Immunotherapy and biologics in the management of IgE-mediated food allergy: Systematic review and meta-analyses of efficacy and safety.

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. POPULATION: Human adults, children, and adolescents with IgE-mediated FA. INTERVENTION: IT and/or biologics. COMPARATOR: Placebo or standard-of-care (allergen avoidance). OUTCOME: 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.

Core Outcome Set for IgE-mediated food allergy clinical trials and observational studies of interventions: International Delphi consensus study 'COMFA'.

BACKGROUND: IgE-mediated food allergy (FA) is a global health concern with substantial individual and societal implications. While diverse intervention strategies have been researched, inconsistencies in reported outcomes limit evaluations of FA treatments. To streamline evaluations and promote consistent reporting, the Core Outcome Measures for Food Allergy (COMFA) initiative aimed to establish a Core Outcome Set (COS) for FA clinical trials and observational studies of interventions. METHODS: The project involved a review of published clinical trials, trial protocols and qualitative literature. Outcomes found as a result of review were categorized and classified, informing a two-round online-modified Delphi process followed by hybrid consensus meeting to finalize the COS. RESULTS: The literature review, taxonomy mapping and iterative discussions with diverse COMFA group yielded an initial list of 39 outcomes. The iterative online and in-person meetings reduced the list to 13 outcomes for voting in the formal Delphi process. One more outcome was added based on participant suggestions after the first Delphi round. A total of 778 participants from 52 countries participated, with 442 participating in both Delphi rounds. No outcome met a priori criteria for inclusion, and one was excluded as a result of the Delphi. Thirteen outcomes were brought to the hybrid consensus meeting as a result of Delphi and two outcomes, 'allergic symptoms' and 'quality of life' achieved consensus for inclusion as 'core' outcomes. CONCLUSION: In addition to the mandatory reporting of adverse events for FA clinical trials or observational studies of interventions, allergic symptoms and quality of life should be measured as core outcomes. Future work by COMFA will define how best to measure these core outcomes.

Diagnosis and Management of Pollen Food Allergy Syndrome to Nuts.

Oral allergy syndrome or pollen food allergy syndrome (PFAS) represents a common clinical conundrum when the reported trigger food is a tree nut (usually almond or hazelnut) or peanut. The PFAS may give rise to uncertainty about the potential severity of the future reactions, indications for prescribing epinephrine, and the extent of the necessary dietary avoidance. As a food allergy, secondary to cross-reactivity with airborne pollen, PFAS usually manifests toward the end of the first decade of life as contact urticaria of the oropharyngeal mucous membranes. Molecular allergology facilitates diagnosis and risk stratification by establishing the profile of sensitization. Exclusive sensitization to pathogenesis-related proteins family 10 (PR10) and profilins indicates that signs and symptoms are due to PFAS, whereas sensitization to seed storage proteins with or without sensitization to PR10 and profilins may indicate a more severe primary nut allergy phenotype. Management relies on avoidance of the specific nut trigger, advice on the likelihood of more severe local or systemic symptoms, and treatment of reactions according to the severity. Future studies are needed to better delineate the risk of systemic reactions in individuals with nut PFAS and to establish the role of food or pollen allergen immunotherapy for the prevention or moderation of this condition.

Systematic review and meta-analyses on the accuracy of diagnostic tests for IgE-mediated food allergy.

