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3.  Guidelines for the Diagnosis and Management of Food Allergy in the United States 
Food allergy is an important public health problem that affects children and adults and may be increasing in prevalence. Despite the risk of severe allergic reactions and even death, there is no current treatment for food allergy: the disease can only be managed by allergen avoidance or treatment of symptoms. The diagnosis and management of food allergy also may vary from one clinical practice setting to another. Finally, because patients frequently confuse nonallergic food reactions, such as food intolerance, with food allergies, there is an unfounded belief among the public that food allergy prevalence is higher than it truly is. In response to these concerns, the National Institute of Allergy and Infectious Diseases, working with 34 professional organizations, federal agencies, and patient advocacy groups, led the development of clinical guidelines for the diagnosis and management of food allergy. These Guidelines are intended for use by a wide variety of health care professionals, including family practice physicians, clinical specialists, and nurse practitioners. The Guidelines include a consensus definition for food allergy, discuss comorbid conditions often associated with food allergy, and focus on both IgE-mediated and non-IgE-mediated reactions to food. Topics addressed include the epidemiology, natural history, diagnosis, and management of food allergy, as well as the management of severe symptoms and anaphylaxis. These Guidelines provide 43 concise clinical recommendations and additional guidance on points of current controversy in patient management. They also identify gaps in the current scientific knowledge to be addressed through future research.
PMCID: PMC4241964  PMID: 21134576
food; allergy; anaphylaxis; diagnosis; disease management; guidelines
5.  Identification, Epidemiology and Chronicity of Pediatric Esophageal Eosinophilia from 1982–1999 
Eosinophilic Esophagitis (EE) is now a commonly encountered disorder that was rarely diagnosed a decade ago.
We aimed to determine the epidemiologic and histologic features of retrospective pediatric esophageal eosinophilia before the first case of EE at our institution was recognized.
Esophageal biopsies obtained between 1982–1999 with reflux esophagitis were re-examined and re-organized into 2 groups based on peak esophageal eosinophil number (<15 eos/hpf, ≥ 15 eos/hpf). The epidemiology and histology of the entire cohort and a population based cohort were evaluated.
807 biopsies from 666 patients were re-examined; 198 patients had ≥ 15 eos/hpf. Among a population-based cohort of patients with ≥ 15 eos/hpf, there was a modest increase in incidence (p < 0.001; IRR 1.18; CI 1.09–1.28). After correcting for a 40-fold increase in the number of endoscopies during this time period, the proportion of biopsies with ≥ 15 eos/hpf did not change (0.08 in 1982 vs. 0.08 in 1996 (peak), (p = 0.9; IRR 1.02; CI 0.73 –1.44). Patients who had as few as 5 eos/hpf were more likely to have persistent esophageal eosinophilia on repeat EGD, evidence of basal layer hyperplasia and lamina propria fibrosis compared to patients with < 5 eos/hpf (p <0.001).
Esophageal Eosinophilia, at levels consistent with EE, was present among 30% of patients diagnosed with reflux esophagitis and the incidence of esophageal eosinophilia did not change over time. Patients with ≥ 5 eos/hpf had evidence of other histologic abnormalities and were likely to have persistent esophageal eosinophilia.
PMCID: PMC4115587  PMID: 20620567
eosinophilic esophagitis; incidence; diagnosis; chronic esophagitis; eosinophil; esophagitis; epidemiology; retrospective
6.  NIAID-Sponsored 2010 Guidelines for Managing Food Allergy: Applications in the Pediatric Population 
Pediatrics  2011;128(5):955-965.
Data from many studies have suggested a rise in the prevalence of food allergies during the past 10 to 20 years. Currently, no curative treatments for food allergy exist, and there are no effective means of preventing the disease. Management of food allergy involves strict avoidance of the allergen in the patient's diet and treatment of symptoms as they arise. Because diagnosis and management of the disease can vary between clinical practice settings, the National Institute of Allergy and Infectious Diseases (NIAID) sponsored development of clinical guidelines for the diagnosis and management of food allergy. The guidelines establish consensus and consistency in definitions, diagnostic criteria, and management practices. They also provide concise recommendations on how to diagnose and manage food allergy and treat acute food allergy reactions. The original guidelines encompass practices relevant to patients of all ages, but food allergy presents unique and specific concerns for infants, children, and teenagers. To focus on those concerns, we describe here the guidelines most pertinent to the pediatric population.
PMCID: PMC3208961  PMID: 21987705
food allergy; food hypersensitivity; infants; children; guidelines; anaphylaxis
7.  Long-term Outcomes in Pediatric-Onset Esophageal Eosinophilia 
Pediatric eosinophilic esophagitis (EoE) is a newly recognized antigen-induced form of chronic esophagitis.
Characterization of long-term clinical outcomes in pediatric EoE patients is needed.
From histologic review of 3,817 pediatric esophageal biopsies from 1982–1999, we conducted a nested case-control study of patients with retrospectively-identified histologic eosinophilic esophagitis (rEoE) and chronic esophagitis (CE), as well as an age-matched control cohort. Participants were asked to complete validated health-related outcome questionnaires.
