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.).

Food insecurity and allergic diseases: A call to collective action.

Food security encompassess the concept of access by all people at all times to enough food for an active, healthy life. Conversely, food insecurity (FI) refers to household-level economic and social conditions of limited or uncertain access to adequate food. FI is a key social determinant of health that can negatively affect nutrition and health outcomes, as it is estimated that 10.2% of the US population meets criteria for FI. Recognizing the impact of FI on our patients and families is critical to promote health equity and optimize health outcomes. This review focuses on FI and allergic disease from the perspective of key multisector stakeholders within the field of allergy and immunology as well as from the larger health care arena, highlighting key resources and initiatives important to patients. Collectively, as specialists in allergy and immunology, and within the medical field more broadly, we must leverage our unique roles as we interface with patients and families and serve as committed advocates for change. Developing innovative strategies to promote health equity can provide a pathway forward for all children, adults, and families to gain access to healthy, nutritious food as part of their routine lifestyle. This is a call to action.

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.

Food Insecurity and Health Inequities in Food Allergy.

PURPOSE OF REVIEW: The intersection of food insecurity among those with food allergy is a growing public health concern. Both food allergy and food insecurity have profound implications on health, social, and economic outcomes. The interaction of social determinants of health, poverty, racism, housing insecurity, and access to care has direct impact on individuals with food allergy. RECENT FINDINGS: There is increasing evidence that universal screening for food insecurity is vital in the routine care of patients with food allergy. Individuals with food allergy who are also burdened by food insecurity face unique challenges related to the need to maintain dietary modifications often with expensive specialized diets, which are difficult to access. This may lead to limited dietary options, malnutrition, increased financial burden, and social isolation. While there are available resources and support systems that can assist individuals with food allergies in managing food insecurity, there is an increasing need for advocacy and inclusivity in policy frameworks involving multiple stakeholders. Multi-sector efforts involving healthcare providers and advocacy and government agencies are necessary to support policy changes that protect the rights and well-being of individuals affected by food allergy and food insecurity. By increasing awareness, improving access to safe, affordable, allergen-free food, and advocating for policy change, we can work toward ensuring universal access to safe, nutritious food for all individuals, regardless of their food allergy status or socioeconomic background.

Efficacy and safety of oral immunotherapy in children aged 1-3 years with peanut allergy (the Immune Tolerance Network IMPACT trial): a randomised placebo-controlled study.

BACKGROUND: For young children with peanut allergy, dietary avoidance is the current standard of care. We aimed to assess whether peanut oral immunotherapy can induce desensitisation (an increased allergic reaction threshold while on therapy) or remission (a state of non-responsiveness after discontinuation of immunotherapy) in this population. METHODS: We did a randomised, double-blind, placebo-controlled study in five US academic medical centres. Eligible participants were children aged 12 to younger than 48 months who were reactive to 500 mg or less of peanut protein during a double-blind, placebo-controlled food challenge (DBPCFC). Participants were randomly assigned by use of a computer, in a 2:1 allocation ratio, to receive peanut oral immunotherapy or placebo for 134 weeks (2000 mg peanut protein per day) followed by 26 weeks of avoidance, with participants and study staff and investigators masked to group treatment assignment. The primary outcome was desensitisation at the end of treatment (week 134), and remission after avoidance (week 160), as the key secondary outcome, were assessed by DBPCFC to 5000 mg in the intention-to-treat population. Safety and immunological parameters were assessed in the same population. This trial is registered on ClinicalTrials.gov, NCT03345160. FINDINGS: Between Aug 13, 2013, and Oct 1, 2015, 146 children, with a median age of 39·3 months (IQR 30·8-44·7), were randomly assigned to receive peanut oral immunotherapy (96 participants) or placebo (50 participants). At week 134, 68 (71%, 95% CI 61-80) of 96 participants who received peanut oral immunotherapy compared with one (2%, 0·05-11) of 50 who received placebo met the primary outcome of desensitisation (risk difference [RD] 69%, 95% CI 59-79; p<0·0001). The median cumulative tolerated dose during the week 134 DBPCFC was 5005 mg (IQR 3755-5005) for peanut oral immunotherapy versus 5 mg (0-105) for placebo (p<0·0001). After avoidance, 20 (21%, 95% CI 13-30) of 96 participants receiving peanut oral immunotherapy compared with one (2%, 0·05-11) of 50 receiving placebo met remission criteria (RD 19%, 95% CI 10-28; p=0·0021). The median cumulative tolerated dose during the week 160 DBPCFC was 755 mg (IQR 0-2755) for peanut oral immunotherapy and 0 mg (0-55) for placebo (p<0·0001). A significant proportion of participants receiving peanut oral immunotherapy who passed the 5000 mg DBPCFC at week 134 could no longer tolerate 5000 mg at week 160 (p<0·001). The participant receiving placebo who was desensitised at week 134 also achieved remission at week 160. Compared with placebo, peanut oral immunotherapy decreased peanut-specific and Ara h2-specific IgE, skin prick test, and basophil activation, and increased peanut-specific and Ara h2-specific IgG4 at weeks 134 and 160. By use of multivariable regression analysis of participants receiving peanut oral immunotherapy, younger age and lower baseline peanut-specific IgE was predictive of remission. Most participants (98% with peanut oral immunotherapy vs 80% with placebo) had at least one oral immunotherapy dosing reaction, predominantly mild to moderate and occurring more frequently in participants receiving peanut oral immunotherapy. 35 oral immunotherapy dosing events with moderate symptoms were treated with epinephrine in 21 participants receiving peanut oral immunotherapy. INTERPRETATION: In children with a peanut allergy, initiation of peanut oral immunotherapy before age 4 years was associated with an increase in both desensitisation and remission. Development of remission correlated with immunological biomarkers. The outcomes suggest a window of opportunity at a young age for intervention to induce remission of peanut allergy. FUNDING: National Institute of Allergy and Infectious Disease, Immune Tolerance Network.

