Omalizumab (OMA) is gaining recognition as a promising therapeutic approach for IgE-mediated food allergies in pediatric patients. We conducted a review analyzing 22 studies, including randomized controlled trials, observational studies, and case reports, to evaluate the efficacy and safety of OMA in food allergy management in children and adolescents. The results indicate that OMA, whether used as monotherapy or in combination with oral immunotherapy (OIT), significantly increases allergen tolerance, reduces the severity of allergic reactions, and improves patients' quality of life. When used alongside OIT, OMA reduced adverse reactions during dose escalation and maintenance phases, facilitating safer and more effective desensitization. Additionally, OMA demonstrated benefits beyond food allergy management, including improved asthma control and a reduction in food allergy-related anxiety. However, challenges remain, including high costs, the need for standardized treatment protocols, and limitations related to total IgE thresholds for eligibility. While OMA has been FDA-approved for food allergy treatment in the United States, further research is needed to establish long-term efficacy, optimal dosing strategies, and its role in sustained tolerance development. Future research should focus on optimizing treatment protocols and identifying which patients will benefit the most. Integrating omalizumab into food allergy management could revolutionize pediatric care, offering hope for a safer, more effective approach to desensitization.

Background: Food allergies are a growing global health concern, particularly among children, with no widely approved curative treatment beyond strict allergen avoidance. Oral immunotherapy (OIT) has emerged as a promising strategy to induce desensitization, yet its implementation is limited due to high rates of allergic reactions and patient non-compliance. Omalizumab, a monoclonal anti-IgE antibody, has been proposed as an adjunct to OIT to enhance safety and efficacy. Objective: This systematic review and meta-analysis aim to evaluate the efficacy and safety of omalizumab in combination with OIT for IgE-mediated food allergy in children. Methods: A systematic literature search was conducted in PubMed/MEDLINE and Cochrane Central databases to identify randomized controlled trials (RCTs), controlled clinical trials (CCTs), and observational studies assessing omalizumab as an adjunct to OIT in pediatric food allergy. Studies were evaluated for desensitization rates, immunological changes, adverse events, and quality-of-life improvements. Results: OIT combined with omalizumab led to significantly higher rates of desensitization, allowing patients to tolerate higher doses of allergens in a shorter timeframe compared to OIT alone. Omalizumab was associated with a reduction in adverse reactions, including anaphylaxis, and improved treatment adherence. However, the long-term sustainability of tolerance post-omalizumab discontinuation remains uncertain. Conclusions: Omalizumab facilitates rapid and effective desensitization in pediatric food allergy, enhancing the safety of OIT. Further research is needed to determine optimal treatment duration, long-term outcomes, and cost-effectiveness before widespread clinical adoption.

Immunoglobulin E (IgE)-mediated food allergy has been dramatically increasing in incidence over the last few decades. The combinations of both genetic and environmental factors that affect the microbiome and immune system have demonstrated significant roles in its pathogenesis. The morbidity, and at times mortality, that occurs as the result of this specific, reproducible, but impaired immune response is due to the nature of the shift from a regulatory T (Treg) cellular response to a T helper 2 (Th2) cellular response. This imbalance caused by food allergens results in an interleukin (IL)-4 and IL-13 dominant environment that drives B cell activation and differentiation into IgE-producing plasma cells. The resulting symptoms can range from mild to more severe anaphylaxis, and even death. Current therapeutic strategies involve avoidance and broad symptom management upon accidental exposure; however, no definitive cure exists. This narrative review highlights how the elucidation of the pathogenesis of IgE-mediated food allergy resulted in the development of therapeutics that are more specific to these individual receptors and molecules which have been relatively successful in mitigating this potentially life-threatening allergic response. However, potential adverse effects and re-sensitization following the conclusion of treatment has urged the need for improved therapeutic methods. Therefore, given the understanding of their mechanism of action and the overlap with the mechanism of IgE-mediated food allergies, probiotics and small molecule natural compounds may provide novel therapeutic and preventative strategies. This is compelling, as they have demonstrated success in clinical trials and may provide hope to improve quality of life in allergy patients.

Food allergy is a growing problem that can have a significant impact on both the individual, the family, and society. We are entering a new era of food allergy management with the recent US Food and Drug Administration approvals of 2 therapies for food allergy. IgE is now known to play a critical role in allergic diseases, including food allergy. Ant-IgE therapy has been under investigation for decades and is now approved for asthma, urticaria, nasal polyps, and most recently, IgE-mediated food allergy. Here, we evaluate what is known about the safety and efficacy of anti-IgE therapy as monotherapy and in combination with oral immunotherapy. In addition, we will highlight important practical considerations and key knowledge gaps.

Omalizumab was recently approved by the US Food and Drug Administration for treatment of any single food allergy or multiple food allergies in children aged 1 year and older and adults. There is currently no formal guidance regarding recommended best practices for omalizumab use in food allergy, including patient selection, anticipated goals and outcomes of therapy, procedure for monitoring patients who elect to start omalizumab therapy, and ways in which omalizumab can be incorporated into the landscape of food allergy management and daily clinical practice. This work group report was developed by the food allergy therapies subcommittee of the Adverse Reactions to Foods Committee within the American Academy of Allergy, Asthma & Immunology. Consensus, evidence-based guidance regarding experts' recommendations for using omalizumab to treat children and adults with food allergy was developed by using modified Delphi methodology. In iterative fashion, a total of 8 statements regarding how to use omalizumab to treat patients with food allergy were developed by 16 clinical experts. This guidance provides the clinician with a suggested approach to patient selection, initiation of therapy, monitoring of efficacy, and long-term follow-up care. The role of preference-sensitive care is emphasized, with most statements offering care recommendations relevant to the culture and values of a particular practice setting.

