they can provide, and it is very important take into account that they must be interpreted by well-trained personnel to avoid misdiagnosis and restrictive diets that are not necessary, impacting on the patient’s quality of life. Studies on alternative diagnostic methods are underway: (i) evaluation of IgE binding to areas (epitopes) on allergens including affinity of binding [ 34 – 36 ]; (ii) additional markers being evaluated include cytokines, Treg cells, and T cell number and function; B cell activity; DNA methylation signatures [37]; (iii) bioinformatics approaches with machine learning technology that takes into consideration multiple variables [ 38 ]. These alternative diagnostic methods have the advantage of not putting the patient at risk. However, they may be less sensitive and should be interpreted cautiously. 5. Primary Prevention and Management of FA Currently, the traditional approach for managing FA is based on patient education, strict avoidance of the offending food, and prompt treatment of adverse reactions resulting from accidental exposure. Children and families are provided with patient-specific emergency medication and a management plan on how to treat allergic reactions [ 23 ]. Recently, with advances in allergy research, a more active approach to managing FA is being adopted. This approach includes early dietary introduction of potentially allergenic foods, as a means to prevent the development of allergy; actively testing for related allergens, once a specific FA has been identified (anticipatory testing); active monitoring and desensitization to known food allergens and active risk management. Although these approaches have the potential to significantly improve quality of life and reduce the development of further allergies, they may significantly increase the complexity of managing children with FA. The ideal scenario in actively managing FA would be primary prevention. Over the last two decades, there have been significant changes with respect to infant feeding guidance. Complementary feeding was recommended to be delayed until 6 months, with longer delays for specific allergenic foods such as peanuts [ 39 ]. This was based on very limited data and has now been withdrawn. Current valid guidelines, written in 2008, recommend exclusive breastfeeding for 6 months and avoidance of potentially allergenic foods (peanuts, other nuts, seeds, milk, eggs, wheat, fish or shellfish) until 6 months of age with no recommendation for any maternal allergen avoidance during pregnancy or lactation. However, even these data are starting to be challenged, as evidence suggests that early introduction of an allergic food may actually play an important role in the prevention of the development of FA with different foods such as peanut, cow milk, or egg [ 40 – 42 ]. Moreover, the Learning Early About Peanut Allergy (LEAP) study evaluated the effect of early peanut consumption on the risk of developing peanut allergy, finding an improvement in peanut tolerance in high-risk allergy patients, those with atopic dermatitis and/or egg allergy. The Enquiring About Tolerance (EAT) study is testing the hypothesis that the introduction of six allergenic foods (cow’s milk, egg, wheat, sesame, fish, and peanut) into the diet of infants from 3 months of age, alongside continued breastfeeding, results in a reduced prevalence of FA by 3 years of age. In summary, there are promising results looking at the early introduction of allergenic foods into the diet of infants; however, more rigorous study outcomes are awaited, suggesting that the window of opportunity may vary depending on the food. There are several ongoing interventional studies, which will provide more definitive guidance on introductory feeding for infants. Foods 2021,10, 1037 6 of 23 Recently, anticipatory testing was proposed: the diagnostic process for IgE-mediated FA involves taking an allergy-focused history, followed by targeted allergy testing (either SPTs or sIgE testing), and in cases where diagnostic doubt remains, OFC continues to be the gold standard diagnostic test. Recent FA diagnostic guidance recommends allergy testing to the allergen suspected of causing the index reaction and known co-allergens [ 43 ]. It seems that this anticipatory approach has the potential advantages of avoiding unwanted allergic reactions in the community, avoiding unnecessary restrictions in the diet, and also, facilitating early introduction, potentially preventing development of allergy to coallergens, which requires further investigation. Moreover, this anticipatory approach could have the ability to accurately diagnose FA and differentiate it from sensitization. For example, a Spanish study that evaluated a group of children allergic to nuts describes that sensitization to a particular plant-food LTP did not always cause clinical symptoms with that plant-food. Indeed, 69% (40/58) and 63% (17/27) of peach- and walnut-tolerant subjects had positive rPru p 3- and nJug r 