Immunodeficiency and bone marrow failure with mosaic and germline TLR8 gain of function.

Inborn errors of immunity (IEI) are a genetically heterogeneous group of disorders with a broad clinical spectrum. Identification of molecular and functional bases of these disorders is important for diagnosis, treatment, and an understanding of the human immune response. We identified 6 unrelated males with neutropenia, infections, lymphoproliferation, humoral immune defects, and in some cases bone marrow failure associated with 3 different variants in the X-linked gene TLR8, encoding the endosomal Toll-like receptor 8 (TLR8). Interestingly, 5 patients had somatic variants in TLR8 with <30% mosaicism, suggesting a dominant mechanism responsible for the clinical phenotype. Mosaicism was also detected in skin-derived fibroblasts in 3 patients, demonstrating that mutations were not limited to the hematopoietic compartment. All patients had refractory chronic neutropenia, and 3 patients underwent allogeneic hematopoietic cell transplantation. All variants conferred gain of function to TLR8 protein, and immune phenotyping demonstrated a proinflammatory phenotype with activated T cells and elevated serum cytokines associated with impaired B-cell maturation. Differentiation of myeloid cells from patient-derived induced pluripotent stem cells demonstrated increased responsiveness to TLR8. Together, these findings demonstrate that gain-of-function variants in TLR8 lead to a novel childhood-onset IEI with lymphoproliferation, neutropenia, infectious susceptibility, B- and T-cell defects, and in some cases, bone marrow failure. Somatic mosaicism is a prominent molecular mechanism of this new disease.

Allergen-specific T cells and clinical features of food allergy: Lessons from CoFAR immunotherapy cohorts.

BACKGROUND: Allergen-specific IL-4+ and IL-13+ CD4+ cells (type 2 cells) are essential for helping B cells to class-switch to IgE and establishing an allergic milieu in the gastrointestinal tract. The role of T cells in established food allergy is less clear. OBJECTIVE: We examined the food allergen-specific T-cell response in participants of 2 food allergen immunotherapy trials to assess the relationship of the T-cell response to clinical phenotypes, including response to immunotherapy. METHODS: Blood was obtained from 84 participants with peanut allergy and 142 participants with egg allergy who underwent double-blind placebo-controlled food challenges. Peanut- and egg-responsive T cells were identified by CD154 upregulation after stimulation with the respective extract. Intracellular cytokines and chemokine receptors were also detected. The response to peanut epicutaneous immunotherapy (Peanut Epicutaneous Phase II Immunotherapy Clinical Trial [CoFAR6]; 49 participants receiving epicutaneous immunotherapy) and egg oral immunotherapy or a baked egg diet (Baked Egg or Egg Oral Immunotherapy for Children With Egg Allergy [CoFAR7]; 92 participants) was monitored over time. RESULTS: Peanut-specific type 2 and CCR6+ T cells were negatively correlated with each other and differently associated with immune parameters, including specific IgE level and basophil activation test result. At baseline, type 2 cells, but not CCR6+ cells, were predictive of clinical parameters, including a successfully consumed dose of peanut and baked egg tolerance. Exposure to peanut or egg immunotherapy was associated with a decrease in type 2 cell frequency. At baseline, high egg-specific type 2 cell frequency was the immune feature most predictive of oral immunotherapy failure. CONCLUSION: Food-specific type 2 T cells at baseline are informative of threshold of reactivity and response to immunotherapy.