After an average of 15 years following initial endoscopy, both cohorts, 42/198 rEoE and 67/468 CE patients (as well as 100 age-matched controls), completed questionnaires. Compared to control patients, quality of life was significantly decreased among rEoE patients (P<0.001) and CE patients (P<0.001). Rates of dysphagia (rEoE 49%; CE 37%; control 6%) and food impaction (rEoE 40%; CE 14%; control 3%) were significantly increased in the rEoE cohort compared to controls (P<0.001, P<0.001 respectively). Increased esophageal eosinophil counts (OR 1.6; 95% CI 1.1–2.5; P<0.05) during childhood were predictive of dysphagia during early adulthood. Food allergy (OR 2.7; CI 1.2, 6.0; P<0.01), allergic rhinitis (OR 3.5; CI 1.8, 6.8; P<0.001), and asthma (OR 2.1; CI 1.04, 4.3; P=0.04) were associated with dysphagia. Food impaction was more common among patients with reported food allergy than those without (OR 3.1; CI 1.2, 7.8; P=0.02).
Esophageal eosinophilia is associated with reduced quality of life and persistent symptoms 15 years after presentation. Elevated esophageal eosinophil counts and the occurrence of food allergy and atopy in childhood increase the rate of dysphagia in young adulthood.
PMCID: PMC3130990  PMID: 21636117
eosinophilic esophagitis; pediatric; patient-reported outcomes; natural history; eosinophil
8.  The Greater Cincinnati Pediatric Clinic Repository: A Novel Framework for Childhood Asthma and Allergy Research 
Allergic disorders, including asthma, allergic rhinitis, atopic dermatitis, eosinophilic esophagitis, and food allergy, are a major global health burden. The study and management of allergic disorders is complicated by the considerable heterogeneity in both the presentation and natural history of these disorders. Biorepositories serve as an excellent source of data and biospecimens for delineating subphenotypes of allergic disorders, but such resources are lacking.
In order to define subphenotypes of allergic disease accurately, we established an infrastructure to link and efficiently utilize clinical and epidemiologic data with biospecimens into a single biorepository called the Greater Cincinnati Pediatric Clinic Repository (GCPCR). Children with allergic disorders as well as healthy controls are followed longitudinally at hospital clinic, emergency department, and inpatient visits. Subjects' asthma, allergy, and skin symptoms; past medical, family, social, diet, and environmental histories; physical activity; medication adherence; perceived quality of life; and demographics are ascertained. DNA is collected from all participants, and other biospecimens such as blood, hair, and nasal epithelial cells are collected on a subset.
To date, the GCPCR has 6,317 predominantly Caucasian and African American participants, and 93% have banked DNA. This large sample size supports adequately powered genetic, epidemiologic, environmental, and health disparities studies of childhood allergic diseases.
The GCPCR is a unique biorepository that is continuously evaluated and refined to achieve and maintain rigorous clinical phenotype and biological data. Development of similar disease-specific repositories using common data elements is necessary to enable studies across multiple populations of comprehensively phenotyped patients.
PMCID: PMC3377950  PMID: 22768387
9.  What is new in the treatment of eosinophilic eosophagitis? 
Clinical and Translational Allergy  2011;1(Suppl 1):S69.
PMCID: PMC3354300
10.  Variants of thymic stromal lymphopoietin and its receptor associate with eosinophilic esophagitis 
The genetic etiology of eosinophilic esophagitis (EE) has been largely unexplored until a recent genome-wide association study identified a disease susceptibility locus on 5q22, a region that harbors the thymic stromal lymphopoietin (TSLP) gene. However, it is unclear whether the observed genetic associations with EE are disease-specific or confounded by the high rate of allergy in EE patients. In addition, the genetic contributions of other allergy associated genes to EE risk have not been explored.
We aimed to delineate single nucleotide polymorphisms (SNP)s that associated with EE apart from allergy.
We utilized a custom array containing 738 SNPs in 53 genes implicated in allergic and/or immune responses to genotype 220 allergic or 246 non-allergic controls and a discovery cohort of 170 EE patients. We replicated a statistically significant SNP association in an independent case-control cohort and examined the induction of the candidate gene in primary esophageal epithelial cells.
A single SNP residing in the TSLP gene reached Bonferroni LD adjusted significance and only when EE cases were compared with allergic controls (rs10062929, P = 4.11 × 10−5, odds ratio = 0.35). A non-synonymous polymorphism in the TSLP receptor on Xp22.3 and Yp11.3 was significantly associated with disease only in male EE patients. Primary esophageal epithelial cells expressed TSLP mRNA following Toll-like receptor 3 (TLR3) stimulation.
These data collectively identify TSLP as a candidate gene critically involved in EE susceptibility beyond its role in promoting Th2 responses.
