Clinical and molecular correlates of the Index of Severity for Eosinophilic Esophagitis.

BACKGROUND: The Index of Severity for Eosinophilic Esophagitis (I-SEE) is a new expert-defined clinical tool that classifies disease severity of eosinophilic esophagitis (EoE). OBJECTIVE: We aimed to determine whether I-SEE is associated with patient characteristics, molecular features of EoE, or both. METHODS: We analyzed a prospective cohort of patients with EoE from the Consortium of Eosinophilic Gastrointestinal Disease Researchers (CEGIR). Associations between I-SEE and clinical and molecular features (assessed by an EoE diagnostic panel [EDP]) were assessed. RESULTS: In 318 patients with chronic EoE (209 adults, 109 children), median total I-SEE score was 7.0, with a higher symptoms and complications score in children than adults (4.0 vs 1.0; P < .001) and higher inflammatory and fibrostenotic features scores in adults than children (3.0 vs 1.0 and 3.0 vs 0, respectively; both P < .001). Total I-SEE score had a bimodal distribution with the inactive to moderate categories and severe category. EDP score correlated with total I-SEE score (r = -0.352, P < .001) and both inflammatory and fibrostenotic features scores (r = -0.665, P < .001; r = -0.446, P < .001, respectively), but not with symptoms and complications scores (r = 0.047, P = .408). Molecular severity increased from inactive to mild and moderate, but not severe, categories. Longitudinal changes of modified I-SEE scores and inflammatory and fibrostenotic features scores reflected histologic and molecular activity. CONCLUSIONS: I-SEE score is associated with select clinical features across severity categories and with EoE molecular features for nonsevere categories, warranting further validation.

Nonepithelial Gene Expression Correlates With Symptom Severity in Adults With Eosinophilic Esophagitis.

BACKGROUND: The mechanistic basis of the variable symptomatology seen in eosinophilic esophagitis (EoE) remains poorly understood. OBJECTIVE: We examined the correlation of a validated, patient-reported outcome metric with a broad spectrum of esophageal transcripts to uncover potential symptom pathogenesis. METHODS: We extracted data from 146 adults with EoE through the Consortium of Eosinophilic Gastrointestinal Disease Researchers. Patients were subgrouped by esophageal dilation history. We compared a validated patient-reported outcome metric, the EoE Activity Index (EEsAI), with a set of transcripts expressed in the esophagus of patients with EoE, the EoE Diagnostic Panel (EDP). We used single-cell RNA sequencing data to identify the cellular source of EEsAI-related EDP genes and further analyzed patients with mild and severe symptoms. RESULTS: The EEsAI correlated with the EDP total score, especially in patients without recent esophageal dilation (r = -0.31; P = .003). We identified 14 EDP genes that correlated with EEsAI scores (r ≥ 0.3; P < .05). Of these, 11 were expressed in nonepithelial cells and three in epithelial cells. During histologic remission, only four of 11 nonepithelial genes (36%) versus all three epithelial genes (100%) had decreased expression to less than 50% of that in active EoE. Fibroblasts expressed five of 11 nonepithelial EEsAI-associated EDP genes (45%). A subset of nonepithelial genes (eight of 11; 73%), but not EoE-representative genes (none of four; 0%; CCL26, CAPN14, DSG1, and SPINK7), was upregulated in patients with EoE with the highest versus lowest symptom burden. CONCLUSION: The correlation of symptoms and nonepithelial esophageal gene expression substantiates that nonepithelial cells (eg, fibroblasts) likely contribute to symptom severity.

Pharmacologic Management of Eosinophilic Esophagitis.

Proton pump inhibitors (PPIs), swallowed topical corticosteroids (STSs), and dupilumab are highly effective therapies for the treatment of eosinophilic esophagitis. Shared decision-making informs the choice of therapy and factors such as ease of use, safety, cost, and efficacy should be addressed. PPIs are the most common medication utilized early in the disease course; however, for nonresponders, STSs are an excellent alternative. Dupilumab is unlikely to replace PPIs or STSs as first-line therapy, except in highly specific circumstances. Identification of novel biologic pathways and the development of small molecules may lead to a wider range of treatment options in the future.

