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.

Omalizumab for the Treatment of Multiple Food Allergies.

BACKGROUND: Food allergies are common and are associated with substantial morbidity; the only approved treatment is oral immunotherapy for peanut allergy. METHODS: In this trial, we assessed whether omalizumab, a monoclonal anti-IgE antibody, would be effective and safe as monotherapy in patients with multiple food allergies. Persons 1 to 55 years of age who were allergic to peanuts and at least two other trial-specified foods (cashew, milk, egg, walnut, wheat, and hazelnut) were screened. Inclusion required a reaction to a food challenge of 100 mg or less of peanut protein and 300 mg or less of the two other foods. Participants were randomly assigned, in a 2:1 ratio, to receive omalizumab or placebo administered subcutaneously (with the dose based on weight and IgE levels) every 2 to 4 weeks for 16 to 20 weeks, after which the challenges were repeated. The primary end point was ingestion of peanut protein in a single dose of 600 mg or more without dose-limiting symptoms. The three key secondary end points were the consumption of cashew, of milk, and of egg in single doses of at least 1000 mg each without dose-limiting symptoms. The first 60 participants (59 of whom were children or adolescents) who completed this first stage were enrolled in a 24-week open-label extension. RESULTS: Of the 462 persons who were screened, 180 underwent randomization. The analysis population consisted of the 177 children and adolescents (1 to 17 years of age). A total of 79 of the 118 participants (67%) receiving omalizumab met the primary end-point criteria, as compared with 4 of the 59 participants (7%) receiving placebo (P<0.001). Results for the key secondary end points were consistent with those of the primary end point (cashew, 41% vs. 3%; milk, 66% vs. 10%; egg, 67% vs. 0%; P<0.001 for all comparisons). Safety end points did not differ between the groups, aside from more injection-site reactions in the omalizumab group. CONCLUSIONS: In persons as young as 1 year of age with multiple food allergies, omalizumab treatment for 16 weeks was superior to placebo in increasing the reaction threshold for peanut and other common food allergens. (Funded by the National Institute of Allergy and Infectious Diseases and others; ClinicalTrials.gov number, NCT03881696.).

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.

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.

Exploratory immunogenicity outcomes of peanut oral immunotherapy: Findings from the PALISADE trial.

BACKGROUND: Immunoglobulin E (IgE) and immunoglobulin G4 (IgG4) to peanut and its components may influence the clinical reactivity to peanut. Allergen-specific immunotherapy is known for modifying both IgE and IgG4. Peanut oral immunotherapy may influence these serological parameters. METHODS: Exploratory analyses of serological data from participants receiving peanut (Arachis hypogaea) allergen powder-dnfp (PTAH) and placebo in the double-blind, randomized, phase 3 PALISADE trial were conducted to evaluate potential relationships between peanut-specific and peanut component-specific (Ara h 1, Ara h 2, Ara h 3, Ara h 6, Ara h 8, and Ara h 9) IgE and IgG4 levels and clinical outcomes. RESULTS: A total of 269 participants (PTAH, n = 202; placebo, n = 67) were analyzed. No relationship was observed between specific IgE and IgG4 levels at screening and maximum tolerated peanut protein dose during screening or response status during exit double-blind placebo-controlled food challenge (DBPCFC). In PTAH-treated participants, no relationship was observed between IgE and IgG4 levels at screening and maximum symptom severity during exit DBPCFC. Postscreening ratios (ie, postscreening/screening) in the PTAH group were significant at the end of updosing and exit visit for most components. Postscreening changes in specific IgE levels were more pronounced with PTAH versus placebo for most components. CONCLUSIONS: Specific IgE and IgG4 levels at screening are not correlated with screening or exit DBPCFC results, and are not predictive of clinical response to PTAH. Peanut (Arachis hypogaea) allergen powder-dnfp contains the relevant and immunodominant allergens, inducing immunological changes with the treatment. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02635776.

Altered Symptom Perception in Children With Asthma Is Associated With Poor Childhood Opportunity and Adverse Outcomes.