Food insecurity in children and adults with food allergies.

Food allergy is a substantial public health concern associated with risk of severe or potentially life-threatening reactions and requiring life-altering changes in dietary habits. This increasingly prevalent health concern is associated with adverse medical, nutritional, psychosocial, and economic effects on the estimated 32 million affected individuals in the United States. Management of food allergy requires life-altering dietary modifications and constant vigilance to avoid implicated allergens to minimize the risk of anaphylaxis, which can lead to considerable anxiety and reduced quality of life. Specialized diets are expensive and often difficult to access, particularly for low-income and minority individuals with food allergy. The overlap of food insecurity with diet-treated illnesses further increases the burden on patients with food allergies and their families, with overall rates of food insecurity increasing substantially during the coronavirus disease 2019 pandemic. Universal screening to identify food insecure households and connect them with appropriate resources is a critical step in addressing unmet needs at the individual and family level. At the systems level, integrated advocacy approaches addressing the complex interplay between multiple societal issues such as poverty, systemic racism, wage inequality, housing insecurity, lack of transportation, and other social determinants of health are vital to ensure access to safe, healthy, nutritionally complete options for patients with food allergies and their families.

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.

Epicutaneous immunotherapy for treatment of peanut allergy: Follow-up from the Consortium for Food Allergy Research.

BACKGROUND: Consortium for Food Allergy Research investigators previously reported 52-week outcomes from a randomized controlled trial of peanut epicutaneous immunotherapy, observing modest and statistically significant induction of desensitization, highest in children ages 4 to 11 years. OBJECTIVE: We sought to evaluate changes in efficacy, safety, and mechanistic parameters following extended open-label peanut epicutaneous immunotherapy. METHODS: Peanut-allergic participants (4-25 years) received 52 weeks of placebo (PLB), Viaskin Peanut 100 µg (VP100) or 250 µg (VP250), and then crossed over to VP250 for PLB (PLB-VP250) and VP100 (VP100-VP250) participants and continued treatment for VP250 participants (total = 130 weeks of active epicutaneous immunotherapy). Efficacy was assessed by double-blind, placebo-controlled food challenge (5044 mg peanut protein), and adherence, safety, and mechanistic parameters were evaluated. RESULTS: At week 130, desensitization success was achieved in 1 of 20 (5%) PLB-VP250, 5 of 24 (20.8%) VP100-VP250, and 9 of 25 (36%) VP250 participants, with median successfully consumed dose change from baseline of 11.5 mg, 141.5 mg, and 400 mg, respectively. Median age (years) for week 130 desensitization success was 6.2 years (interquartile range, 5.2-9.1) versus 9.4 years (interquartile range, 7.6-12.8) for failures (P < .001). Adherence was 96%. Adverse reactions were predominantly local patch-site reactions. Significant increases in peanut- and Ara h2-specific IgG4 observed at week 52 persisted to week 130. By a post hoc analysis, there were no statistically significant increases from week 52 to week 130 in either desensitization success or successfully consumed dose. CONCLUSIONS: Extended treatment with VP250 was well tolerated, and desensitization observed at week 52 persisted between weeks 52 and 130. Treatment success was observed predominantly in younger participants, with younger age at initiation of active therapy an important predictor of success.

Dual transcriptomic and epigenomic study of reaction severity in peanut-allergic children.