The development of targeted therapies for atopic diseases, urticaria, and angioedema with biologics is progressing rapidly: New "targets" of clinical-therapeutic relevance have been identified, the corresponding targeted antibodies developed, tested in clinical trials, and approved for therapy. These include the anti-IgE antibody omalizumab (also effective and approved for the treatment of urticaria), the anti-IL-4/13 receptor-specific antibody dupilumab, the two anti-IL-13 antibodies lebrikizumab and tralokinumab, the anti-TSLP antibody tezepelumab, the two anti-IL-5 antibodies mepolizumab and reslizumab, and the anti-IL5 receptor-specific antibody benralizumab for the treatment of atopic diseases. For the treatment of hereditary angioedema, C1 inhibitor and the antibody lanadelumab (directed against kallikrein) have also long been approved as biologics in addition to low-molecular substances. Other therapeutic antibodies are in various stages of development. Furthermore, the range of indications for some very effective biologics has been successfully expanded to include additional diseases. In this context, the first results on biologic therapy of food allergy and eosinophilic esophagitis are interesting. Biologics that address different target structures are also increasingly being administered in combination, either simultaneously or sequentially, in order to achieve optimal efficacy. A developing area is the use of biologics in children and the observation of immunological and non-immunological side effects. In some cases, new unexpected side effects and hypersensitivity reactions have emerged, which in turn raise pathomechanistic questions, such as conjunctivitis with dupilumab therapy, which only appears to occur in the treatment of atopic dermatitis but not in the treatment of other atopic diseases. In dermatology, paradoxical reactions have been described under therapy with some biologics. And immune reactions of type alpha to epsilon to biologics (hypersensitivity reactions) continue to be a clinically relevant problem, whereby the selection of an alternative therapeutic agent is a challenge and the diagnostics that support this have not yet been sufficiently incorporated into routine work.

Immunoglobulin E (IgE)-mediated food allergies are the most common type of food allergy, often causing rapid symptoms after exposure to allergens posing a serious health risk and a high impact on patient's and caregiver's quality of life. Omalizumab, a humanized anti-IgE monoclonal antibody, reduces allergic reactions by binding to circulating IgE. Omalizumab has been successfully used in allergic asthma, chronic rhinosinusitis with nasal polyps, and chronic urticaria, and was recently approved for treating IgE-mediated food allergies by the US Food and Drug Administration (FDA). This GA2LEN ANACARE Consensus Statement presents our position on the use of omalizumab for treating IgE-mediated food allergies, based on a systematic review and meta-analysis, experience with use for other conditions, and expert consensus achieved via an eDelphi process. Following publication of the recent OUtMATCH study (stage 1) results and subsequent FDA approval, we propose that there is now sufficient evidence to recommend omalizumab as the only drug currently available that can mechanistically reduce IgE-mediated food allergic reactions. We acknowledge that the evidence does not reach the highest level of evidence which would be needed for a guideline recommendation.

Immunoglobuin E (IgE)-mediated food allergies greatly impact patients and their families, causing financial and emotional stress, and placing them at risk for lifethreatening reactions. Until recently, food allergies have been treated with allergen avoidance and emergency treatment of allergic reactions. Omalizumab was recently approved in adults and children greater than one year who are allergic to one or more foods for the prevention of serious allergic reactions in the setting of accidental exposure. Omalizumab also shows promise when combined with oral immunotherapy for possible allergen ingestion. Other classes of biologics and small molecule inhibitors have also demonstrated potential for use in preventing and treating food allergy.

This review delves into the potential of manipulating the microbiome to enhance oral tolerance in food allergy, focusing on food allergen-specific immunotherapy (FA-AIT) and the use of adjuvants, with a significant emphasis on probiotics. FA-AIT, including oral (OIT), sublingual (SLIT), and epicutaneous (EPIT) immunotherapy, has shown efficacy in desensitizing patients and achieving sustained unresponsiveness (SU). However, the long-term effectiveness and safety of FA-AIT are still under investigation. Probiotics, particularly strains of Lactobacillus, play a crucial role in enhancing immune tolerance by promoting regulatory T cells (Tregs) and modulating cytokine profiles. These probiotics can induce semi-mature dendritic cells, enhance CD40 expression, inhibit IL-4 and IL-5, and promote IL-10 and TGF-β, thus contributing to mucosal defense and immunological tolerance. Clinical trials combining probiotics with FA-AIT have demonstrated improved desensitization rates and immune tolerance in food-allergic patients. For example, the combination of Lactobacillus rhamnosus with peanut OIT resulted in a significantly higher rate of SU compared to the placebo group, along with notable immune changes such as reduced peanut-specific IgE and increased IgG4 levels. The review also explores other adjuvants in FA-AIT, such as biologic drugs, which target specific immune pathways to improve treatment outcomes. Additionally, nanoparticles and herbal therapies like food allergy herbal formula 2 (FAHF-2) are discussed for their potential to enhance allergen delivery and immunogenicity, reduce adverse events, and improve desensitization. In conclusion, integrating probiotics and other adjuvants into FA-AIT protocols could significantly enhance the safety and efficacy of FA-AIT, leading to better patient outcomes and quality of life.