BACKGROUND: Effective asthma self-management requires that children recognize their asthma symptoms when they occur. However, some children have altered symptom perception, which impairs their ability to respond to their asthma symptoms in a timely manner. OBJECTIVE: To characterize the prevalence and features of altered symptom perception in children aged 5 to 18 years. We hypothesized that children with altered symptom perception would have more features of uncontrolled asthma, more health inequity, and poorer longitudinal asthma outcomes over 12 months. METHODS: Children (N = 371) completed an outpatient research visit for clinical characterization. Altered symptom perception was defined by discordance between child responses on the 6-item Asthma Control Questionnaire and medical provider-elicited symptoms. Electronic medical records were reviewed for 12 months for the occurrence of an asthma exacerbation treated with systemic corticosteroids and an asthma exacerbation prompting an emergency department visit. RESULTS: Approximately 15% of children had altered symptom perception and their asthma features were similar to those of children with uncontrolled asthma. Children with altered symptom perception were uniquely distinguished by non-White race and more severe prior exacerbations. These children also resided in ZIP codes with the poorest childhood opportunity (ie, poorest education, health and environmental features, and socioeconomic features). Outcomes of children with altered symptom perception were equally disparate with approximately 2-fold higher odds of a future exacerbation and approximately 3-fold higher odds of an emergency department visit for asthma. CONCLUSIONS: Altered symptom perception is present in a small but significant number of children with asthma and is related to poorer childhood opportunity and other health inequities that require additional intervention.

Social determinants of health influence preschool and caregiver experiences during symptoms and exacerbations of wheezing.

BACKGROUND: Social determinants of health have been inadequately studied in preschool children with wheezing and their caregivers but may influence the care received. OBJECTIVE: To evaluate the symptom and exacerbation experiences of wheezing preschool children and their caregivers, stratified by risk of social vulnerability, over 1 year of longitudinal follow-up. METHODS: A total of 79 caregivers and their preschool children with recurrent wheezing and at least 1 exacerbation in the previous year were stratified by a composite measure of social vulnerability into "low" (N = 19), "intermediate" (N = 27), and "high" (N = 33) risk groups. Outcome measures at the follow-up visits included child respiratory symptom scores, asthma control, caregiver-reported outcome measures of mental and social health, exacerbations, and health care utilization. The severity of exacerbations reflected by symptom scores and albuterol use and exacerbation-related caregiver quality of life were also assessed. RESULTS: Preschool children at high risk of social vulnerability had greater day-to-day symptom severity and more severe symptoms during acute exacerbations. High-risk caregivers were also distinguished by lower general life satisfaction at all visits and lower global and emotional quality of life during acute exacerbations which did not improve with exacerbation resolution. Rates of exacerbation or emergency department visits did not differ, but intermediate- and high-risk families were significantly less likely to seek unscheduled outpatient care. CONCLUSION: Social determinants of health influence wheezing outcomes in preschool children and their caregivers. These findings argue for routine assessment of social determinants of health during medical encounters and tailored interventions in high-risk families to promote health equity and improve respiratory outcomes.

Retail Food Equivalents for Post-Oral Immunotherapy Dosing in the Omalizumab as Monotherapy and as Adjunct Therapy to Multi-Allergen Oral Immunotherapy in Food-Allergic Children and Adults (OUtMATCH) Clinical Trial.

BACKGROUND: Patients with food allergy may be advised to introduce specific foods into their diets, both to increase tolerance gradually and as next steps after completing oral immunotherapy or other therapeutic interventions. However, the safe use of retail foods depends on the ability to establish the specific allergen protein content of these foods. OBJECTIVE: To develop a systematic approach to estimate the protein content of peanut, milk, egg, wheat, cashew, hazelnut, and walnut in a variety of retail food equivalents for each allergen and associated patient education materials. METHOD: We created an algorithm that used a multistep process with information from product food labels, nutrient databases, independent weighing and measuring of foods, and information provided by manufacturers, including certificates of analysis, and e-mail communication to estimate the allergen protein content of multiple retail foods for each of seven allergens. Once a variety of retail food equivalents for each allergen and allergen serving size was determined, we developed participant education handouts, which were reviewed by study teams at 10 food allergy centers, the National Institute of Allergy and Infectious Diseases, and the Consortium for Food Allergy Research coordinating center. After 1 year of use, multiple queries were addressed and the retail food equivalents and educational materials were reviewed and edited. RESULTS: We identified a variety of retail food equivalents for seven allergens at six serving sizes, and created 48 unique patient education materials. CONCLUSION: Our results provide extensive guidance on a variety of retail equivalents for seven foods, and a method to estimate retail food protein equivalents systematically with ongoing reassessment.

