Assessing Disparities in the Prevalence of Atopic Comorbidities Among Food-Allergic Children.

BACKGROUND: Previous studies have reported that Black children with food allergy (FA) have higher risk of atopic comorbidities than White children. OBJECTIVE: Our study sought to understand if disparities in the prevalence of atopic comorbidities among children with FA are driven by individual and community-level socioeconomic status (SES). METHODS: We analyzed data from a prospective, multicenter cohort investigating the natural history of pediatric atopy: the Food Allergy Outcomes Related to White and African American Racial Differences (FORWARD) study. A validated, multicomponent area deprivation index (ADI) percentile score was tabulated by the census block group for each subject's home address. The association of ADI with atopic comorbidities in FA was assessed via multivariable regression analysis. RESULTS: Of the 700 children in this study, the mean ADI was 37.7 (95% confidence interval: 35.6-39.7). The mean ADI was higher in children with asthma (43.3) compared with those without asthma (31.8), which remained significant after adjusting for race (P < .0001). Children with allergic rhinitis (AR) had a higher mean ADI (39.1) compared with those without (33.4) (P = .008). ADI was associated with secondhand smoking, parents' education, and household income. Black children had a higher risk for asthma after adjusting for ADI and SES-related factors. CONCLUSION: The independent association of ADI with asthma and AR, regardless of race, suggests a role of neighborhood-level socioeconomic deprivation in the development of these conditions among children with FA. Black children with FA remained at higher risk for asthma after adjusting for SES-related variables, which can indicate an independent risk for asthma in these children.

Monoclonal Antibodies for Treatment of Eosinophilic Esophagitis.

Eosinophilic esophagitis (EoE) is a chronic inflammatory disease of the esophagus affecting both children and adults, with debilitating and progressive symptoms. EoE has shown an explosive epidemiological rise in the past few decades. Many patients experience a poor level of disease control despite maximal use of available guideline-based therapies, which seriously hampers their quality of life. Diet restrictions and systemic and topical corticosteroids are the current mainstays of EoE therapy, but are associated with significant efficacy, treatment compliance, and safety issues such as oral or esophageal candidiasis, growth retardation, osteopenia, osteoporosis, glucose intolerance, and cataract formation. As EoE is a chronic inflammatory disease, immune cells and cytokines are responsible for the inflammatory response and symptoms. Monoclonal antibodies specifically targeting these pathophysiologic effectors offer more potent relief of histologic and clinical disease features while keeping off-target adverse effects to a minimum. Herein, we have reviewed the current evidence regarding efficacy and safety of monoclonal antibodies including mepolizumab (anti-IL-5), reslizumab (anti-IL-5), QAX576 (anti-IL-13), omalizumab (anti-immunoglobulin-E), and infliximab (anti-TNF-α) in treatment of EoE. Our review indicates that although the use of monoclonal antibodies for EoE treatment is safe with limited and reversible adverse events, however, it is not yet possible to reach a final verdict on the efficacy of mAbs in EoE. Future well-designed studies are needed to clarify the exact role of mAbs in EoE.

Defects of B-cell terminal differentiation in patients with type-1 Kabuki syndrome.

BACKGROUND: Kabuki syndrome (KS) is a complex multisystem developmental disorder associated with mutation of genes encoding histone-modifying proteins. In addition to craniofacial, intellectual, and cardiac defects, KS is also characterized by humoral immune deficiency and autoimmune disease, yet no detailed molecular characterization of the KS-associated immune phenotype has been reported. OBJECTIVE: We sought to characterize the humoral immune defects found in patients with KS with lysine methyltransferase 2D (KMT2D) mutations. METHODS: We comprehensively characterized B-cell function in a cohort (n = 13) of patients with KS (age, 4 months to 27 years). RESULTS: Three quarters (77%) of the cohort had a detectable heterozygous KMT2D mutation (50% nonsense, 20% splice site, and 30% missense mutations), and 70% of the reported mutations are novel. Among the patients with KMT2D mutations (KMT2D(Mut/+)), hypogammaglobulinemia was detected in all but 1 patient, with IgA deficiency affecting 90% of patients and a deficiency in at least 1 other isoform seen in 40% of patients. Numbers of total memory (CD27(+)) and class-switched memory B cells (IgM(-)) were significantly reduced in patients with KMT2D(Mut/+) mutations compared with numbers in control subjects (P < .001). Patients with KMT2D(Mut/+) mutations also had significantly reduced rates of somatic hypermutation in IgG (P = .003) but not IgA or IgM heavy chain sequences. Impaired terminal differentiation was noted in primary B cells from patients with KMT2D(Mut/+) mutations. Autoimmune pathology was observed in patients with missense mutations affecting the SET domain and its adjacent domains. CONCLUSIONS: In patients with KS, autosomal dominant KMT2D mutations are associated with dysregulation of terminal B-cell differentiation, leading to humoral immune deficiency and, in some cases, autoimmunity. All patients with KS should undergo serial clinical immune evaluations.