Clinicopathologic Correlations in Eosinophilic Gastrointestinal Disorders.

Eosinophilic gastrointestinal disorders (EGIDs) are a collection of disorders characterized by allergy-driven inflammation of the gastrointestinal (GI) tract. Affected patients typically present with nonspecific symptoms of GI dysfunction and are frequently found to have mucosal abnormalities during endoscopy as well as increased eosinophil levels on tissue biopsy that are felt to be responsible for generating the clinical findings. Each of these findings is important in both the diagnosis and management of EGIDs. Understanding the impact of histopathologic and endoscopic changes on clinical signs and symptoms is critical to developing an understanding of the natural history of these disorders as well as to the generation of validated assessment tools and targeted therapies. We explore these relationships in this review.

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.

Genetic variants at the 16p13 locus confer risk for eosinophilic esophagitis.

Eosinophilic esophagitis (EoE) is a chronic inflammatory disease of the esophagus triggered by immune hypersensitivity to food. Herein, we tested whether genetic risk factors for known, non-allergic, immune-mediated diseases, particularly those involving autoimmunity, were associated with EoE risk. We used the high-density Immunochip platform, encoding 200,000 genetic variants for major auto-immune disease. Accordingly, 1214 subjects with EoE of European ancestry and 3734 population controls were genotyped and assessed using data directly generated or imputed from the previously published GWAS. We found lack of association of EoE with the genetic variants in the major histocompatibility complex (MHC) class I, II, and III genes and nearly all other loci using a highly powered study design with dense genotyping throughout the locus. Importantly, we identified an EoE risk locus at 16p13 with genome-wide significance (Pcombined=2.05 × 10-9, odds ratio = 0.76-0.81). This region is known to encode for the genes CLEC16A, DEXI, and CIITI, which are expressed in immune cells and esophageal epithelial cells. Suggestive EoE risk were also seen 5q23 (intergenic) and 7p15 (JAZF1). Overall, we have identified an additional EoE risk locus at 16p13 and highlight a shared and unique genetic etiology of EoE with a spectrum of immune-associated diseases.

Phenotypic Characterization of Eosinophilic Esophagitis in a Large Multicenter Patient Population from the Consortium for Food Allergy Research.

BACKGROUND: Eosinophilic esophagitis (EoE) is increasingly common, but data on phenotypic aspects are still incomplete. OBJECTIVES: To describe the clinical, endoscopic, and histopathologic features of a large number of children and adults with EoE across the United States. METHODS: This was a multisite single visit registry enrolling subjects aged 6 months to 65 years with EoE. Participants provided responses regarding their medical history, with verification of the diagnosis and history by the study teams. RESULTS: A total of 705 subjects were analyzed (median [interquartile range] age at enrollment 11.2 [6.7-17.7] years, 68.2% male, 87.9% whites). Of these, 67 subjects had concurrent gastrointestinal eosinophilia, with gastric mucosa most common. An age- and race-dependent time gap was present between symptom onset and time of diagnosis (adults and whites with longer gap). Food allergy and atopic dermatitis were associated with a decrease in this gap. Symptoms varied with age (more dysphagia and food impaction in adults) and with race (more vomiting in non-whites). Esophageal rings and strictures at diagnosis were more common in adults, although esophageal eosinophilia was comparable among age groups. Concomitant allergic disease (91%), infectious/immunologic disorders (44%), neurodevelopmental disorders (30%), and failure to thrive (21%) were common. Depression/anxiety increased with age. EoE was reported in 3% of parents and 4.5% of siblings. CONCLUSIONS: Gastrointestinal eosinophilia is present in approximately 10% of patients with EoE; the symptom-diagnosis time gap is influenced by age, race, food allergy, and atopic dermatitis; symptoms vary with race; concurrent infectious/immunologic disorders and mental health disorders are common; and the level of esophageal eosinophils is comparable in patients with and without fibrostenotic features.