BACKGROUND: Unexpected allergic reactions to peanut are the most common cause of fatal food-related anaphylaxis. Mechanisms underlying the variable severity of peanut-allergic reactions remain unclear. OBJECTIVES: We sought to expand mechanistic understanding of reaction severity in peanut allergy. METHODS: We performed an integrated transcriptomic and epigenomic study of peanut-allergic children as they reacted in vivo during double-blind, placebo-controlled peanut challenges. We integrated whole-blood transcriptome and CD4+ T-cell epigenome profiles to identify molecular signatures of reaction severity (ie, how severely a peanut-allergic child reacts when exposed to peanut). A threshold-weighted reaction severity score was calculated for each subject based on symptoms experienced during peanut challenge and the eliciting dose. Through linear mixed effects modeling, network construction, and causal mediation analysis, we identified genes, CpGs, and their interactions that mediate reaction severity. Findings were replicated in an independent cohort. RESULTS: We identified 318 genes with changes in expression during the course of reaction associated with reaction severity, and 203 CpG sites with differential DNA methylation associated with reaction severity. After replicating these findings in an independent cohort, we constructed interaction networks with the identified peanut severity genes and CpGs. These analyses and leukocyte deconvolution highlighted neutrophil-mediated immunity. We identified NFKBIA and ARG1 as hubs in the networks and 3 groups of interacting key node CpGs and peanut severity genes encompassing immune response, chemotaxis, and regulation of macroautophagy. In addition, we found that gene expression of PHACTR1 and ZNF121 causally mediates the association between methylation at corresponding CpGs and reaction severity, suggesting that methylation may serve as an anchor upon which gene expression modulates reaction severity. CONCLUSIONS: Our findings enhance current mechanistic understanding of the genetic and epigenetic architecture of reaction severity in peanut allergy.

Induction of sustained unresponsiveness after egg oral immunotherapy compared to baked egg therapy in children with egg allergy.

BACKGROUND: While desensitization and sustained unresponsiveness (SU) have been shown with egg oral immunotherapy (OIT), the benefits of baked egg (BE) therapy for egg allergy have not been well studied. OBJECTIVES: This study sought to evaluate the safety and efficacy of BE ingestion compared with egg OIT in participants allergic to unbaked egg but tolerant to BE. METHODS: Children who are BE-tolerant but unbaked egg reactive ages 3 to 16 years were randomized to 2 years of treatment with either BE or egg OIT. Double-blind, placebo-controlled food challenges were conducted after 1 and 2 years of treatment to assess for desensitization, and after 2 years of treatment followed by 8 to 10 weeks off of treatment to assess for SU. Mechanistic studies were conducted to assess for immune modulation. A cohort of participants who are BE-reactive underwent egg OIT and identical double-blind, placebo-controlled food challenges as a comparator group. RESULTS: Fifty participants (median age 7.3 years) were randomized and initiated treatment. SU was achieved in 3 of 27 participants assigned to BE (11.1%) versus 10 of 23 participants assigned to egg OIT (43.5%) (P = .009). In the BE-reactive comparator group, 7 of 39 participants (17.9%) achieved SU. More participants who are BE-tolerant withdrew from BE versus from egg OIT (29.6% vs 13%). Dosing symptom frequency in participants who are BE-tolerant was similar with BE and egg OIT, but more frequent in participants who are BE-reactive. Egg white-specific IgE, skin testing, and basophil activation decreased similarly after BE and egg OIT. CONCLUSIONS: Among children allergic to unbaked egg but tolerant to BE, those treated with egg OIT were significantly more likely to achieve SU than were children ingesting BE.

An evaluation of factors influencing response to epicutaneous immunotherapy for peanut allergy in the PEPITES trial.