3-sIgE, respectively. Similarly, 9.1% (18/46) hazelnut-tolerant individuals had positive rCor a 8, whereas for peanut it was 36.8% (14/38, Ara h 9 + ) and for wheat it was 26.2% (33/126, rTria 14 + ). Therefore, sIgE and SPTs without a supporting clinical history cannot be used in isolation to definitively diagnose FA [ 44 ]. However, for now, an OFC may be required to make a definitive diagnosis, and despite the ongoing improvements in diagnostics, anticipatory testing will inevitably lead to diagnostic uncertainty. As a result, numerous food challenges are likely to be required to make a definitive diagnosis when a patient with no history of consumption is identified as having evidence of sensitization. The economic impact of this will require further study. However, this approach will allow a more precise and prompter diagnosis, the prevention of reactions with potential severe consequences, and the prevention of unnecessary avoidance of related foods [3]. 6. Allergen-Specific Treatments FA patients remain asymptomatic when avoiding the ingestion of the food involved. This implies that the only available treatment is the prescription of a restrictive diet that clearly worsens the quality of life of the patient and may even be unnecessary. However, FA patients can develop serious reactions due to the inadvertent and involuntary intake of food. Therefore, there is a need to develop safe and long-term effective therapies [ 45 , 46 ]. In this sense, specific immunotherapy (sIT) in which controlled quantities of an allergen are given to a patient in order to induce tolerance has been proposed as a reliable alternative approach for FA treatment. 6.1. Cellular and Molecular Mechanisms 6.1.1. Regulatory and Tolerogenic Mechanisms The sensitization process starts with the uptake of food allergens or antigens in the gut by special epithelial cells called microfold cells (M cells) and/or goblet-cell-associated antigen passages [ 47 ]. In the gut, CX3CR1 + DCs uptake antigens directly from the lumen and show a higher inflammatory potential than the CD103 + CX3CR1 − DC population [ 48 , 49 ]. These last cells have tolerogenic effects and can induce tolerance [ 50 ]. After first contact with the allergen, CD103 + CX3CR1 − DCs can migrate to mesenteric lymph nodes in a CCR7-dependent manner [ 51 ], promoting the proliferation of T regulatory (Treg) cells by means of transforming growth factor beta (TGF- β ) and retinaldehyde dehydrogenase 2 (RALDH2) [ 52 ]. Therefore, migration of CD103 + DCs is necessary for induction of tolerance. Moreover, it is very important how the antigen is uptaken to produce tolerance, which has to be through CD103+CX3CR1−DCs. Treg cells play a key role in oral tolerance and are essential for modulation of the immunological response [ 53 ]. They express CD25 and the factor forkhead box protein 3 (FOXP3) [ 19 ]. Indeed, this factor has been shown to be differentially expressed in FA. In fact, children with FA showed lower FOXP3 expression and Treg cell percentage after allergen exposure compared to healthy controls [ 54 , 55 ]. Furthermore, immunosuppressive Foods 2021,10, 1037 7 of 23 regulatory B (Breg) cells can also regulate inflammatory response through production of suppressor cytokines such as IL-10, IL-35, and TGF- β [ 56 ]. The overexpression of IL-10 by B cells avoids the maturation of DCs, Th2 cell proliferation, and IgE production [ 57 ]. In spite of the Breg cells role having been studied in several allergies [ 58 ], few human studies have been reported about Breg cells’ responses in FA immunotherapy. 6.1.2. Cellular and Molecular Mechanisms Involved in Immunotherapy Oral immunotherapy (OIT), sublingual immunotherapy (SLIT), and epicutaneous immunotherapy (EPIT) are the current immunotherapy approaches for FA treatment. Although the underlying cellular and molecular mechanisms involved are not yet fully understood, the most widespread hypothesis is that proliferation of Treg cells and release of immunosuppressive cytokines such as IL-10 occur [ 59 ]. Moreover, IT-mediated desensitization is thought to be caused by repeated low doses of antigen exposure during IT treatment, which causes depletion of basophils and mast cells, leading to a reduction of IgE levels [ 60 ] that could be associated with a Treg proliferation producers of IL-10 and TGF- β [ 61 ] and with Th2 profile shifts to Th1, increasing interferon gamma (IFN γ ) production and decreasing that of IL-4 and IL-13 (Figure 2). On the other hand, GATA3 hypermethylation in Th2 cells and hypomethylation of FOXP3 in Treg cells have been discovered in IT-treated mice sensitized to peanut proteins [62]. Figure 2. Cellular mechanisms involved in allergen-specific immunotherapy (ASIT) and non-allergen-specific therapy (NAIT). Different therapies exist in the ASIT, such as OIT, SLIT, and EPIT, and in the NAST such as biologics and microbiota. The cellular mechanism in the ASIT implies low doses of food allergen favoring regulatory responses, with Treg cell proliferation, an immunosuppressive Th2 cytokine production, and an immune activation of the Th1 cytokine production to restore the Th1/Th2 balance. All this decreases the production of allergen-sIgE. On the other hand, NAST using biologics directly blocks IgE (omalizumab) or cytokines involved in the Th2 response (dupilumab and etokimab), avoiding cell signaling and all underlying processes involved in FA. In the same way, microbiota acts on the Treg cells by favoring the release of immunosuppressive cytokines (IL-10) as well as plasma cells increasing the immunoglobulin G (IgG) 4 /IgE ratio. 