Epicutaneous immunotherapy for the treatment of peanut allergy in children and young adults.

BACKGROUND: Peanut allergy is common, life-threatening, and without therapeutic options. We evaluated peanut epicutaneous immunotherapy (EPIT) by using Viaskin Peanut for peanut allergy treatment. OBJECTIVE: We sought to evaluate the clinical, safety, and immunologic effects of EPIT for the treatment of peanut allergy. METHODS: In this multicenter, double-blind, randomized, placebo-controlled study, 74 participants with peanut allergy (ages 4-25 years) were treated with placebo (n = 25), Viaskin Peanut 100 µg (VP100; n = 24) or Viaskin Peanut 250 µg (VP250; n = 25; DBV Technologies, Montrouge, France). The primary outcome was treatment success after 52 weeks, which was defined as passing a 5044-mg protein oral food challenge or achieving a 10-fold or greater increase in successfully consumed dose from baseline to week 52. Adverse reactions and mechanistic changes were assessed. RESULTS: At week 52, treatment success was achieved in 3 (12%) placebo-treated participants, 11 (46%) VP100 participants, and 12 (48%) VP250 participants (P = .005 and P = .003, respectively, compared with placebo; VP100 vs VP250, P = .48). Median change in successfully consumed doses were 0, 43, and 130 mg of protein in the placebo, VP100, and VP250 groups, respectively (placebo vs VP100, P = .014; placebo vs VP250, P = .003). Treatment success was higher among younger children (P = .03; age, 4-11 vs >11 years). Overall, 14.4% of placebo doses and 79.8% of VP100 and VP250 doses resulted in reactions, predominantly local patch-site and mild reactions (P = .003). Increases in peanut-specific IgG4 levels and IgG4/IgE ratios were observed in peanut EPIT-treated participants, along with trends toward reduced basophil activation and peanut-specific TH2 cytokines. CONCLUSIONS: Peanut EPIT administration was safe and associated with a modest treatment response after 52 weeks, with the highest responses among younger children. This, when coupled with a high adherence and retention rate and significant changes in immune pathways, supports further investigation of this novel therapy.

Current and Emerging Therapies for IgE-Mediated Food Allergy.

Food allergies are a growing clinical problem leading to increased health care utilization and decreases in patient quality of life. Current treatment recommendations include strict dietary avoidance of the offending food as well as use of self-injectable epinephrine in case of accidental exposure with allergic reaction. Although many individuals will eventually outgrow their food allergies, a substantial number will not. Significant effort has been made to find novel treatments that protect patients from food-triggered reactions as well as to develop immune-modulating therapies that could lead to tolerance. In this review, three therapies that have shown the most promise for the treatment of food allergies are highlighted: oral immunotherapy, sublingual immunotherapy, and epicutaneous immunotherapy.

Anaphylaxis in food allergy.

Food allergy is a known trigger of anaphylaxis. Although the awareness of food allergies has improved, food-related allergic reactions and anaphylaxis still commonly occur. The recognition of anaphylaxis, its prompt treatment, and patient education are important for the prevention of future food reactions. Patients and health care providers should also recognize the importance of epinephrine as the primary treatment of anaphylaxis. When food-related anaphylaxis occurs, patients should receive education regarding their food allergies, an epinephrine auto-injector, and follow-up with a food allergy specialist to reduce the risk of future food-related reactions.

Correlations between basophil activation, allergen-specific IgE with outcome and severity of oral food challenges.