The European Academy of Allergy and Clinical Immunology (EAACI) is updating the Guidelines on Food Allergy Diagnosis. We aimed to undertake a systematic review of the literature with meta-analyses to assess the accuracy of diagnostic tests for IgE-mediated food allergy. We searched three databases (Cochrane CENTRAL (Trials), MEDLINE (OVID) and Embase (OVID)) for diagnostic test accuracy studies published between 1 October 2012 and 30 June 2021 according to a previously published protocol (CRD42021259186). We independently screened abstracts, extracted data from full texts and assessed risk of bias with QUADRAS 2 tool in duplicate. Meta-analyses were undertaken for food-test combinations for which three or more studies were available. A total of 149 studies comprising 24,489 patients met the inclusion criteria and they were generally heterogeneous. 60.4% of studies were in children ≤12 years of age, 54.3% were undertaken in Europe, ≥95% were conducted in a specialized paediatric or allergy clinical setting and all included oral food challenge in at least a percentage of enrolled patients, in 21.5% double-blind placebo-controlled food challenges. Skin prick test (SPT) with fresh cow's milk and raw egg had high sensitivity (90% and 94%) for milk and cooked egg allergies. Specific IgE (sIgE) to individual components had high specificity: Ara h 2-sIgE had 92%, Cor a 14-sIgE 95%, Ana o 3-sIgE 94%, casein-sIgE 93%, ovomucoid-sIgE 92/91% for the diagnosis of peanut, hazelnut, cashew, cow's milk and raw/cooked egg allergies, respectively. The basophil activation test (BAT) was highly specific for the diagnosis of peanut (90%) and sesame (93%) allergies. In conclusion, SPT and specific IgE to extracts had high sensitivity whereas specific IgE to components and BAT had high specificity to support the diagnosis of individual food allergies.

Nomenclature of allergic diseases and hypersensitivity reactions: Adapted to modern needs: An EAACI position paper.

The exponential growth of precision diagnostic tools, including omic technologies, molecular diagnostics, sophisticated genetic and epigenetic editing, imaging and nano-technologies and patient access to extensive health care, has resulted in vast amounts of unbiased data enabling in-depth disease characterization. New disease endotypes have been identified for various allergic diseases and triggered the gradual transition from a disease description focused on symptoms to identifying biomarkers and intricate pathogenetic and metabolic pathways. Consequently, the current disease taxonomy has to be revised for better categorization. This European Academy of Allergy and Clinical Immunology Position Paper responds to this challenge and provides a modern nomenclature for allergic diseases, which respects the earlier classifications back to the early 20th century. Hypersensitivity reactions originally described by Gell and Coombs have been extended into nine different types comprising antibody- (I-III), cell-mediated (IVa-c), tissue-driven mechanisms (V-VI) and direct response to chemicals (VII). Types I-III are linked to classical and newly described clinical conditions. Type IVa-c are specified and detailed according to the current understanding of T1, T2 and T3 responses. Types V-VI involve epithelial barrier defects and metabolic-induced immune dysregulation, while direct cellular and inflammatory responses to chemicals are covered in type VII. It is notable that several combinations of mixed types may appear in the clinical setting. The clinical relevance of the current approach for allergy practice will be conferred in another article that will follow this year, aiming at showing the relevance in clinical practice where various endotypes can overlap and evolve over the lifetime.

Food allergy-A holistic approach to dietary management. A joint EAACI Research & Outreach Committee and INDANA review.

Following a diagnosis of IgE-mediated food allergy, to secure the best outcome, the patient should receive individualized advice tailored to their specific needs, which considers the type and presentation of the food involved, level of exclusion required, risk of cross-contamination and any variance required for age, ethnicity, financial issues, and lifestyle. Issues such as food labels "may contain" statements, and variation in the threshold of reaction and impact of cofactors should also be considered. Most important is the need to ensure that the diagnosis is robust, especially given the nutritional, psychological, and socioeconomic issues that can affect an individual with a diagnosis of food allergy. Unnecessary exclusion of one or more foods that have not triggered allergic reactions, especially in individuals with allergic comorbidities, can result in severe IgE-mediated reactions on re-exposure. Given that food allergies may change over time, the diagnosis should be reviewed, to determine whether resolution is likely, or new-food triggers are reported. Regular assessment is vital, especially during childhood, to ensure reintroduction occurs at an appropriate time, thus enabling increased diversity of the diet and improvement in the quality of life. For some, an IgE-mediated food allergy may necessitate the life-long exclusion of foods, and for others, a food habitually eaten suddenly triggers an allergic reaction in adult life. People of all ages, ethnicities, and socioeconomic backgrounds deserve individual advice on the management of their food allergy to support a healthy diet and improve quality of life.

New arrivals in anaphylaxis to foods.