Background: Epicutaneous immunotherapy (EPIT) for peanut allergy is a potential novel immunotherapy that utilizes the unique cutaneous immunologic properties to induce desensitization. A randomized, double-blind, placebo-controlled Phase 3 trial (PEPITES) in peanut-allergic children 4-11 years demonstrated an epicutaneous patch (DBV712) with 250 µg peanut protein was statistically superior to placebo in inducing desensitization following 12 months of daily treatment. Objective: To investigate what baseline and in-study factors influenced response to DBV712 250 µg, with a focus on patch adhesion, by posthoc analysis of PEPITES data. Methods: A posthoc multivariate model built with log-transformed Month 12 eliciting dose (ED) as the dependent variable was used to assess the influence of baseline characteristics and patch adhesion. Baseline characteristics and treatment response were also evaluated by stratifying subjects into decile subgroups by patch detachment rates over the 12-month study. Results: Multivariate analysis identified higher baseline ED and lower baseline peanut-specific IgE as the variables most predictive of higher Month 12 ED, followed by mean daily patch application duration, baseline SCORing Atopic Dermatitis (SCORAD) score, and age. By decile stratification, no association between patch detachment and treatment response was identified for 80% of DBV712-treated subjects. All DBV712-treated subjects, including those with the highest patch detachment rates, demonstrated treatment benefit measured by fold-changes in geometric mean ED. Conclusion: We identified subject baseline characteristics of higher baseline ED and lower baseline peanut-specific IgE as most predictive of higher Month 12 ED. For the majority of treated subjects, patch detachment did not impact treatment response. A minority of subjects, highly sensitive to peanut at baseline, had lower prespecified responder rates and higher patch detachment rates, yet still benefited from treatment based upon fold-changes in ED.

Impact of food allergy on food insecurity and health literacy in a tertiary care pediatric allergy population.

BACKGROUND: Food insecurity (FI), limited availability of or access to nutritional foods, is linked to poor child/caregiver health. We examined FI in food-allergic and non-food-allergic children to determine whether dietary limitations associated with food allergy increases risk of FI. METHODS: Food-allergic and non-food-allergic children (1-17 years) were recruited from Arkansas Children's Hospital allergy/asthma clinics. The USDA Food Security Survey, the Newest Vital Sign Health Literacy (HL) questionnaire, and the Food Allergy Impact Scale QOL survey were administered. Logistic regression and analysis of covariance models were utilized for data analysis. RESULTS: Subjects (n = 650) included 325 food-allergic and 325 non-food-allergic children. Overall rate of FI was 21.5% (food allergic 22.2% and non-food allergic 20.9%) with no significant difference in the prevalence of FI between groups (OR = 1.30; 95% CI 0.86-1.96; P = 0.21). FI was increased in households of children with both milk and egg allergy when compared to those without food allergy and those with single food allergy (OR = 2.5; 95% CI 1.4-4.6; P = 0.003). Mean HL rates were higher in the food-secure vs food-insecure groups (mean diff = 0.31; 95% CI 0.03-0.59; P = 0.03). Among food-allergic children, QOL was better in the food-secure vs food-insecure group (mean diff = 0.61; 95% CI 0.002-1.23; P = 0.049). CONCLUSION: Food allergy to milk and egg was associated with increased risk of household FI. Food-insecure participants had lower HL than their food-secure counterparts. Further work is needed to define risks associated with FI among food-allergic children to improve screening and management strategies.

Advances in the approach to the patient with food allergy.

Advances in food allergy diagnosis, management, prevention, and therapeutic interventions have been significant over the past 2 decades. Evidence-based national and international guidelines have streamlined food allergy diagnosis and management, whereas paradigm-shifting work in primary prevention of peanut allergy has resulted in significant modifications in the approach to early food introduction in infants and toddlers. Innovative investigation of food allergy epidemiology, systems biology, effect, and management has provided important insights. Although active therapeutic approaches to food allergy remain experimental, progress toward licensed therapies has been substantial. Mechanistic understanding of the immunologic processes underlying food allergy and immunotherapy will inform the future design of therapeutic approaches targeting the food-induced allergic response. Global strategies to mitigate the substantial medical, economic, and psychosocial burden of food allergy in affected subjects and families will require engagement of stakeholders across multiple sectors in research, health care, public health, government, educational institutions, and industry. However, the relationship between the well-informed allergy care provider and the patient and family remains fundamental for optimizing the care of the patient with food allergy.

T Cell-Independent Gamma Interferon and B Cells Cooperate To Prevent Mortality Associated with Disseminated Chlamydia muridarum Genital Tract Infection.