To highlight common mechanistic targets for the treatment of atopic dermatitis (AD) and IgE-mediated food allergy (IgE-FA) with potential to be effective for both diseases and prevent atopic progression.

Data sources were PubMed searches or National Clinical Trials (NCT)-registered clinical trials related to AD, IgE-FA, and other atopic conditions, especially focused on the pediatric population.

Human seminal studies and/or articles published in the past decade were emphasized with reference to preclinical models when relevant. NCT-registered clinical trials were filtered by inclusion of pediatric subjects younger than 18 years with special focus on children younger than 12 years as a critical period when AD and IgE-FA diseases may often be concurrent.

AD and IgE-FA share several pathophysiologic features, including epithelial barrier dysfunction, innate and adaptive immune abnormalities, and microbial dysbiosis, which may be critical for the clinical progression between these diseases. Revolutionary advances in targeted biologic therapies have shown the benefit of inhibiting type 2 immune responses, using dupilumab (anti-interleukin-4Rα) or omalizumab (anti-IgE), to potentially reduce symptom burden for both diseases in pediatric populations. Although the potential for biologics to promote disease remission (AD) or sustained unresponsiveness (IgE-FA) remains unclear, the refinement of biomarkers to predict infants at risk for atopic disorders provides promise for prevention through timely intervention.

AD and IgE-FA exhibit common features that may be leveraged to develop biologic therapeutic strategies to treat both conditions and even prevent atopic progression. Future studies should be designed with consistent age stratification in the pediatric population and standardized regimens of adjuvant oral immunotherapy or dose escalation (IgE-FA) to improve cross-study interpretation.

IgE-mediated food allergy is characterized immunologically by a type 1 immune response triggered upon exposure to specific foods and clinically by a broad range of manifestations and variable severity. Our understanding of food allergy within the allergic march of atopic dermatitis (AD) is still incomplete despite the related risk of unpredictable and potentially severe associated reactions such as anaphylactic shock. The aim of this pilot study was to investigate the effects of dupilumab, an IL-4/IL-13 monoclonal antibody approved for AD, on the allergic sensitization profile of patients with AD and type 1 hypersensitivity-related comorbidities, including oral allergy syndrome, anaphylaxis, and gastrointestinal disorders. We conducted an observational pilot study with a longitudinal prospective design, enrolling 20 patients eligible for treatment with dupilumab. Laboratory exams for total serum IgE, specific IgE, and molecular allergen components were performed at baseline and after 16 weeks of therapy. Our results demonstrate a statistically significant decrease in molecular components, specific IgE for trophoallergens, and specific IgE for aeroallergens following treatment with dupilumab. We suggest that modulating type 2 immunity may decrease IgE-mediated responses assessed with laboratory exams and therefore could minimize allergic symptoms in polysensitized patients. Upcoming results of randomized controlled trials investigating dupilumab in food allergy are highly anticipated to confirm its potential effect in the treatment of IgE-mediated food allergies.

Food allergy (FA) is a potentially life-threatening chronic condition that is becoming an increasing public health problem worldwide. This systematic review (SR) was carried out to inform the development of clinical recommendations on the treatment of IgE-mediated FA with biologics and/or IT for the update of the EAACI guidelines. A SR of randomized-controlled trials or quasi-controlled trials was carried out. Studies were identified via comprehensive search strategies in Medline, Embase, and Cochrane Library, up to April 2022.

Human adults, children, and adolescents with IgE-mediated FA.

IT and/or biologics.

Placebo or standard-of-care (allergen avoidance).

Efficacy (desensitization, sustained unresponsiveness (SU), remission), quality of life, and safety (systemic and local adverse reactions (AR)). The Cochrane RoB tool was used to assess the risk of bias. It was reported according to PRISMA and registered in PROSPERO CRD4202229828. After screening, 121 studies were included (111 for IT and 10 for biologics). Most studies had a high risk of bias and showed high heterogeneity in design and results. Metanalysis showed a positive effect of biologics and IT in terms of relative risk (RR) for achieving tolerance to the culprit food compared to avoidance or placebo. Omalizumab for any FA showed a RR of 2.17 [95% confidence interval: 1.22, 3.85]. For peanut allergy, oral IT (OIT) had a RR of 11.94 [1.76, 80.84] versus avoidance or placebo, sublingual IT (SLIT) had a RR of 3.00 [1.04, 8.66], and epicutaneous IT (EPIT) of 2.16 [1.56, 3.00]. OIT had a RR of 5.88 [2.27, 15.18] for cow's milk allergy, and of 3.43 [2.24, 5.27] for egg allergy. There was insufficient data on SLIT or EPIT for the treatment of egg and milk allergies. Most ARs reported were mild. For OIT the most common AR involved the gastrointestinal system and for EPIT, AR's most commonly affected the skin. There was limited data on severe or life-threatening ARs. There was limited evidence for long term efficacy and quality of life. In conclusion, biologics and IT, alone or in combination, are effective in achieving desensitization while on active treatment but more evidence is needed on long-term tolerance as current evidence is not of high quality. Adverse events while on therapy are generally mild to moderate but a long-term comprehensive safety profile is missing. There is a critical need to optimize and standardize desensitization protocols and outcome measures to facilitate our understanding of the efficacy and safety as well as to allow for comparison between interventions.