PMCID: PMC2904342  PMID: 20620568
Eosinophilic esophagitis; thymic stromal lymphopoietin; single nucleotide polymorphism; allergy; cytokine receptor-like factor 2; Toll-like receptor 3
11.  Anti–IL-5 (mepolizumab) therapy reduces eosinophil activation ex vivo and increases IL-5 and IL-5 receptor levels 
Anti–IL-5 might be a useful therapeutic agent for eosinophilic disorders, yet its immunologic consequences have not been well characterized.
We sought to characterize the hematologic and immunologic effects of anti-IL-5 in human subjects.
The effects of 3-month infusions of mepolizumab were assessed in 25 patients with a variety of eosinophilic syndromes. Samples with increased IL-5 levels after therapy were analyzed by using size exclusion filtration. Immunoreactive IL-5 fraction and plasma samples were subsequently precipitated with saturating concentrations of protein A/G.
Twenty-three patients responded to anti–IL-5 therapy with a decrease in blood eosinophil counts and a reduced percentage of CCR3+ cells by 20- and 13-fold, respectively (P < .0001). Responsiveness was not related to the levels of baseline plasma IL-5 or the presence of FIP1L1-PDGFRA fusion gene. Persistently decreased blood eosinophilia remained for 3 months after final infusion in76%of subjects. Therapy was associated with a large increase in blood IL-5 levels, likely because of a circulating IL-5/mepolizumab complex precipitated with protein A/G, a significant increase in eosinophil IL-5 receptor α expression, and increased percentage of CD4+ and CD8+ cells producing intracellular IL-5 (P <.05). Additionally, anti-IL-5 therapy decreased eotaxin-stimulated eosinophil shape change ex vivo.
Anti–IL-5 therapy induces a dramatic and sustained decrease in blood eosinophilia (including CCR3+ cells), decreased eosinophil activation, and increased circulating levels of IL-5 in a variety of eosinophilic disorders. Increased levels of IL-5 receptor α and lymphocyte IL-5 production after anti–IL-5 therapy suggest an endogenous IL-5 autoregulatory pathway.
PMCID: PMC2749495  PMID: 18410960
Anti–IL-5; cytokines; eosinophilia; esophagitis; hypereosinophilic; IL-5; inflammation; mepolizumab
Eosinophilic esophagitis (EE) occurs in families, but neither familial EE clustering nor phenotype/genotype of familial compared with sporadic EE have not been reported.
Record review confirmed patient kinship and provided clinical information. Slide review confirmed the diagnosis (threshold peak number •24 eosinophils/hpf).
Fifty-nine members (41 males, 18 females) of 26 families were 3 months to 47 years of age (mean age 10.3 years) at diagnosis. The only recorded race was Caucasian. In four families, a parent of an affected male had EE. The most common complaint at diagnosis was dysphagia (68% of patients). Endoscopy showed esophageal mucosal furrows (93% of patients), and exudates (44%). Fifty-one percent had asthma. Skin prick tests to food and aeroallergens were positive in 76% and 71%, respectively. Familial EE characteristics (clinical, endoscopic, pathological, and global esophageal transcript expression profile analysis) were similar to sporadic EE, except among patients with mucosal furrows: familial patients had lower peak eosinophil counts in the distal esophagus (P = 0.03) compared with sporadic patients. The basic characteristics of EE (e.g., eosinophil levels, rate of atopy) did not vary with patient age. Using genome wide microarray analysis, no significant differences (P<0.05, FDR) were observed between familial and sporadic EE. Among all patients, chest pain was more common in females (P = 0.02), and thickened mucosa in males (P = 0.006).
These data support a familial pattern of inheritance of EE and a pathogenesis shared with sporadic EE. EE should be considered in symptomatic family members of patients who have EE.
PMCID: PMC2701188  PMID: 18434257
13.  Eotaxin-3 and a uniquely conserved gene-expression profile in eosinophilic esophagitis 
Journal of Clinical Investigation  2006;116(2):536-547.
Eosinophilic esophagitis (EE) is an emerging disorder with a poorly understood pathogenesis. In order to define disease mechanisms, we took an empirical approach analyzing esophageal tissue by a genome-wide microarray expression analysis. EE patients had a striking transcript signature involving 1% of the human genome that was remarkably conserved across sex, age, and allergic status and was distinct from that associated with non-EE chronic esophagitis. Notably, the gene encoding the eosinophil-specific chemoattractant eotaxin-3 (also known as CCL26) was the most highly induced gene in EE patients compared with its expression level in healthy individuals. Esophageal eotaxin-3 mRNA and protein levels strongly correlated with tissue eosinophilia and mastocytosis. Furthermore, a single-nucleotide polymorphism in the human eotaxin-3 gene was associated with disease susceptibility. Finally, mice deficient in the eotaxin receptor (also known as CCR3) were protected from experimental EE. These results implicate eotaxin-3 as a critical effector molecule for EE and provide insight into disease pathogenesis.
PMCID: PMC1359059  PMID: 16453027

Results 1-13 (13)