6.2. Specific Types of Treatments According to Types of Foodstuffs FA-immunotherapy (FA-IT) is an allergen-specific approach to FA handling based on progressively increasing a particular food allergen until reaching a daily maintenance dosage to achieve desensitization [ 63 , 64 ]. Indeed, allergen immunotherapy is currently introduced into clinical practice and it is accepted worldwide [ 65 , 66 ]. However, there are still many unknown aspects which have to be resolved such as the achievement of persistent tolerance [ 67 ] and others related to management. In addition, the current Foods 2021,10, 1037 8 of 23 coronavirus pandemic (COVID-19) situation must be taken into account, and some reports advise discontinuation of immunotherapy in children infected with severe acute respiratory syndrome coronavirus 2 virus (SARS-CoV-2), because intercurrent viral infections could act as triggers of mild adverse effects or systemic allergic reactions [ 68 ]. In pediatric patients suspected of infection as well as in subjects who have recovered from the COVID-19 disease, continuing immunotherapy is recommended but with reduction of the current maintenance dose [ 69 ]. However, more studies are needed to determine the efficacy of this treatment. Thus, in this part of review we address the different types of treatments according to food allergens (Table 1). 6.2.1. AIT for Plant-Food Allergy Hazelnut allergy is the major cause of FA in Europe; therefore, developing therapy is essential for management. Ten allergenic molecules from hazelnuts have been identified and characterized [ 92 ]. However, Cor a 9 and Cor a 14 are highly specific for primary hazelnut allergy and strongly associated with severe reactions [ 93 ]. A recent study, performed by Morally and coworkers, on children younger than 18 years affected by hazelnut allergy demonstrated that OIT protected against this specific allergy [ 70 ]. In this retrospective study, they observed that more than 30% of patients reached desensitization to hazelnut after six months of OIT. Moreover, they reported that this therapeutic approach was safe for patients, with no adverse events associated with hazelnut OIT. Peanut allergy is often lifelong, persisting into adulthood in 80% of cases, and in the US, it affects up to 2.2% of children and 1.8% of adults [ 7 , 94 ]. The major peanut allergens recognized by the US population are Ara h 1, Ara h 2, and Ara h 3, which are often associated with severe symptoms. However, in Spain, patients recognized these peanut allergens less and were more often sensitized to Ara h 9 [ 95 ]. Fortunately, for peanut allergy there are emerging therapies and approved drugs to treat this disorder [ 96 , 97 ], which are described below. The OIT, SLIT, and EPI for the treatment of peanut allergy have been studied in clinical trials with promising results in terms of efficacy [ 77 , 81 ]. A systematic review reported by Chu et al. in 2019 showed that patients undergoing peanut OIT had higher anaphylaxis risk and frequency and achieved a modest degree of desensitization than participants receiving treatment with peanut [ 71 ]. Nevertheless, an OIT for peanut allergy, named Palforzia, has been the first approved drug by the US Food and Drug Administration (FDA) in 2020 for patients aged 4 through 17 years with a confirmed diagnosis of peanut allergy [ 72 ]. Moreover, other programs for walnut allergies have been announced [ 98 ]; however, research continues for the optimization of FA OIT in terms of efficacy, safety, and patient’s quality of life. Regarding peanut allergy and EPIT, a study evaluated the safety and its immunological effects [ 81 ]. The results obtained showed that EPIT was safe and associated with a moderate response to treatment after 52 weeks, with a high adherence rate and significant changes in the immunological response (an increase in peanut-specific IgG 4 levels and IgG 4 /IgE ratios in peanut EPIT-treated participants, along with trends toward reduced basophil activation and peanut-specific Th2 cytokines). Another study performed with Viaskin Peanut (patch) in EPIT, which is under revision by the US FDA, has shown clinical effectiveness [ 99 ]. However, the efficacy and safety of these therapies continue under revision. Foods 2021,10, 1037 9 of 23 Table 1. Summary of the therapeutic approaches for FA in the last 5 years. Treatment References