PURPOSE OF REVIEW: More people are excluding wheat from their diet, or turning to a more sustainable diet in which includes meat substitutes or is mainly or wholly plant-based. This increases the availability of new foods and with it the increasing likelihood of novel allergens. RECENT FINDINGS: There is a growing body of evidence which suggests that allergies to seeds and legumes are increasing potentially due to their use in concentrated form in vegan or health foods. Insects can be a sustainable source of protein, but mealworm could provoke symptoms in individuals sensitized or allergic to shellfish or house dust mite. Novel plant food allergens such as gibberellin-regulated proteins and thaumatin-like proteins are increasingly being reported as significant causes of severe reactions to fruits. SUMMARY: these findings make it even more imperative to take a full dietary history to ensure apparent idiopathic anaphylaxis is not in reality due to a novel food, especially in cases where other forms of the food are tolerated. Given the lack of diagnostic tests for these novel foods, a prick-to-prick skin prick test should be performed with the suspected food. There is currently more work needed to define and sequence many of the allergens involved.

Addressing educational gaps through multidisciplinary team education in eosinophilic oesophagitis management.

Once considered a rare disease, eosinophilic oesophagitis (EoE) is becoming increasingly prevalent, yet many healthcare professionals (HCPs) remain unfamiliar with the underlying pathophysiology and optimal management approaches. For this study, we developed a faculty-led, online, continuing medical education activity on EoE. The effectiveness of this activity was evaluated according to Moore's framework, with changes in knowledge and competence (Moore's Levels 3 and 4) assessed for a cohort of gastroenterologists, dietitians, allergists and immunologists (N = 300), using questionnaires completed before and after participation. Changes in HCP confidence in treating EoE were also reported and remaining educational gaps were identified. The activity was viewed by a global audience of 5,330 participants within 6 months, and significant improvements in knowledge and competence were reported following participation in the activity across all specialities, regions and experience (mean [standard deviation] score pre- versus post-activity: 4.32 [1.38] versus 5.46 [0.82]; p < 0.001). Confidence in treating EoE also increased from pre- to post-activity, with the proportion of participants reporting that they felt moderately or extremely confident increasing from 53% to 82%. Several educational unmet needs were identified, which can be used to inform the design of future educational activities in EoE.

Hidden and Rare Food Allergens in Pediatric Age.

In food allergy management, the avoidance of the allergen that caused the reaction plays a fundamental role. Nevertheless, that can be thwarted in case of accidental exposure to a rare or hidden allergen, causing the adoption of a monotonous diet and a consequent reduction in the quality of life of the patient and their family. The identification of a rare and hidden allergen is an important diagnostic challenge, taking into account that a significant proportion of all food reactions is in reality due to them. The aim of the present review is to provide the pediatric allergist an overview of the possible sources of rare and hidden food allergens, taking into consideration the routes of exposure to these potential allergens with the main examples published in the scientific literature and the distinction between types of direct or cross-contamination. The identification of the allergen responsible for the reaction and the provision of a dietary advice customized for the specific individual's dietary habits is essential to improve quality of life of the familiar nucleus and to reduce the risk of further allergic reactions.

The immune-supportive diet in allergy management: A narrative review and proposal.

The role of nutrition is increasingly recognized in the management of chronic immune diseases. However, the role of an immune-supportive diet as adjuvant therapy in the management of allergic disease has not been similarly explored. This review assesses the existing evidence for a relationship between nutrition, immune function, and allergic disease from a clinical perspective. In addition, the authors propose an immune-supportive diet to enhance dietary interventions and complementing other therapeutic options for allergic disease from early life to adulthood. A narrative review of the literature was conducted, to determine the evidence of the relationship between nutrition and immune function, overall health, epithelial barrier function, and gut microbiome, particularly in relation to allergy. Studies on food supplements were excluded. The evidence was assessed and utilized to develop a sustainable immune-supportive diet to complement other therapies in allergic disease. The proposed diet consists of a highly diverse range of fresh, whole, and minimally processed plant-based and fermented foods supplemented with moderate amounts of nuts, omega-3-rich foods and animal-based products in proportional amounts of the EAT-Lancet diet, such as (fatty) fish, (fermented) milk products which may be full-fat and eggs, lean meat or poultry, which may be free-range or organic.

A review of cannabis allergy in the early days of legalization.