Food Allergy Management Practices Utilizing Individual Patient Thresholds: A Work Group Report of the AAAAI Adverse Reactions to Foods Committee.

The paradigm for food allergy management has been strict avoidance of the food allergen. There is literature supporting a "high-threshold" phenotype, those who tolerate a small-to-modest amount of allergen but react to larger amounts. There is no consensus for best practice for these "high-threshold" individuals. We sought to understand management practices of "high-threshold" reactors using a survey that was distributed to a random sample of fellows and members of the American Academy of Allergy, Asthma, and Immunology. There were 89 respondents from the United States and Canada (11% response rate), with 64 (72%) answering all questions. Participants worked in private (52%) and academic practice (38%) and saw a median of 30 food allergic patients monthly. Eighty-one percent of respondents reported management strategies other than strict avoidance. When threshold was known, strategies ranged from allowing ingestion up to a specified amount (57%), proactively advising ingestion to a certain amount (56%), or oral immunotherapy (47%). Participants were more likely to choose a permissive approach for a mild reaction in a high-threshold milk-allergic patient compared with a peanut-allergic patient (83% vs 71%, p=.01). Important factors that influenced the approach included severity of reaction (52%), comfort with family/patient using emergency medications (42%), and family/patient preferences (41%). These survey results suggest that food allergy management recommendations are no longer binary in nature, with clinicians solely recommending avoidance for those who are allergic and ingestion for those who may not be.

Food Allergen Immunotherapy in Preschool Children: Do We Have the Evidence?

Standard care for the management of food allergies previously centered on allergen avoidance and the treatment of adverse reactions after allergen exposure. An increase in the development of immunotherapy treatments for food allergy has occurred over the past 2 decades, with many centers now offering immunotherapy. Previous studies mainly focused on school-age children in whom food allergies are likely to be persistent. However, there is increasing evidence that delivering immunotherapy for food allergy to preschool-age children may deliver higher rates of success, and that peanut allergen immunotherapy leads the way. Conversely, the natural resolution of food allergies occurs primarily in these younger age groups, resulting in challenges to selecting patients who will ultimately benefit from these treatments. Both immunotherapy and natural history studies reveal the inherent plasticity of the immune system in early life, which may be more amenable to intervention, but this raises a delicate yet unknown balance between the optimal timing of intervention versus waiting for natural resolution of the food allergy. Here we review the evidence for early food allergen immunotherapy in preschoolers, and present the pros and cons of this approach while acknowledging important research gaps in this age group.

Current and future treatments for peanut allergy.

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.

Oral Immunotherapy for Peanut Allergy in Children 1 to Less Than 4 Years of Age.

Oral Immunotherapy for Peanut Allergy in ChildrenThis trial enrolled children 1 to <4 years of age who had allergic symptoms from peanut protein during screening. Participants received peanut allergen powder-dnfp (PTAH) or placebo for approximately 12 months; 73.5% of participants receiving PTAH tolerated a single dose of ≥600 mg peanut protein versus 6.3% of the placebo group.

Manufacturing processes of peanut (Arachis hypogaea) allergen powder-dnfp.