Food Benefits Limitations Allergen-specific therapy OIT [70–72] Hazelnut Safe desensitization. Robust, possible sustained. Time-consuming Side effects Peanut Effective desensitization. Palforzia increases the amount of consumed peanut protein. [73,74] Milk Improvement and safety in a continued fixed, low dose. [75] Egg Effective and a humoral immune response. [76] Fish Parvalbumin–OIT consisted of a quick build-up phase. Target dose equivalent to a typical portion of fish. SLIT [77] Peanut Clinically meaningful and safe desensitization in children. Minor side effects, brief exposure. Lower food intake threshold than OIT [59,78–80] Egg Decrease in sIgE levels. Peach Desensitization and cellular immunological changes. EPIT [81] Peanut Increase in the food tolerance in children. Minor side effects. Less robust than OIT More effective in those younger in age Non-allergen specific therapy Omalizumab (anti-IgE) [82,83] Peanut As monotherapy, threshold increased for food allergens and decreased dietary restrictions. As adjuvant with OIT, rapid oral desensitization. Lower rates of allergic reactions from IT. No effect on likelihood of developing sustained unresponsiveness Expensive Dupilumab (anti-IL-4) [84,85] Multi-food As adjuvant with OIT, efficacy improved for multi-food OIT. Safe and rapid desensitization. Faster dose escalation. Etokimab (anti-IL-33) [86] Milk As adjuvant with OIT, basophil reactivity modification. Foods 2021,10, 1037 16 of 23 selectively foster their growth and activity. The prebiotics are oligosaccharides that are not digested or absorbed in the gastrointestinal tract before they reach the large intestine, where specific microbiota can use them for improved growth and activity. Although prebiotic supplementation in infants was found to be associated with decreased risk of asthma and eczema; in some investigations there have been no significant effects on the development of FA found so far [134]. Synbiotics are combinations of probiotics and prebiotics. It is thought that they might be more effective than probiotics or prebiotics alone because the provision of both together delivers a synergistic combination of desired microbes and the components they need to thrive and drive the host community [ 135 ]. A prospective study of infants with cow’s milk allergy receiving a synbiotic-containing amino-acid-based formula improved the fecal microbiota of them [ 89 ]. In this case, the synbiotics used in this trial included the probiotic Bifidobacterium breve M-16V in combination with the prebiotics oligofructose and acidic oligosaccharides. However, more studies are required to confirm this therapeutic effect of synbiotics supplementation in desensitizing FA. It is a promising therapeutic strategy for improving the gut ecosystem and reducing FA responses. FMT is a possible therapeutic for FA. Transplantation of fecal bacteria from a healthy donor to a disease recipient can re-establish gut microbiota diversity leading to the resolution of symptoms. The studies in murine models to identify the microbiota were the basis for FMT in humans with FA. They showed that FMT from healthy human infants and transplanted into a food-allergic mouse model protected from anaphylaxis after allergen exposure, whereas anaphylaxis was not abrogated when FMT was performed with stools taken from food-allergic infants [ 136 , 137 ]. Other mouse studies, investigating clusters impacted by dysbiosis in infants, utilized a type of mouse, Il4raF709, which is genetically prone to FA, showing that the bacteriotherapy containing commensal Clostridiales strains with or without Bacteroidales strains both prevented and treated FA. In fact, the bacteriotherapy induced expression by Treg cells in a MyD88/ROR γ t dependent manner, which suppresses FA in infants and mice [ 90 ]. In a different FA mouse model, with another species of Clostridia known as Anaerostipes caccae, demonstrated that intestinal bacteria were critical for regulating allergic responses to dietary antigens [91]. The research advances in the microbiome field have moved FA therapy into the arena of microbiome-related human clinical trials. Regarding this, a small phase 1 trial (NCT02960074) is evaluating the safety and tolerability of encapsulated FM, which is administered via oral for the treatment of peanut allergy in adults. In addition, another study (NCT03936998) is determining if VE416 in combination with vancomycin (an antibiotic) could be used as OIT in peanut allergy patients. VE416 is a set of commensal bacteria capsules pre-treated with vancomycin to facilitate the colonization of the transferred bacteria. Although the available data in this field remain limited and the relevant scientific work has just begun, this recent success in reducing infantile allergy colitis symptoms suggests that fecal microbiota transplantation can be a feasible strategy to arrest FA responses. 