The recent approval of omalizumab for the treatment of IgE-mediated food allergy is an important step forward for the millions of food allergy patients in the United States. Through the depletion of circulating IgE and the subsequent reduction of FcεR1 on key effector cells, patients increase their tolerance to food allergens. However, omalizumab does not permit patients to eat foods that they are allergic to with impunity. Rather, it protects them from most accidental exposures. In addition, omalizumab does not cure food allergy and has not demonstrated true immunomodulation. Thus, omalizumab might be a lifelong therapy for some patients. Furthermore, there are many important questions and issues surrounding the appropriate administration of omalizumab to treat food allergy, which we discuss. Managing treatment of patients with disease that falls outside the dosing range, assessing treatment response or nonresponse, addressing its appropriateness for patients older than 55, and determining whether immunotherapy plus omalizumab provides any advantage over omalizumab alone all need to be examined. Identifying appropriate patients for this therapy is critical given the cost of biologics. Indeed, not all food allergy patients are good candidates for this therapy. Also, when and how to stop omalizumab therapy in patients who may have outgrown their food allergy needs to be elucidated. Thus, although this therapy provides a good option for patients with food allergies, much information is needed to determine how best to use this therapy. Despite many unanswered questions and issues, we provide clinicians with some practical guidance on implementing this therapy in their patients.

The frequency of food allergies varies between 2% and 10%, depending on characteristics including age, region, race, and method of diagnosis self-reported by patients or oral food challenges (OFCs). The most common allergies reported are tree nuts (1.2%), milk (1.9%), peanuts (2.2%), and shellfish (1.3%). Omalizumab injection has now been approved by the FDA for the treatment of immunoglobulin E-mediated food allergies in specific adults and children aged one year or older. This medication reduces the risk of allergic reactions (Type I), which can include anaphylaxis, when an individual accidentally encounters one or more food allergens. Omalizumab functions by binding to IgE and altering IgE-mediated pathways, which lessens IgE's capacity to cause allergic reactions. Promising outcomes from clinical trials and case studies include lowered anaphylactic risk and enhanced tolerance to allergens. Omalizumab, however, may have adverse effects; thus, close observation is required. Overall, this review sheds light on the efficacy, safety, and clinical implications of omalizumab, highlighting its potential as a useful intervention for IgE-mediated food allergies.

Food allergy is an increasing public health problem in children and adults. In addition to the risk of potentially severe reactions, food allergy can have a significant burden on quality of life, nutrition, cost of living, and social activities. Traditionally, treatment has primarily included strict food allergen avoidance and use of emergency medications to treat an allergic reaction. However, in recent years, there have been significant strides in the advancement of food allergy treatment, including the approval of the first and only approved therapy (peanut oral immunotherapy) for food allergy in 2020. Clinical trials have primarily focused on food allergen immunotherapy (oral, epicutaneous, sublingual). Building off of a foundation of promising data supporting the efficacy of food oral immunotherapy and our greater understanding of the underlying mechanism of immunotherapy, newer approaches, including alternative routes of delivery, adjuncts to therapy, modified allergens, and utilization in younger patients, aim to provide safer and more effective treatment approaches to the millions of patients burdened by food allergy.

Despite promising advancements in oral immunotherapy for food allergies, medical implementation faces limitations. Non-specific treatment options based on inhibiting the type 2 inflammatory pathway, including monoclonal antibodies, are under investigation. TNX-901 and omalizumab have demonstrated increased reaction thresholds, reducing adverse events in peanut-allergic patients. Dupilumab, blocking the IL-4 receptor, shows positive results in both food allergies and eosinophilic esophagitis. Antibodies against alarmins and anti-IL-5, such as etokimab and mepolizumab, have proven efficacy in preclinical studies and clinical trials. While further studies are needed to establish their practical clinical use and determine suitability for different types of food allergies, these monoclonal antibodies present a promising horizon for the treatment of such conditions.

Preventing food allergies is key to reducing the incidence of the disease. Exclusive breastfeeding is recommended during the first months of life, in addition to supplementation with vitamin D and, due to the importance of the microbiota, addition of probiotics, prebiotics and symbiotic. Currently, late exposure to foods is controversial, and it is suggested to introduce allergenic foods early, trying not to expose the cutaneous route. The application of biologics in food allergy is an evolving area of research and treatment. Biologics are indicated in diseases evaluated in various studies, such as atopic dermatitis, and are approved by the FDA for prescription; However, its potential administration in the treatment of severe allergic reactions caused by food is still debated. These therapies may change the way food allergy is addressed in the future, but they are still in experimental stages and not widely available. Food anaphylaxis is a life-threatening allergic reaction that requires quick action. Prevention involves avoiding the triggering food, awareness of symptoms, and availability of epinephrine for immediate administration in case of a reaction.

IgE-induced mast cell (MC) degranulation can be inhibited by IgG antibodies, signaling via FcγRIIb, but the effects of IgG on IgE-induced MC transcription are unknown.

We sought to assess inhibitory IgG:FcγRIIb effects on MC responses to IgE using complementary transcriptomic and functional approaches.

RNA sequencing was performed on bone marrow-derived MCs from wild-type and FcγRIIb-deficient mice to identify genes activated following IgE receptor crosslinking that were further modulated in the presence of antigen-specific IgG in an FcγRIIb-dependent fashion. Parallel analyses of signaling pathways and allergic responses in vivo were performed to assess the impact of these changes in gene expression.