Background: Important components of drug safety, efficacy, and acceptability involve manufacturing and testing of the drug substance and drug product. Peanut flour sourcing/processing and manufacturing processes may affect final drug product allergen potency and contamination level, possibly impacting drug safety, quality, and efficacy. We describe key steps in the manufacturing processes of peanut (Arachis hypogaea) allergen powder-dnfp (PTAH; Palforzia®), a drug used in oral immunotherapy (OIT) for the treatment of peanut allergy. Methods: Established criteria for source material must be met for manufacturing PTAH drug product. Degree of roasting was determined with a Hunter colorimeter. Protein/allergen content, identity, potency, safety, and quality of each batch of PTAH drug substance were assessed with a combustion analyzer, allergen-specific Western blot (immunoblotting), ELISA, and HPLC. Contaminants (ie, aflatoxin) were measured by UPLC. Results: Roasting degree beyond "light roast" was associated with variable degrees of protein allergen degradation, or potentially aggregation. Relative potency and amounts of protein allergens showed variability due in part to seasonal/manufacturing variability. Proportion of lots not meeting aflatoxin limits has increased in recent years. Up to 60% of peanut flour source material failed to meet screening selection acceptance criteria for proceeding to drug substance testing, mostly because of failure to meet potency acceptance criteria. Other lots were rejected due to safety (ie, aflatoxin) and quality. Influence of potency variation, within specification parameters, on safety/tolerability observed in trials was considered low, in part due to stringent controls placed at each step of manufacturing. Conclusions: Extensive variability in allergen potency is a critical issue during immunotherapy, particularly during OIT initial dose escalation and up-dosing, as it may result in lack of efficacy or avoidable adverse allergic reactions. Based on EU and US regulatory requirements, the production of PTAH includes manufacturing controls to ensure drug product safety, potency, and quality. For example, although PTAH contains all peanut allergens, each lot has met strict criteria ensuring consistent allergenic potency of Ara h 1, Ara h 2, and Ara h 6. The rigor of PTAH's manufacturing process ensures reliable dose consistency and stability throughout its shelf life.

Participant characteristics and safety outcomes of peanut oral immunotherapy in the RAMSES and ARC011 trials.

BACKGROUND: Clinical trials (PALISADE [ARC003], ARTEMIS [ARC010]) proving efficacy and safety of peanut (Arachis hypogaea) allergen powder-dnfp (PTAH) have used double-blind, placebo-controlled food challenges (DBPCFCs) to screen for eligibility and to evaluate efficacy. In routine clinical practice, individuals with peanut allergy do not always undergo food challenges to confirm diagnosis or determine candidacy for treatment. OBJECTIVE: To describe PTAH safety and tolerability in participants selected by clinical history and peanut sensitization parameters not undergoing DBPCFCs during trials and to compare findings with previously published data. METHODS: RAMSES (ARC007) was a 6-month, phase 3, randomized, double-blind, placebo-controlled trial in children aged 4 to 17 years with physician-confirmed peanut allergy. ARC011 was the subsequent 6-month follow-on maintenance PTAH study. The primary end point for RAMSES and ARC011 was the frequency of treatment-emergent adverse events (AEs). We descriptively compared baseline characteristics and safety outcomes from RAMSES and ARC011 to participants undergoing DBPCFCs in phase 3 PALISADE and ARTEMIS trials. RESULTS: In 506 patients randomized to study treatment, baseline characteristics appeared balanced among groups. Proportion of participants with at least 1 AE was 55% for PTAH vs 33.9% for placebo during initial dose escalation and 98.8% vs 94.0% during updosing, respectively. Most participants with AEs had mild or moderate events. The most common AEs were gastrointestinal. Comparisons to pooled PALISADE and ARTEMIS data revealed higher baseline median peanut-specific immunoglobulin E and skin prick test values for RAMSES participants. Safety outcomes during trial periods were comparable. CONCLUSION: Safety data from clinically selected children with peanut allergy receiving PTAH do not seem different from those in phase 3 trials requiring DBPCFC to enter trials.

Kinetics of basophil hyporesponsiveness during short-course peanut oral immunotherapy.