BACKGROUND: Double-blinded, placebo-controlled food challenges (DBPCFCs) remain the gold standard for diagnosing food allergies. Skin prick tests (SPTs) and allergen-specific IgE (sIgE) are routinely used in medical practice but are not sufficient to predict severity of clinical reactivity. OBJECTIVE: To compare the utility of SPT wheal diameter, sIgE, allergen-specific IgG4 (sIgG4), total IgE (tIgE), sIgE/sIgG4 and sIgE/tIgE ratios, peanut component-specific IgE, and basophil activation in predicting outcome and severity of reactions at DBPCFCs. METHODS: Sixty-seven subjects (12-45 years old) underwent DBPCFCs for peanut, tree nut, fish, shrimp, and/or sesame as part of screening for enrollment in a clinical trial. The SPT, sIgE, tIgE, sIgG4, and peanut component-specific IgE (if applicable) levels were measured. CD63 upregulation on basophils in response to in vitro allergen challenge was analyzed by flow cytometry. Correlations between these measurements and DBPCFC severity scores were analyzed. RESULTS: The SPT and sIgE showed a weak correlation with DBPCFC severity scores, but tIgE and sIgG4 did not. The sIgE/sIgG4 ratio differentiated between positive and negative reactions but did not correlate with DBPCFC severity scores. A low positive correlation was seen between DBPCFC severity score and Ara h 2 IgE, whereas a low negative correlation with Ara h 8 IgE was observed. Basophil activation was positively correlated with DBPCFC severity scores. Receiver operating characteristic curves showed basophil reactivity had the largest area under the curve at 0.904 and sIgE at 0.870. CONCLUSION: These results indicate that basophil activation testing can enhance discrimination between allergic and nonallergic individuals and could serve as an additional tool to predict clinical severity.

Genome-wide association analysis of eosinophilic esophagitis provides insight into the tissue specificity of this allergic disease.

Eosinophilic esophagitis (EoE) is a chronic inflammatory disorder associated with allergic hypersensitivity to food. We interrogated >1.5 million genetic variants in EoE cases of European ancestry and subsequently in a multi-site cohort with local and out-of-study control subjects. In addition to replicating association of the 5q22 locus (meta-analysis P=1.9×10(-16)), we identified an association at 2p23 spanning CAPN14 (P=2.5×10(-10)). CAPN14 was specifically expressed in the esophagus, was dynamically upregulated as a function of disease activity and genetic haplotype and after exposure of epithelial cells to interleukin (IL)-13, and was located in an epigenetic hotspot modified by IL-13. Genes neighboring the top 208 EoE-associated sequence variants were enriched for esophageal expression, and multiple loci for allergic sensitization were associated with EoE susceptibility (4.8×10(-2)

Treatment of Hymenoptera venom allergy: an update.

PURPOSE OF REVIEW: To review and summarize the studies published between 2012 and 2014 about the use of venom immunotherapy (VIT) to treat Hymenoptera hypersensitivity. RECENT FINDINGS: Several studies reconfirm the effectiveness of VIT in both children and adults, and provide a better understanding of its immune-modulating effects. There are concerns about its cost-effectiveness; however, VIT versus self-injectable epinephrine alone when stung is the preferred treatment of choice for affected individuals when quality-of-life issues are considered. Ultrarush VIT may be as effective in children as in adults but is associated with a high risk of systemic allergic reactions (SARs). Controversy continues about the use of angiotensin-converting enzyme inhibitors and their potential for increased SARs while on VIT. Individuals with mast cell disorders, female sex, honeybee allergy, and those receiving rush or ultrarush VITs are at higher risk for SARs. Elevated baseline serum tryptase levels greater than 20 µg/l, SARs during VIT, and honeybee sensitivity are risk factors for VIT failure. SUMMARY: VIT remains the gold standard to treat Hymenoptera-allergic individuals to prevent future sting-induced SARs in both children and adults.

Sustained unresponsiveness to peanut in subjects who have completed peanut oral immunotherapy.