Rapid changes in the transcription of 879 genes occurred in MCs activated by IgE, peaking at 1 hour. Surprisingly, only 12% of these were altered by IgG signaling via FcγRIIb, including numerous transcripts involved in orchestrating type 2 responses linked to spleen tyrosine kinase signaling. Consistent with this finding, IgG suppressed IgE-induced phospho-intermediates in the spleen tyrosine kinase signaling pathway. In vivo studies confirmed that the IgG-mediated suppression of both systemic anaphylaxis and MC-driven tissue recruitment of inflammatory cells following allergen challenge was dependent on FcγRIIb. In contrast, genes in the STAT5a cell survival pathway were unaltered by IgG, and STAT5a phosphorylation increased after IgE-induced MC activation but was unaffected by IgG.

Our findings indicate that inhibitory IgG:FcγRIIb signals block an IgE-induced proallergic program but spare a prosurvival program.

The incidence of IgE-mediated food allergy (FA) has continued to increase over the years which places substantial burden on patient health and quality of life. With no cure for this disease, the mainstay of management has been allergen avoidance. However, there have been advancements in FA treatment in recent years with multiple clinical trials utilizing novel and innovative therapeutic strategies. A landmark event came in 2020 with the first drug approval for food allergy with the approval of a product for peanut oral immunotherapy. In addition to oral immunotherapy, different delivery systems of immunotherapy (SLIT, EPIT) are being studied in addition to probiotics, biologic agents - used as monotherapy and as an adjunct, and modified allergens has taken place with the hope to further enhance existing therapeutic options. The hope through these continued developments is for therapies to emerge that will provide a more comprehensive benefit to this patient population.

There has been rapid growth in the field of immunoglobulin E-mediated food allergy therapeutics, with 1 US Food and Drug Administration-approved therapy in 2020 and several others in various stages of investigation. Oral immunotherapy is the approach with the longest track record of study and provides desensitization for most individuals undertaking the therapy. However, the therapy must be maintained for continued clinical protection, and adverse effects of the therapy are frequent. There is a need to improve allergen immunotherapy safety and durability and to provide a treatment that can target multiple food allergies. In this review, we discuss novel adjunct therapies that may improve safety, such as omalizumab, Bruton's tyrosine kinase inhibitors, and agonists of sialic acid-binding immunoglobulin-like lectin-8, which suppress hypersensitivity responses. We also discuss approaches that may improve magnitude or durability of the treatment response, such as dupilumab and Janus kinase 1 inhibitors.

Anaphylaxis is an acute, potentially life-threatening systemic allergic reaction for which there are no known reliable preventative therapies. Its primary cell mediator, the mast cell, has several pathophysiologic roles and functions in IgE-mediated reactions that continue to be poorly understood. Recent advances in the understanding of allergic mechanisms have identified novel targets for inhibiting mast cell function and activation. The prevention of anaphylaxis is within reach with new drugs that could modulate immune tolerance, mast cell proliferation and differentiation, and IgE regulation and production. Several US Food and Drug Administration-approved drugs for chronic urticaria, mastocytosis, and cancer are also being repurposed to prevent anaphylaxis. New therapeutics have not only shown promise in potential efficacy for preventing IgE-mediated reactions, but in some cases, they are able to inform us about mast cell mechanisms in vivo. This review summarizes the most recent advances in the treatment of anaphylaxis that have arisen from new pharmacologic tools and our current understanding of mast cell biology.

A better understanding of the most recent scientific literature in the use of biological therapy in the treatment of patients with IgE-mediated food allergy.

A systematic review and meta-analysis demonstrated safety and effectiveness of omalizumab in the treatment of food allergy. The findings support the potential use of omalizumab as a monotherapy or as an adjunct to oral immunotherapy in IgE-mediated cow's milk allergy. The potential use of other biologics in the management of food allergy is subject of speculation.

Different biological therapies are under evaluation for food allergic patients. The advance in literature will guide for a personalized treatment in the near future. However, additional research is needed to better understand the best candidate for each treatment, the optimal dose and timing.

Mast cells act as key effector cells of inflammatory responses through degranulation. Mast cell degranulation is induced by the activation of cell surface receptors, such as FcεRI, MRGPRX2/B2, and P2RX7. Each receptor, except FcεRI, varies in its expression pattern depending on the tissue, which contributes to their differing involvement in inflammatory responses depending on the site of occurrence. Focusing on the mechanism of allergic inflammatory responses by mast cells, this review will describe newly identified mast cell receptors in terms of their involvement in degranulation induction and patterns of tissue-specific expression. In addition, new drugs targeting mast cell degranulation for the treatment of allergy-related diseases will be introduced.

IgE-mediated food allergy affects 6-8% of the population in the United States. Type 2 immune responses are central to the pathogenesis of food allergy, but type 2 CD4+ T cell responses have been found to be heterogeneous in food allergy suggesting a division of labor between Tfh13 and peTH2 cells in promotion of IgE class switching, modulation of intestinal barrier function, and regulation of mast cell expansion. Oral immunotherapy for the treatment of food allergy incompletely targets subsets of type 2 immunity in a transient manner, but new therapeutics targeting different levels of type 2 immunity are in current or planned trials for food allergy. These new treatments and the basis for their use are the focus of this review.