Cannabis allergy is a burgeoning field; consequently, research is still in its infancy and allergists' knowledge surrounding this topic is limited. As cannabis legalization expands across the world, it is anticipated that there will be an increase in cannabis use. Thus, we hypothesize that a concomitant rise in the incidence of allergy to this plant can be expected. Initiatives aimed at properly educating health care professionals are therefore necessary. This review presents the most up-to-date information on a broad range of topics related to cannabis allergy. Although the clinical features of cannabis allergy are becoming more well described and recognized, the tools available to make a correct diagnosis are meager and often poorly accessible. In addition, research on cannabis allergy is still taking its first steps, and new and potentially groundbreaking findings in this field are expected to occur in the next few years. Finally, although therapeutic approaches are being developed, patient and physician education regarding cannabis allergy is certainly needed.

Anaphylaxis across Europe: are pollen food syndrome and lipid transfer protein allergy so far apart?

PURPOSE OF REVIEW: Traditionally pollen-food syndrome (PFS) is considered to be a mild cross-reacting food allergy affecting only Northern Europe, with lipid transfer protein (LTP) allergy being more severe and mainly occurring in Southern Europe. This review seeks to update the reader on both types of plant food allergy and to determine whether the stereotypical presentations of these plant food allergies remain the same, with a particular focus on reaction severity. RECENT FINDINGS: Recent findings suggest that both these types of plant food allergy occur in children and adults. Although it is true that PFS allergy is more prevalent in Northern Europe and LTP allergy is more well known in Southern Europe, these conditions are not hidebound by geography, and the increasing spread and allergenicity of pollen due to global warming continues to change their presentation. Both conditions have a spectrum of symptom severity, with PFS sometimes presenting with more severe symptoms, including anaphylaxis and LTP allergy with milder reactions. SUMMARY: It is important to consider that in many parts of Europe, reactions to plant foods, especially fruits or vegetables, could be mediated either by pollen cross-reactivity or primary sensitization to LTP allergens. All those presenting with symptoms to plant foods will benefit from a detailed clinical history and appropriate tests so that an accurate diagnosis can be made, and correct management implemented.

BSACI guideline for the diagnosis and management of pollen food syndrome in the UK.

Pollen food syndrome (PFS) is a highly prevalent food allergy affecting pollen-sensitized children and adults. Sufferers experience allergic symptoms when consuming raw plant foods, due to the homology between the pollen allergens and unstable proteins in these foods. The triggers involved can vary depending on the pollen sensitization, which in turn is affected by geographical location. The British Society of Allergy and Clinical Immunology (BSACI) Standards of Care Committee (SOCC) identified a need to develop a guideline for the diagnosis and management of PFS in the United Kingdom (UK). Guidelines produced by the BSACI use either the GRADE or SIGN methodology; due to a lack of high-quality evidence these recommendations were formulated using the SIGN guidelines, which is acknowledged to be less robust than the GRADE approach. The correct diagnosis of PFS ensures the avoidance of a misdiagnosis of a primary peanut or tree nut allergy or confusion with another plant food allergy to non-specific lipid transfer proteins. The characteristic foods involved, and rapid-onset oropharyngeal symptoms, mean PFS can often be diagnosed from the clinical history alone. However, reactions involving tree nuts, peanuts and soya milk or severe/atypical reactions to fruits and vegetables may require additional diagnostic tests. Management is through the exclusion of known trigger foods, which may appear to be simple, but is highly problematic if coupled with a pre-existing food allergy or for individuals following a vegetarian/vegan diet. Immunotherapy to pollens is not an effective treatment for PFS, and although oral or sublingual immunotherapy to foods seems more promising, large, controlled studies are needed. The typically mild symptoms of PFS can lead to an erroneous perception that this condition is always easily managed, but severe reactions can occur, and anxiety about the onset of symptoms to new foods can have a profound effect on quality of life.

Effects of Exercise and Sleep Deprivation on Reaction Severity During Oral Peanut Challenge: A Randomized Controlled Trial.

