World Allergy Organization (WAO) Diagnosis and Rationale for Action against Cow's Milk Allergy (DRACMA) guideline update - XII - Recommendations on milk formula supplements with and without probiotics for infants and toddlers with CMA.

Background: Cow's milk allergy (CMA) is the most common food allergy in infants. The replacement with specialized formulas is an established clinical approach to ensure adequate growth and minimize the risk of severe allergic reactions when breastfeeding is not possible. Still, given the availability of multiple options, such as extensively hydrolyzed cow's milk protein formula (eHF-CM), amino acid formula (AAF), hydrolyzed rice formula (HRF) and soy formulas (SF), there is some uncertainty as to the most suitable choice with respect to health outcomes. Furthermore, the addition of probiotics to a formula has been proposed as a potential approach to maximize benefit. Objective: These evidence-based guidelines from the World Allergy Organization (WAO) intend to support patients, clinicians, and others in decisions about the use of milk specialized formulas, with and without probiotics, for individuals with CMA. Methods: 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 review by stakeholders. Results: After reviewing the summarized evidence and thoroughly discussing the different management options, the WAO guideline panel suggests: a) using an extensively hydrolyzed (cow's milk) formula or a hydrolyzed rice formula as the first option for managing infants with immunoglobulin E (IgE) and non-IgE-mediated CMA who are not being breastfed. An amino-acid formula or a soy formula could be regarded as second and third options respectively; b) using either a formula without a probiotic or a casein-based extensively hydrolyzed formula containing Lacticaseibacillus rhamnosus GG (LGG) for infants with either IgE or non-IgE-mediated CMA.The issued recommendations are labeled as "conditional" following the GRADE approach due to the very low certainty about the health effects based on the available evidence. Conclusions: If breastfeeding is not available, clinicians, patients, and their family members might want to discuss all the potential desirable and undesirable consequences of each formula in infants with CMA, integrating them with the patients' and caregivers' values and preferences, local availability, and cost, before deciding on a treatment option. We also suggest what research is needed to determine with greater certainty which formulas are likely to be the most beneficial, cost-effective, and equitable.

Improving clinical practice through patient registries in allergy and immunology.

Patient registries are a mechanism for collecting data on allergic and immunologic diseases that provide important information on epidemiology and outcomes that can ultimately improve patient care. Key criteria for establishing effective registries include the use of a clearly defined purpose, identifying the target population and ensuring consistent data collection. Registries in allergic diseases include those for diseases such as inborn errors of immunity, food allergy, asthma and anaphylaxis, pharmacological interventions in vulnerable populations, and adverse effects of pharmacologic interventions including hypersensitivity reactions to drugs and vaccines. Important insights gained from patient registries in our field include contributions in phenotype and outcomes in inborn errors of immunity, the risk for adverse reactions in food-allergic patients in multiple settings, the benefits and risk of biologic medications for asthma during pregnancy, vaccine safety, and the categorization and genetic determination of risk for severe cutaneous adverse reactions to medications. Impediments to the development of clinically meaningful patient registries include the lack of funding resources for registry establishment and the quality, quantity, and consistency of available data. Despite these drawbacks, high-quality and successful registries are invaluable in informing clinical practice and improving outcomes in patients with allergic and immunological diseases.

Preparing Patients for Oral Immunotherapy (PPOINT): International Delphi consensus for procedural preparation and consent.

BACKGROUND: Despite the promise of oral immunotherapy (OIT) to treat food allergies, this procedure is associated with potential risk. There is no current agreement about what elements should be included in the preparatory or consent process. OBJECTIVE: We developed consensus recommendations about the OIT process considerations and patient-specific factors that should be addressed before initiating OIT and developed a consensus OIT consent process and information form. METHODS: We convened a 36-member Preparing Patients for Oral Immunotherapy (PPOINT) panel of allergy experts to develop a consensus OIT patient preparation, informed consent process, and framework form. Consensus for themes and statements was reached using Delphi methodology, and the consent information form was developed. RESULTS: The expert panel reached consensus for 4 themes and 103 statements specific to OIT preparatory procedures, of which 76 statements reached consensus for inclusion specific to the following themes: general considerations for counseling patients about OIT; patient- and family-specific factors that should be addressed before initiating OIT and during OIT; indications for initiating OIT; and potential contraindications and precautions for OIT. The panel reached consensus on 9 OIT consent form themes: benefits, risks, outcomes, alternatives, risk mitigation, difficulties/challenges, discontinuation, office policies, and long-term management. From these themes, 219 statements were proposed, of which 189 reached consensus, and 71 were included on the consent information form. CONCLUSION: We developed consensus recommendations to prepare and counsel patients for safe and effective OIT in clinical practice with evidence-based risk mitigation. Adoption of these recommendations may help standardize clinical care and improve patient outcomes and quality of life.