BACKGROUND: Oral immunotherapy (OIT) leads to suppression of mast cell and basophil degranulation along with changes in the adaptive immune response. OBJECTIVES: This study aimed to determine how rapidly these effects occur during OIT and more broadly, the kinetics of basophil and mast cell suppression throughout the course of therapy. METHODS: Twenty participants, age 4 to 12 years, were enrolled in a peanut OIT trial and assessed for desensitization and sustained unresponsiveness after 9 months of therapy. Blood was collected 5 times in the first month and then intermittently throughout to quantify immunoglobulins and assess basophil activation by CD63, CD203c, and phosphorylated SYK (pSYK). RESULTS: Twelve of 16 participants that completed the trial were desensitized after OIT, with 9 achieving sustained unresponsiveness after discontinuing OIT for 4 weeks. Basophil hyporesponsiveness, defined by lower CD63 expression, was detected as early as day 90. pSYK was correlated with CD63 expression, and there was a significant decrease in pSYK by day 250. CD203c expression remained unchanged throughout therapy. Interestingly, although basophil activation was decreased across the cohort during OIT, basophil activation did not correlate with individual clinical outcomes. Serum peanut-specific IgG4 and IgA increased throughout therapy, whereas IgE remained unchanged. CONCLUSIONS: Suppression of basophil activation occurs within the first 90 days of peanut OIT, ultimately leading to suppression of signaling through pSYK.

Oral desensitization therapy for peanut allergy induces dynamic changes in peanut-specific immune responses.

BACKGROUND: The PALISADE study, an international, phase 3 trial of peanut oral immunotherapy (POIT) with AR101, resulted in desensitization in children and adolescents who were highly allergic to peanut. An improved understanding of the immune mechanism induced in response to food allergen immunotherapy would enable more informed and effective therapeutic strategies. Our main purpose was to examine the immunological changes in blood samples from a subset of peanut-allergic individuals undergoing oral desensitization immunotherapy with AR101. METHODS: Blood samples obtained as part of enrollment screening and at multiple time points during PALISADE study were used to assess basophil and CD4+ T-cell reactivity to peanut. RESULTS: The absence of clinical reactivity to the entry double-blinded placebo-controlled peanut challenge (DBPCFC) was accompanied by a significantly lower basophil sensitivity and T-cell reactivity to peanut compared with DBPCFC reactors. At baseline, peanut-reactive TH2A cells were observed in many but not all peanut-allergic patients and their level in peripheral blood correlates with T-cell reactivity to peanut and with serum peanut-specific IgE and IgG4 levels. POIT reshaped circulating peanut-reactive T-cell responses in a subset-dependent manner. Changes in basophil and T-cell responses to peanut closely paralleled clinical benefits to AR101 therapy and resemble responses in those with lower clinical sensitivity to peanut. However, no difference in peanut-reactive Treg cell frequency was observed between groups. CONCLUSION: Oral desensitization therapy with AR101 leads to decreased basophil sensitivity to peanut and reshapes peanut-reactive T effector cell responses supporting its potential as an immunomodulatory therapy.

Protocol design and synopsis: Omalizumab as Monotherapy and as Adjunct Therapy to Multiallergen OIT in Children and Adults with Food Allergy (OUtMATCH).

Background: Food allergy is common and causes substantial morbidity and even mortality. Safe and effective treatments for food allergy would therefore be highly desirable, especially for individuals with multiple food allergies. Objectives: Our aim was to describe a phase 3 study on treatment of patients with multiple food allergies with omalizumab. Methods: The study was developed as a collaboration between the Consortium for Food Allergy Research, the National Institute of Allergy and Infectious Diseases, and 2 industry sponsors (Genentech and Novartis). Results: The study is currently under way, enrolling participants from age 1 year to age 55 years who are allergic to peanut and at least 2 other foods (including milk, egg, wheat, cashew, hazelnut, and walnut). The study is designed to address 3 major questions. First, stage 1 will study the potential value of omalizumab for the treatment of patients with peanut allergy and at least 2 other common food allergens. Second, stage 2 will directly compare treatment of patients with multifood allergies using omalizumab as monotherapy versus treatment with omalizumab-facilitated multiallergen oral immunotherapy in which omalizumab is used as an adjunctive treatment. Third, stage 3 will address the longer-term outcomes following these treatment approaches, including the introduction of dietary forms of the study foods to induce or maintain desensitization. Conclusions: This phase 3 study will provide important information on the potential of omalizumab to treat patients with multiple food allergies.