CD4 T cells and antibody are required for optimal acquired immunity to Chlamydia muridarum genital tract infection, and T cell-mediated gamma interferon (IFN-γ) production is necessary to clear infection in the absence of humoral immunity. However, the role of T cell-independent immune responses during primary infection remains unclear. We investigated this question by inoculating wild-type and immune-deficient mice with C. muridarum CM001, a clonal isolate capable of enhanced extragenital replication. Genital inoculation of wild-type mice resulted in transient dissemination to the lungs and spleen that then was rapidly cleared from these organs. However, CM001 genital infection proved lethal for STAT1-/- and IFNG-/- mice, in which IFN-γ signaling was absent, and for Rag1-/- mice, which lacked T and B cells and in which innate IFN-γ signaling was retained. In contrast, B cell-deficient muMT mice, which can generate a Th1 response, and T cell-deficient mice with intact B cell and innate IFN-γ signaling survived. These data collectively indicate that IFN-γ prevents lethal CM001 dissemination in the absence of T cells and suggests a B cell corequirement. Adoptive transfer of convalescent-phase immune serum but not naive IgM to Rag1-/- mice infected with CM001 significantly increased the survival time, while transfer of naive B cells completely rescued Rag1-/- mice from CM001 lethality. Protection was associated with a significant reduction in the lung chlamydial burden of genitally infected mice. These data reveal an important cooperation between T cell-independent B cell responses and innate IFN-γ in chlamydial host defense and suggest that interactions between T cell-independent antibody and IFN-γ are essential for limiting extragenital dissemination.

Novel baseline predictors of adverse events during oral immunotherapy in children with peanut allergy.

BACKGROUND: Though peanut oral immunotherapy (OIT) is a promising investigational therapy, its potential is limited by substantial adverse events (AEs), which are relatively understudied. OBJECTIVE: A retrospective analysis was conducted, pooling data from 3 pediatric peanut OIT trials, comprising the largest analysis of peanut OIT safety to date. METHODS: We pooled data from 104 children with peanut allergy from 3 peanut OIT studies. We catalogued AEs from parental reports, daily symptom diaries, and dose escalations. We included events that were considered likely related to OIT and identified potential baseline predictors of higher AE rates using generalized linear regression models. RESULTS: Eighty percent of subjects experienced likely related AEs during OIT (72% during buildup and 47% during maintenance). Of these AEs, over 90% occurred while at home. Approximately 42% of subjects experienced systemic reactions, and 49% experienced gastrointestinal symptoms. Twenty percent of subjects dropped out, with half (10% of the overall group) due to persistent gastrointestinal symptoms. Baseline allergic rhinitis (AR) and peanut SPT wheal size were significant predictors of higher overall AE rates. SPT wheal size predicted increased gastrointestinal AEs, and AR predicted increased systemic reactions. Over the course of OIT, 61% of subjects received treatment for likely related AEs, 59% with antihistamines and 12% with epinephrine. CONCLUSIONS: Peanut OIT is associated with frequent AEs, with rates declining over time, and most graded mild. However, systemic reactions and intolerable gastrointestinal AEs do occur and are significantly associated with AR and peanut SPT wheal size, respectively. Further study is needed of predictive biomarkers and the overall risks and benefits of OIT.

Effects of allergen sensitization on response to therapy in children with eosinophilic esophagitis.

BACKGROUND: In children with eosinophilic esophagitis (EoE) foods are the most common disease triggers, but environmental allergens are also suspected culprits. OBJECTIVE: To determine the effects of environmental allergen sensitization on response to treatment in children with EoE in the southeastern United States. METHODS: Patients 2 to 18 years old who were referred to the Arkansas Children's Hospital Eosinophilic Gastrointestinal Disorders Clinic from January 2012 to January 2016 were enrolled in a prospective, longitudinal cohort study with collection of demographics, clinical symptoms, medical history, allergy sensitization profiles, and response to treatment over time. Comparisons were made between complete responders (peak esophageal eosinophil count <15 per high-power field [HPF]) and nonresponders (>25 eosinophils per HPF) after treatment with diet elimination alone, swallowed corticosteroids alone, or diet elimination and swallowed corticosteroids. Sensitization patterns to environmental allergens found in the southeastern United States were analyzed for the effect on treatment response. RESULTS: A total of 223 individuals were enrolled. Of these, 182 had environmental allergy profiling and at least one endoscopy while receiving proton pump inhibitor (PPI) therapy. Twenty-nine individuals had PPI-responsive EoE and were excluded from further analysis, leaving 123 individuals with non-PPI-responsive EoE who were further analyzed; 72 (58.5%) were complete responders and 33 (26.8%) were nonresponders. Seventeen individuals (13.8%) were partial responders (≥1 but ≤25 eosinophils per HPF) and excluded from further analysis. Nonresponders were more likely to be sensitized to perennial allergens (P = .02). There was no significant difference in response based on seasonal allergen sensitization. Individuals with mold or cockroach sensitization were more likely to fail combination diet and swallowed corticosteroid treatment (P = .02 and P = .002). CONCLUSION: Perennial allergen and mold sensitization may lead to nonresponse to EoE treatment in some patients. Additional studies are needed to further understand the effect of environmental allergens on EoE. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01779154.