Tolerance development in cow's milk-allergic children receiving amino acid-based formula with synbiotics: 36-Months follow-up of a randomized controlled trial (PRESTO Study).

The objective of the present study is to assess the rates of acquired tolerance to cow's milk (CM) after 36 months in subjects who consumed amino acid-based formula with synbiotics (AAF-S) or amino acid-based formula without synbiotics (AAF) during a 1-year intervention period in early life as part of the PRESTO study (Netherlands Trial Register number NTR3725). Differences in CM tolerance development between groups were analysed using a logistic regression model. Results show that the proportion of subjects (mean [±SD] age, 3.8 ± 0.27 years) who developed CM tolerance after 36 months was similar in the group receiving AAF-S (47/60 [78%]) and in the group receiving AAF (49/66 [74%]) (p = 0.253), that is, figures comparable to natural outgrowth of CM allergy. Our data suggest that the consumption of AAF and absence of exposure to CM peptides do not slow down CM tolerance acquisition.

Sustained silencing peanut allergy by xanthopurpurin is associated with suppression of peripheral and bone marrow IgE-producing B cell.

Introduction: Peanut allergy is an immunoglobulin E (IgE) mediated food allergy. Rubia cordifolia L. (R. cordifolia), a Chinese herbal medicine, protects against peanut-induced anaphylaxis by suppressing IgE production in vivo. This study aims to identify IgE-inhibitory compounds from the water extract of R. cordifolia and investigate the underlying mechanisms using in vitro and in vivo models. Methods: Compounds were isolated from R. cordifolia water extract and their bioactivity on IgE production was assessed using a human myeloma U266 cell line. The purified active compound, xanthopurpurin (XPP), was identified by LC-MS and NMR. Peanut-allergic C3H/HeJ mice were orally administered with or without XPP at 200µg or 400µg per mouse per day for 4 weeks. Serum peanut-specific IgE levels, symptom scores, body temperatures, and plasma histamine levels were measured at challenge. Cytokines in splenocyte cultures were determined by ELISA, and IgE + B cells were analyzed by flow cytometry. Acute and sub-chronic toxicity were evaluated. IL-4 promoter DNA methylation, RNA-Seq, and qPCR analysis were performed to determine the regulatory mechanisms of XPP. Results: XPP significantly and dose-dependently suppressed the IgE production in U266 cells. XPP significantly reduced peanut-specific IgE (>80%, p <0.01), and plasma histamine levels and protected the mice against peanut-allergic reactions in both early and late treatment experiments (p < 0.05, n=9). XPP showed a strong protective effect even 5 weeks after discontinuing the treatment. XPP significantly reduced the IL-4 level without affecting IgG or IgA and IFN-γ production. Flow cytometry data showed that XPP reduced peripheral and bone marrow IgE + B cells compared to the untreated group. XPP increased IL-4 promoter methylation. RNA-Seq and RT-PCR experiments revealed that XPP regulated the gene expression of CCND1, DUSP4, SDC1, ETS1, PTPRC, and IL6R, which are related to plasma cell IgE production. All safety testing results were in the normal range. Conclusions: XPP successfully protected peanut-allergic mice against peanut anaphylaxis by suppressing IgE production. XPP suppresses murine IgE-producing B cell numbers and inhibits IgE production and associated genes in human plasma cells. XPP may be a potential therapy for IgE-mediated food allergy.

Current and future perspectives on the consensus guideline for food protein-induced enterocolitis syndrome (FPIES).

Food protein-induced enterocolitis syndrome (FPIES) is a non-IgE mediated food allergy presenting with delayed onset of projectile vomiting in the absence of cutaneous and respiratory symptoms. The pathophysiology of FPIES remains poorly characterized. The first international consensus guidelines for FPIES were published in 2017 and provided clinicians with parameters on the diagnosis and treatment of FPIES. The guidelines have served as a resource in the recognition and management of FPIES, contributing to an increased awareness of FPIES. Since then, new evidence has emerged, shedding light on adult-onset FPIES, the different phenotypes of FPIES, the recognition of new food triggers, center-specific food challenge protocols and management of acute FPIES. Emerging evidence indicates that FPIES impacts both pediatric and adult population. As a result, there is growing need to tailor the consensus guidelines to capture diagnoses in both patient groups. Furthermore, it is crucial to provide food challenge protocols that meet the needs of both pediatric and adult FPIES patients, as well as the subset of patients with atypical FPIES. This review highlights the evolving clinical evidence relating to FPIES diagnosis and management published since the 2017 International FPIES Guidelines. We will focus on areas where recent published evidence may support evolution or revision of the guidelines.