BACKGROUND: The severity of allergic reactions to foods can vary markedly. Little is known of variations in reaction severity within or between individuals or the effects of cofactors. OBJECTIVE: We examined the effects of sleep deprivation and exercise and repeat challenges on the severity and patterns of allergic reactions to peanut. METHODS: In a randomized crossover study, adults with peanut allergy underwent 3 open peanut challenges in random order: with exercise after each dose, with sleep deprivation preceding challenge, and with no intervention. The primary outcome was eliciting dose, reported elsewhere. Reaction severity was a secondary outcome, evaluated using a weighted log-transformed numerical severity score. Analyses estimated the difference in severity between nonintervention challenge and challenges with exercise or sleep deprivation, adjusting for challenge order and using the highest dose tolerated by each individual across all their challenges. Symptom pattern reproducibility was assessed by comparing symptom sequences using pairwise sequence alignment to obtain a percentage match in symptom pattern. RESULTS: Eighty-one participants (mean age 25 y) completed at least 1 postbaseline challenge. Sleep deprivation, but not exercise, significantly increased severity score by 48% (95% CI 12%-84%; P = .009) compared with no intervention. A 38% increase in severity was observed between the first and the last postbaseline challenge (95% CI 1%-75%; P = .044). The average pairwise match of symptoms within individuals was 82.4% and across individuals was 78.3%. CONCLUSIONS: A novel severity score demonstrates that sleep deprivation and repeated challenges increase reaction severity. Understanding factors affecting severity is essential for effective risk management. We also show that symptom patterns in repeat peanut challenges are similar within and between individuals.

Impact of cannabis knowledge and attitudes on real-world practice.

BACKGROUND: Increased cannabis consumption worldwide challenges allergists because of an upsurge in cannabis allergy and need to discuss cannabis with patients. OBJECTIVE: To determine the knowledge, attitudes, and practices regarding cannabis among allergists and their approach to recognizing and diagnosing suspected cannabis allergy. METHODS: The International Allergist Canna Knowledge, Attitudes, and Practices Survey was completed by members from 3 International Allergy Societies. Survey questions included the following: 13 on cannabis attitudes, 7 on cannabis knowledge, and 4 on real-world allergy practices. Knowledge level was dichotomized and Statistical Package for the Social Sciences TwoStep Cluster Analysis grouped participants by attitudes. Multivariate analysis determined the relationship of knowledge and attitude to practice delivery. RESULTS: Of 570 eligible surveys started, 445 (78.1%) were completed. Participants were 49.7% of female sex, 65.9% aged 24 to 56 years, approximately 70% in practice for more than or equal to 10 years, and 29.2% practicing in an area where cannabis use is illegal. Of the respondents, 43.1% reported consulting on patients with suspected cannabis allergy and 54.7% had undertaken skin prick testing, in vitro cannabis testing, or both. Statistically significant differences were found between the 3 societies for most variables analyzed. Analysis of attitudes revealed 3 clusters named Traditional, Progressive, and Unsure. Those with more progressive attitudes toward cannabis and who had more knowledge were more comfortable speaking to patients about cannabis and more often asked patients on how often and how they used cannabis (all P < .001). CONCLUSION: Varying knowledge and attitudes toward cannabis affecting comfort communicating with patients about cannabis were found in members of 3 allergy societies supporting the need for more cannabis research and education.

Cannabis-related allergies: An international overview and consensus recommendations.

Cannabis is the most widely used recreational drug in the world. Cannabis sativa and Cannabis indica have been selectively bred to develop their psychoactive properties. The increasing use in many countries has been accelerated by the COVID-19 pandemic. Cannabis can provoke both type 1 and type 4 allergic reactions. Officially recognized allergens include a pathogenesis-related class 10 allergen, profilin, and a nonspecific lipid transfer protein. Other allergens may also be relevant, and recognition of allergens may vary between countries and continents. Cannabis also has the potential to provoke allergic cross-reactions to plant foods. Since cannabis is an illegal substance in many countries, research has been hampered, leading to challenges in diagnosis since no commercial extracts are available for testing. Even in countries such as Canada, where cannabis is legalized, diagnosis may rely solely on the purchase of cannabis for prick-to-prick skin tests. Management consists of avoidance, with legal issues hindering the development of other treatments such as immunotherapy. Education of healthcare professionals is similarly lacking. This review aimed to summarize the current status of cannabis allergy and proposes recommendations for the future management of this global issue.