BACKGROUND: Although peanut oral immunotherapy (OIT) has been conclusively shown to cause desensitization, it is currently unknown whether clinical protection persists after stopping therapy. OBJECTIVE: Our primary objective was to determine whether peanut OIT can induce sustained unresponsiveness after withdrawal of OIT. METHODS: We conducted a pilot clinical trial of peanut OIT at 2 US centers. Subjects age 1 to 16 years were recruited and treated for up to 5 years with peanut OIT. The protocol was modified over time to permit dose increases to a maximum of 4000 mg/d peanut protein. Blood was collected at multiple time points. Clinical end points were measured with 5000-mg double-blinded, placebo-controlled food challenges once specific criteria were met. RESULTS: Of the 39 subjects originally enrolled, 24 completed the protocol and had evaluable outcomes. Twelve (50%) of 24 successfully passed a challenge 1 month after stopping OIT and achieved sustained unresponsiveness. Peanut was added to the diet. At baseline and the time of challenge, such subjects had smaller skin test results, as well as lower IgE levels specific for peanut, Ara h 1, and Ara h 2 and lower ratios of peanut-specific IgE/total IgE compared with subjects not passing. There were no differences in peanut IgG4 levels or functional activity at the end of the study. CONCLUSIONS: This is the first demonstration of sustained unresponsiveness after peanut OIT, occurring in half of subjects treated for up to 5 years. OIT favorably modified the peanut-specific immune response in all subjects completing the protocol. Smaller skin test results and lower allergen-specific IgE levels were predictive of successful outcome.

Clinical manifestations of food allergy.

Adverse reactions to foods are a diverse group of clinical syndromes resulting from immunologic and non-immunologic responses to food ingestion. Symptoms can range from mild, self-limiting reactions to severe, life-threatening reactions depending on the mechanism. This review primarily focuses on the clinical manifestations of immunologically derived adverse food reactions or food allergies.The true prevalence of food allergy is unknown. Up to 25% of the general population believes that they may be allergic to some food; however, the actual prevalence of food allergy diagnosed by a provider appears to be 1.5% to 2% of the adult population and approximately 6% to 8% of children. This discrepancy makes it imperative that clinicians are aware of the different food allergy syndromes. With a clear understanding of the clinical manifestations of food allergies, an accurate diagnosis and treatment plan can be formulated. Failing to do so may result in unnecessary dietary restrictions that may adversely affect nutritional status, growth, and quality of life.Most food allergic reactions are secondary to a limited number of foods, and the most common foods causing allergic reactions in children include milk, egg, peanuts, tree nuts, and fish. In adolescents and adults, allergies to peanuts, tree nuts, fish, and shellfish are most prevalent. Food allergies can result from immunoglobulin E (IgE)-mediated, non-IGE-mediated, or mixed IgE/non-IgE mechanisms. The purpose of this review is to discuss the clinical manifestations of each of these types of food allergy.

A comparison of asthma prevalence and morbidity between rural and urban schoolchildren in Arkansas.

BACKGROUND: Asthma disproportionately affects minority and low-income children. Investigations that focus on high-risk pediatric populations outside the inner city are limited. OBJECTIVE: To compare asthma prevalence and morbidity in urban and rural children in Arkansas. METHODS: We administered a validated survey to parents of children enrolled in urban and rural school districts in Arkansas. Rates of asthma diagnosis, asthma symptoms, medication use, and health care utilization were compared between urban and rural groups. RESULTS: Age and sex distributions were similar; however, 85% of rural and 67% of urban children were black and 78% of rural and 37% of urban children had state-issued medical insurance (P < .001 for both). Provider-diagnosed asthma was similar in the rural vs urban groups (19% vs 20%); however, rural children were more commonly diagnosed as having chronic bronchitis (7% vs. 2%, P < .001). Rural children had more asthma morbidity compared with urban children, including recurrent trouble breathing (odds ratio [OR], 1.9; 95% confidence interval [CI], 1.5-2.2), recurrent cough (OR, 2.2; 95% CI, 1.9-2.6), recurrent chest tightness (OR, 1.8; 95% CI, 1.5-2.2), and repeated episodes of bronchitis (OR, 2.2; 95% CI, 1.7-2.8) during the preceding 2 years. Rural children were more likely to report symptoms consistent with moderate to severe asthma compared with urban children (46% vs. 35%, P < .001). There were no differences in health care utilization between groups. CONCLUSION: Asthma prevalence was similar between representative rural and urban groups in Arkansas, but asthma morbidity was significantly higher in the rural group.