The Future of Food Allergy Management: Advancements in Therapies.

PURPOSE OF REVIEW: To review current and future treatment options for IgE-mediated food allergy. RECENT FINDINGS: Recent years have seen major developments in both allergen-specific and allergen-non-specific treatment options, with the first FDA-approved peanut oral immunotherapy (OIT) product becoming available in 2020. In addition to OIT, other immunotherapy modalities, biologics, adjunct therapies, and novel therapeutics are under investigation. Food allergy is a potentially life-threatening condition associated with a significant psychosocial impact. Numerous products and protocols are under investigation, with most studies focusing on OIT. A high rate of adverse events, need for frequent office visits, and cost remain challenges with OIT. Further work is needed to unify outcome measures, develop treatment protocols that minimize adverse events, establish demographic and clinical factors that influence candidate selection, and identify patient priorities.

Evaluation of clinical outcomes of efficacy in food allergen immunotherapy trials, COFAITH EAACI task force.

Food allergy is a global public health problem that until recent years lacked any aetiological treatment supported by academy, industry and regulators. Food immunotherapy (AIT) is an evolving treatment option, supported by clinical practice and industry trial data. Recent AIT meta-analyses have highlighted the difficulty in pooling safety and efficacy data from AIT trials, due to secondary heterogeneity in the study. An EAACI task force (CO-FAITH) initiated by the Paediatric Section was created to focus on AIT efficacy outcomes for milk, egg and peanut allergy rather than in trial results. A systematic search and a narrative review of AIT controlled clinical trials and large case series was conducted. A total of 63 manuscripts met inclusion criteria, corresponding to 23, 21 and 22 studies of milk, egg and peanut AIT, respectively. The most common AIT efficacy outcome was desensitization, mostly defined as tolerating a maintenance phase dose, or reaching a particular dose upon successful exit oral food challenge (OFC). However, a large degree of heterogeneity was identified regarding the dose quantity defining this outcome. Sustained unresponsiveness and patient-reported outcomes (e.g. quality of life) were explored less frequently, and to date have been most rigorously described for peanut AIT versus other allergens. Change in allergen threshold assessed by OFC remains the most common efficacy measure, but OFC methods suffer from heterogeneity and methodological disparity. This review has identified multiple heterogeneous outcomes related to measuring the efficacy of AIT. Efforts to better standardize and harmonize which outcomes, and how to measure them must be carried out to help in the clinical development of safe and efficacious food allergy treatments.

Identifying Children at Risk of Growth and Nutrient Deficiencies in the Food Allergy Clinic.

BACKGROUND: Food allergies affect growth in children by decreasing the availability of nutrients through decreased dietary intake, increased dietary needs, food-medication interactions, and psychosocial burden. Guidelines on food allergy management frequently recommend nutrition counseling and growth monitoring of children with food allergies. OBJECTIVE: To provide clear guidance for clinicians to identify children with food allergies who are at nutritional risk and ensure prompt intervention. METHODS: We provide a narrative review summarizing information from national and international guidelines, retrospective studies, population studies, review articles, case reports, and case series to identify those with food allergy at greatest nutritional risk, determine the impact of nutritional interventions on growth, and develop guidance for risk reduction in children with food allergies. RESULTS: Children with food allergies are at increased risk of nutritional deficiencies and poor growth. Nutritional assessment and intervention can improve outcomes. Identifying poor growth is an important step in the nutrition assessment. Therefore, growth should be assessed at each allergy evaluation. Interventions to ensure adequate dietary intake for growth include appropriately prescribed elimination diets, breast-feeding support and assessment, supplemental formula, vitamin and/or mineral supplementation, appropriate milk substitutes, and timely introduction of nutrient-dense complementary foods. Access to foods of appropriate nutritional value is an ongoing concern. CONCLUSION: Nutrition intervention or referral to registered dietitian nutritionists with additional training and/or experience in food allergy may result in improved growth and nutrition 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.