Continuing insight into the molecular mechanisms of atopic disorders has enabled the development of biologics to precisely target these diseases. Food allergy (FA) and eosinophilic gastrointestinal disorders (EGIDs) are driven by similar inflammatory molecular mechanisms and exist along the same atopic disease spectrum. Therefore, many of the same biologics are being investigated to target key drivers of mechanisms shared across the disease states. The enormous potential of biologics for the treatment of FA and EGIDs is highlighted by the significant increases in the number of ongoing clinical trials (more than 30) evaluating their use in these disease states, as well as by the recent US Food and Drug Administration approval of dupilumab for the treatment of eosinophilic esophagitis. Here we discuss past and current research into the use of biologics in FA and EGIDs and their potential role in improving treatment options in the future, with the need to have biologics widely clinically available.

Oral immunotherapy (OIT) is now recognized as an alternative active treatment to strict food avoidance in certain patients with IgE-mediated food allergy. Studies have confirmed the efficacy of OIT to desensitize children with allergy to cow's milk, eggs, and peanuts. The benefits, risks, and constraints of OIT are becoming increasingly well understood. However, there is no consensual criteria to select patients to whom OIT could be proposed, and many issues remain to address including the definitions of desensitization and long-term efficacy, the assessment of patient's experience in real life, the optimization of buildup and maintenance protocols, and the utility of multiple food OIT. The recent authorization by medical agency concerning the first medicine for peanut OIT is a step forward towards higher standardization in the practice of OIT. This article summarizes in comprehensive narrative format data on efficacy, tolerance, impact on quality of life and adverse effects of OIT and discuss elements to consider in clinical practice before starting OIT.

Asthma, chronic urticaria, and atopic dermatitis are some of the most numerous allergic diseases affecting children. Recent advances in the understanding of their specific intracellular molecular pathways have led to the approval of monoclonal antibodies targeting definite inflammatory molecules in order to control symptoms and improve quality of life. Less is known about other allergic and immunologic disorders such as rhinosinusitis with nasal polyps, eosinophilic esophagitis, anaphylaxis, and food allergy undergoing allergen immunotherapy. The increasing evidence of the molecular mechanisms underlying their pathogeneses made it possible to find in children new indications for known biological drugs, such as omalizumab and dupilumab, and to develop other ones even more specific. Promising results were recently obtained, although few are currently approved in the pediatric population. In this review, we aim to provide the latest evidence about the role, safety, and efficacy of biologic agents to treat allergic and immunologic diseases in children.

In patients with wheat-dependent exercise-induced anaphylaxis (WDEIA), anaphylactic shock occurs frequently, therefore avoidance of wheat products is recommended. We aimed to evaluate efficacy and safety of long-term omalizumab treatment for adult patients with WDEIA.

In this phase 2, multicentre single-arm trial, 20 adult patients with WDEIA were enrolled (UMIN 000019250). All patients were administered 150-600 mg of omalizumab subcutaneously and evaluations (basophil activation and blood examination) were performed at regular intervals during administration period (0-48 weeks) and observation period (48-68 weeks). Primary endpoint was proportion of the patients who achieved a basophil activation rate below 10% with fractionated wheat preparations, and secondary endpoint was proportion of the patients with no allergic reactions after wheat products ingestion.

During the omalizumab treatment, more than 80% of the patients achieved the basophil activation rate less than 10% against all fractionated wheat preparations, and 68.8% of the patients who achieved the primary endpoint experienced no allergic reaction. During the observation period, the proportion of the patients who achieved a basophil activation rate below 10% decreased gradually, and the proportion of patients with positive allergic reactions increased gradually thereafter and reached maximum of 46.7%. Severe adverse events were not observed during the study.

Long-term omalizumab treatment is safe and effective for adult patients with WDEIA when assessed by basophil activation rate with wheat allergens as well as allergic reactions after lifting of restrictions on wheat intake. However, this is not enough to achieve desensitization.

Peanut oral immunotherapy (POIT) has emerged as an active management option for peanut allergy, with an FDA-approved product now available for therapy. Allergic reactions, including anaphylaxis, can occur during therapy and their management is key in optimizing this treatment and patient outcomes.

In this manuscript, we will review the rates of allergic reactions and anaphylaxis in seminal peanut oral immunotherapy research studies. We will examine factors that can alter the risk of anaphylaxis and describe various strategies, including adjunct therapies, that have the potential to mitigate anaphylaxis risk based on published evidence.

Rates of anaphylaxis and epinephrine administration vary in different research studies, but there is consensus that most POIT-related allergic reactions are mild or moderate and not severe. Certain external factors (for example, tiredness, exercise, viral illness) as well as uncontrolled allergic co-morbidities (asthma, allergic rhinitis) have been shown to increase the risk of anaphylaxis during OIT. The search of biomarkers who may predict who is at risk for severe allergic reactions is ongoing. Adjunct therapies have shown promise, but further studies are required to optimize their use alongside POIT. Our understanding of anaphylaxis during POIT has increased in recent years, resulting in better management strategies. However, future plans will need to involve all stakeholders, including physicians, patients and families, researchers, public health authorities, and the food, hospitality, and catering industries.

Peanut allergy (PA) is a common, burdensome childhood disease that in most patients continues into adulthood and has historically been untreatable. However, peanut oral immunotherapy (POIT) is increasingly being incorporated into allergy practices, using both the first FDA-approved product, PTAH (previously AR101; Palforzia™, Aimmune Therapeutics), as well as store-bought peanut products. POIT in preschoolers continues to gain more acceptance as evidence accrues that it is a safe and feasible approach that may have distinct advantages. There are many new therapeutic interventions currently under study with a variety of different approaches and potential mechanisms. With respect to other forms of immunotherapy, none are currently approved, but the epicutaneous approach is the most well-studied and others are being actively investigated, including sublingual, subcutaneous, and intralymphatic. Biologics are gaining evidence both as adjunctive treatments to POIT and as monotherapy. Omalizumab is the most widely studied biologic for PA but others also have potential. Looking ahead to a future therapeutic landscape of choice, allergists will need to understand each patient's goal of treatment through shared decision-making and fully evaluate the risks, benefits, and alternatives of each new therapy.