Long-term treatment with egg oral immunotherapy enhances sustained unresponsiveness that persists after cessation of therapy.

BACKGROUND: We previously reported the results of a randomized placebo-controlled study of egg oral immunotherapy (eOIT) in which 27.5% of subjects achieved sustained unresponsiveness (SU) after 2 years. Here we report the results of treatment through 4 years and long-term follow-up. OBJECTIVE: We sought to evaluate the efficacy and safety of eOIT in participants treated up to 4 years. METHODS: Children with egg allergy (5-18 years old) received eOIT (n = 40) for up to 4 years or placebo (n = 15) for 1 year or less. The key outcome was the percentage of subjects achieving SU by year 4. Safety and immunologic assessments were performed, and long-term follow-up questionnaires (LFQs) were administered after study conclusion (LFQ-1) and 1 year later (LFQ-2). RESULTS: Of 40 eOIT-treated subjects, 20 (50.0%) of 40 demonstrated SU by year 4. For those subjects still dosing during years 3 and 4, mild symptoms were present in 12 (54.5%) of 22 subjects. At the time of the LFQ, more subjects receiving eOIT (LFQ-1, 23/34 [68%]; LFQ-2, 21/33 [64%]) were consuming unbaked and baked egg versus placebo (LFQ-1, 2/11 [18%], P = .006; LFQ-2, 3/12 [25%], P = .04). Of subjects achieving SU, 18 (90%) of 20 completed the LFQ, with 18 (100%) of 18 reporting consumption of all forms of egg. When compared with subjects not achieving SU, subjects achieving SU had higher IgG4 values (P = .001) and lower egg skin prick test scores (P = .0002) over time and a lower median baseline ratio of egg-specific IgE to total IgE (1.1% vs 2.7%, P = .04). CONCLUSIONS: SU after eOIT is enhanced with longer duration of therapy and increases the likelihood of tolerating unbaked egg in the diet.

Sublingual immunotherapy for peanut allergy: Long-term follow-up of a randomized multicenter trial.

BACKGROUND: We previously reported the initial results of the first multicenter, randomized, double-blind, placebo-controlled clinical trial of peanut sublingual immunotherapy (SLIT), observing a favorable safety profile associated with modest clinical and immunologic effects in the first year. OBJECTIVE: We sought to provide long-term (3-year) clinical and immunologic outcomes for our peanut SLIT trial. Key end points were (1) percentage of responders at 2 years (ie, could consume 5 g of peanut powder or a 10-fold increase from baseline), (2) percentage reaching desensitization at 3 years, (3) percentage attaining sustained unresponsiveness after 3 years, (4) immunologic end points, and (5) assessment of safety parameters. METHODS: Response to treatment was evaluated in 40 subjects aged 12 to 40 years by performing a 10-g peanut powder oral food challenge after 2 and 3 years of daily peanut SLIT therapy. At 3 years, SLIT was discontinued for 8 weeks, followed by another 10-g oral food challenge and an open feeding of peanut butter to assess sustained unresponsiveness. RESULTS: Approximately 98% of the 18,165 doses were tolerated without adverse reactions beyond the oropharynx, with no severe symptoms or uses of epinephrine. A high rate (>50%) discontinued therapy. By study's end, 4 (10.8%) of 37 SLIT-treated participants were fully desensitized to 10 g of peanut powder, and all 4 achieved sustained unresponsiveness. Responders at 2 years showed a significant decrease in peanut-specific basophil activation and skin prick test titration compared with nonresponders. CONCLUSIONS: Peanut SLIT induced a modest level of desensitization, decreased immunologic activity over 3 years in responders, and had an excellent long-term safety profile. However, most patients discontinued therapy by the end of year 3, and only 10.8% of subjects achieved sustained unresponsiveness.