9. Limitations and Conclusions This review has collected different published studies that show the beneficial effects and limitations to treat FA. FA is still a growing public health concern worldwide, with a high incidence, and constitutes a public health burden in developed countries. One of the main challenges is the clinical management related to the diagnosis and treatment. In recent years, the efforts have been focused on improving treatment. Despite these efforts, some limitations have been found throughout this review, based on a bibliographic search, associated with last studies in FA treatment. In this regard, specific therapeutic approaches, such as ASIT and NASIT, can have several disadvantages: they require a long-time to build up the immune response, after stopping the treatment, the sensitization to the foods involved can reappear, and they can pose a risk to the patients, as they can have an allergic reaction to the food at any given dose. In addition, concerning the use of biologics for FA treatment, results Foods 2021,10, 1037 17 of 23 proving if tolerance response is sustained are required, consensus on how these biologics should be administered is lacking, and, moreover, it is a very expensive therapy. Within NASIT, microbiota also present certain limitations associated with a lack of relevant results and with differences in protocols for assessing sustained unresponsiveness. Even so, these limitations have led to the emergence of new questions that have enabled the development of new treatment tools. These new therapeutic approaches, like the hypoallergens and nanoparticles, are mostly being studied in animal models and in very few cases in humans. Therefore, more studies in humans are needed to address the limitations of these therapeutic approaches in FA. Despite the limitations described above, the ASIT has the potential to balance the immune dysregulation causing the food allergic inflammation and it has demonstrated its ability to prevent future sensitizations, being safe, effective and inducing food tolerance. Therefore, it is necessary to develop new therapeutic strategies that can help manage FA. In this sense, recent developments in FA research have focused on new therapeutic approaches such as the use of the hypoallergens and nanostructures. They are designed to be more safe, precise, and faster than immunotherapy. These therapies are currently at different developmental stages. The hypoallergens have demonstrated to be promising as a way to improve safety and enhance efficacy of immunotherapy; but further studies, particularly in human subjects, will be necessary to confirm safety and efficacy. Nanoparticles are being studied since they can enhance the delivery of the food antigen. Theses nanoparticles can stimulate Th1 and/or T regulatory responses avoiding the IgE cross-linking on mast cells and basophils. These properties open new possibilities for treating not only food allergies but also allergic diseases. On the other hand, NASIT, such as the targets for biological drugs or microbiota, are being developed but none have progressed to the large scale. The use of biologics that function through the inhibition of pathways specific to FA can provide a safe tolerance response to multiple foods. Moreover, the influence of microbiota on the immune system is an exciting area of research and, specifically, the role of probiotics as adjuvants in vaccinations or immunotherapy is very promising. Summarizing, more research is needed to develop an “ideal” therapy that shows promising efficacy in modulating the immune response, facilitating shorter dose phases (which would increase patient adherence to treatment), reducing adverse reactions during treatment, and finally inducing tolerance to food. Author Contributions: Conceptualization, C.M. and F.G.; methodology, F.G., N.P.-S., J.A.C., F.P., and R.N.; writing—original draft preparation, C.M., F.G., N.P.-S., J.A.C., and F.P.; supervision, C.M. and M.J.T. All authors have read and agreed to the published version of the manuscript. Funding: This research was funded by grants from the Institute of Health “Carlos III” (ISCIII) of the Ministry of Economy and Competitiveness: PI17/01318 and PI18/00288. RETICS ARADyAL (RD16/0006/0001) and Sara Borrell (CD20/00085) Program. Andalusian Regional Ministry of Health (PE-0039-2018; RH-0085-2020 and PI-0099-2020), Senior Clinical Researcher Program (B-0005-2019), and Nicolas Monardes Program (RC-0004-2021). Roche Pharma S.A. “Stop Fuga de Cerebros” Program (SFC-0002-2020). Grants were co-funded by the European Regional Development Fund (ERDF). “Una manera de hacer Europa” “Andalucía se mueve con Europa”. Institutional Review Board Statement: Not applicable. Informed Consent Statement: Not applicable. Data Availability Statement: Not applicable. Acknowledgments: We thank Claudia Corazza for her help with the English version of the manuscript. Conflicts of Interest: The authors declare no conflict of interest. References 1. Savage, J.; Johns, C.B. 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