A growing number of studies have shown encouraging results with omalizumab (OMA) as monotherapy and as an adjunct to oral immunotherapy (OMA+OIT) in patients with single/multiple food allergies.

To evaluate the efficacy and safety of OMA or OMA+OIT in patients with immunoglobulin E (IgE)-mediated food allergy.

An extensive literature search (inception to December 31, 2020) was performed to identify randomized, controlled, and observational studies that assessed OMA as monotherapy or OMA+OIT in patients with IgE-mediated food allergy. The outcomes were an increase in tolerated dose of foods, successful desensitization, sustained unresponsiveness, immunological biomarkers, severity of allergic reactions to food, quality of life (QoL), and safety. A P less than .05 was considered significant.

In total, 36 studies were included. The OMA monotherapy (vs pre-OMA) significantly increased the tolerated dose of multiple foods; increased the threshold of tolerated dose for milk, egg, wheat, and baked milk; improved QoL; and reduced food-induced allergic reactions (all P < .01). The OMA+OIT significantly increased the tolerated dose of multiple foods (vs placebo and pre-OMA), desensitization (vs placebo+OIT and pre-OMA) (all P ≤ .01), and improved QoL (vs pre-OMA) and immunoglobulin G4 levels (both P < .01). No major safety concerns were identified.

In IgE-mediated food allergy, OMA can help patients consume multiple foods and allow for food dose escalation. As an adjunct to OIT, OMA can also support high-dose desensitization and higher maintenance doses. Further studies are warranted to empirically evaluate the effect of OMA and confirm these findings.

Sesame allergy is the most prevalent allergy to seeds. Oral immunotherapy (OIT) is defined as continuous consumption of an allergen at special doses and time. Omalizumab (Anti-IgE) increases tolerance to allergens used in OIT. This study evaluated the effectiveness of a new sesame OIT protocol in patients with sesame anaphylaxis in combination with omalizumab.

In this prospective open-label interventional trial study, 11 patients with a history of sesame anaphylaxis were enrolled after confirmation by oral food challenge (OFC) test. At baseline, skin prick test (SPT) and skin prick to prick (SPP) test were performed. Serum sesame-specific IgE (sIgE) levels were measured. The maintenance phase was continued at home with daily sesame intake for 4 months. At the end of month 4, the OFC and above-mentioned tests were repeated to evaluate the treatment effectiveness.

All 11 patients who underwent sesame OIT after 4 months could tolerate a dietary challenge of 22 ml tahini (natural sesame seed, equal to 5,000 mg of sesame protein and higher) and the average of wheal diameter in the SPT and SPP tests significantly decreased after desensitization.

This OIT protocol may be a promising desensitization strategy for patients with sesame anaphylaxis. Also, omalizumab appears to have reduced the severity of reactions.

The unique characteristics of camelid heavy-chain only antibody (HCAb) derived nanobodies (Nbs) have facilitated their employment as tools for research and application in extensive fields including food safety inspection, diagnosis and therapy of diseases, etc., to develop immune detecting techniques or alternative candidates of conventional antibodies as diagnostic and therapeutic reagents. The wide application in the fields of food allergen inspection and immunotherapy has not been addressed as not much results published in the literature. The robust properties and straightforward selecting strategy of Nbs impel the advantageous employment compared with monoclonal antibodies (mAbs) to establish immunoassay and serve as blocking antibodies to compete immunoglobulin E (IgE) binding epitopes on food allergens. More and more efforts have been invested to develop specific Nbs against food allergen proteins, such as macadamia allergen of Mac i 1, peanut allergen of Ara h 3, and lupine allergen of Lup an 1, which demonstrated the potential of Nbs for research and application in food allergen surveillance. Meanwhile, the paratopes of Nbs preferably targeting the unique epitopes of food allergens can provide more possibilities to serve as blocking antibodies to shield IgE binding epitopes for food allergy immunotherapy. Regardless, the research and application of Nbs in the field of food allergen and allergic reactions are expected to attract dramatic focus and produce promising research outputs.

Oral immunotherapy (OIT), thus far, is the most evaluated therapeutic approach for food allergy. However, OIT is not known to lead to a cure, and it carries a risk for allergic reactions. Adjunct therapies to OIT are currently being investigated to evaluate their effect on safety and outcome. Of these therapies, omalizumab is the most evaluated biologic. There is mounting evidence that omalizumab is effective in inducing rapid desensitization of OIT in both single-food and multiallergen OIT, while diminishing the rate of adverse reactions. Evaluation of other adjunct biologics, such as dupilumab and bacterial therapy, is underway.

Oral immunotherapy (OIT) protocols are not standardized, and a wide heterogeneity exists in the literature. OIT protocol variables include the initiation approach (fixed dose versus oral food challenge), buildup speed (slow versus fast), target maintenance dose (low versus high target dose), type of food used, and use of adjuvants among other variables. Most protocols start with an initial escalation day, which is a series of extremely low doses to safely identify the patients who are most allergic, followed by a buildup period over several months to years until the final target maintenance dose is achieved. Doses are generally increased every 1-2 weeks by a factor of 1.25 to 2 and are adapted based on the patient's symptoms. Protocols are increasingly favoring low-maintenance doses over traditional high maintenance doses, although this needs to be discussed and adapted based on the patient's preferences. Accelerated OIT schedules with using a short treatment of omalizumab can be considered in severe food allergy cases.

Immunotherapy is promising as an efficacious treatment for food allergy. Other food allergy treatments are also under development. However, adverse allergic events during treatment, as well as during oral food challenges, are common and reporting is not standardized.

A more nuanced grading scale is needed to create a comprehensive and universal system to categorize adverse events and their severity for food allergy clinical trials.

Starting with the 2012 Consortium for Food Allergy Research (CoFAR) Grading Scale and the World Allergy Organization Grading System, we developed the CoFAR Grading Scale for Systemic Allergic Reactions, Version 3.0, in collaboration with industry partners with expert opinion.

The revised CoFAR Grading Scale for Systemic Allergic Reactions has 5 levels of increasing severity, ranging from generalized urticaria, localized angioedema, rhinitis, and abdominal pain (grade 1) to death (grade 5). Systemic reactions are further categorized within each grade by relevant organ system. Mild, single-system reactions are differentiated from mild, multisystem reactions. Lower respiratory tract symptoms are graded on the basis of response to therapy; those that are refractory to standard treatment (eg, requiring >3 doses of intramuscular epinephrine, continuous intravenous epinephrine infusion, and continuous albuterol nebulization) and respiratory compromise requiring mechanical ventilation are classified as grade 4, life-threatening reactions.

Universal and consistent use of the revised CoFAR Grading Scale beyond the CoFAR centers would allow for better data aggregation and safety comparisons in clinical trials for food allergy.

Food allergy in children is a major health concern, and its prevalence is rising. It is often over-diagnosed by parents, resulting occasionally in unnecessary exclusion of some important food. It also causes stress, anxiety, and even depression in parents and affects the family's quality of life. Current diagnostic tests are useful when interpreted in the context of the clinical history, although cross-sensitivity and inability to predict the severity of the allergic reactions remain major limitations. Although the oral food challenge is the current gold standard for making the diagnosis, it is only available to a small number of patients because of its requirement in time and medical personnel. New diagnostic methods have recently emerged, such as the Component Resolved Diagnostics and the Basophil Activation Test, but their use is still limited, and the latter lacks standardisation. Currently, there is no definite treatment available to induce life-long natural tolerance and cure for food allergy. Presently available treatments only aim to decrease the occurrence of anaphylaxis by enabling the child to tolerate small amounts of the offending food, usually taken by accident. New evidence supports the early introduction of the allergenic food to infants to decrease the incidence of food allergy. If standardised and widely implemented, this may result in decreasing the prevalence of food allergy.

In recent years, off-label and unlicensed drug use has extensively developed in the paediatric population. For a long time, clinical trials in the paediatric population were considered complicated to perform because of ethical problems, causing frequent off-label use. Off-label drug use remains an important public health issue, especially for children with rare conditions or with diseases not responsive to conventional treatments. The present paper is a narrative review of the literature of off-label drug use in children. The aim of our study is to summarize the main works dealing with the off-label use of biological drugs in paediatrics. Further studies analyzing their efficacy, safety, and cost-benefit ratios are needed to extend the use of biological therapies to the paediatric population.

The prevalence of cow's milk allergy (CMA) is approximately 2-4.5% in infants and less than 0.5% in adults. Most children outgrow cow's milk allergy in early childhood, particularly that to the baked milk products. Immunotherapy with unheated cow's milk has been used as a treatment option for those who have not yet outgrown CMA, but the benefits must be balanced with the adverse effects.

These evidence-based guidelines from the World Allergy Organization (WAO) intend to support patients, clinicians, and others in decisions about the use of oral and epicutaneous immunotherapy for the treatment of IgE-mediated CMA.

WAO formed a multidisciplinary guideline panel balanced to include the views of all stakeholders and to minimize potential biases from competing interests. The McMaster University GRADE Centre supported the guideline-development process, including updating or performing systematic evidence reviews. The panel prioritized clinical questions and outcomes according to their importance for clinicians and patients. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach was used, including GRADE Evidence-to-Decision frameworks, which were subject to public comment.

After a careful review of the summarized evidence and thorough discussions the WAO guideline panel suggests: a) using oral immunotherapy with unheated cow's milk in those individuals with confirmed IgE-mediated CMA who value the ability to consume controlled quantities of milk more than avoiding the large adverse effects of therapy, b) not using oral immunotherapy with unheated cow's milk in those who value avoiding large adverse effects of therapy more than the ability to consume controlled quantities of milk, c) using omalizumab in those starting oral immunotherapy with unheated cow's milk, d) not using oral immunotherapy with baked cow's milk in those who do not tolerate both unheated and baked milk, and e) not using epicutaneous immunotherapy outside of a research setting. The recommendations are labeled "conditional" due to the low certainty about the health effects based on the available evidence.

Clinicians, patients, and their family members might want to discuss all the potential desirable and undesirable effects of oral immunotherapy for IgE-mediated CMA and integrate them with the patients' values and preferences before deciding on a treatment option. More robust research is needed to determine with greater certainty which interventions are likely to be the most beneficial with the least harms, and to develop safer, low-cost, and equitable treatments.