Identification, epidemiology, and chronicity of pediatric esophageal eosinophilia, 1982-1999.

BACKGROUND: Eosinophilic esophagitis (EE) is now a commonly encountered disorder that was rarely diagnosed a decade ago. OBJECTIVE: 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. METHODS: Esophageal biopsy specimens obtained between 1982 and 1999 with reflux esophagitis were re-examined and reorganized into 2 groups based on peak esophageal eosinophil number (<15 eosinophils per high-powered field [hpf] and > or =15 eosinophils/hpf). The epidemiology and histology of the entire cohort and a population-based cohort were evaluated. RESULTS: Eight hundred seven biopsy specimens from 666 patients were re-examined; 198 patients had 15 eosinophils/hpf or greater. Among a population-based cohort of patients with 15 eosinophils/hpf or greater, there was a modest increase in incidence (P < .001; incidence rate ratio, 1.18; 95% CI, 1.09-1.28). After correcting for a 40-fold increase in the number of endoscopies during this time period, the proportion of biopsy specimens with 15 eosinophils/hpf or greater did not change (0.08 in 1982 vs 0.08 in 1996 [peak]; P = .9; incidence rate ratio, 1.02; 95% CI, 0.73-1.44). Patients who had as few as 5 eosinophils/hpf were more likely to have persistent esophageal eosinophilia on repeat esophagogastroduodenoscopy, evidence of basal layer hyperplasia, and lamina propria fibrosis compared with patients with less than 5 eosinophils/hpf (P < .001). CONCLUSIONS: Esophageal eosinophilia at levels consistent with EE was present among 30% of patients given diagnoses of reflux esophagitis, and the incidence of esophageal eosinophilia did not change over time. Patients with 5 eosinophils/hpf or greater had evidence of other histologic abnormalities and were likely to have persistent esophageal eosinophilia.

Clinical, pathologic, and molecular characterization of familial eosinophilic esophagitis compared with sporadic cases.

BACKGROUND & AIMS: Eosinophilic esophagitis (EE) occurs in families. METHODS: Record review confirmed patient kinship and provided clinical information. Slide review confirmed the diagnosis (threshold peak number > or = 24 eosinophils/high-power field). RESULTS: Fifty-nine members (41 males, 18 females) of 26 families were 3 months to 47 years of age (mean age, 10.3 y) at diagnosis. The only recorded race was Caucasian. In 4 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, pathologic, 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 = .03) compared with sporadic patients. The basic characteristics of EE (eg, eosinophil levels, rate of atopy) did not vary with patient age. By using genome-wide microarray analysis, no significant differences (P < .05, false-discovery rate) were observed between familial and sporadic EE. Among all patients, chest pain was more common in females (P = .02), and thickened mucosa was more common in males (P = .006). CONCLUSIONS: 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.

Interplay of adaptive th2 immunity with eotaxin-3/c-C chemokine receptor 3 in eosinophilic esophagitis.

BACKGROUND: Pediatric eosinophilic esophagitis (EE) is a recently described disorder associated with atopy. Although studies of esophageal tissue suggest that Th2 cytokines and eotaxin-3 may be crucial in disease pathogenesis, little is known about the systemic immunological phenotypes of children with EE. OBJECTIVES: To define the phenotypes of peripheral blood eosinophils and lymphocytes in EE and to examine for correlations between these parameters and tissue eosinophil numbers and disease severity. PATIENTS AND METHODS: Blood was collected from children with EE, atopic control children without EE, and nonatopic control children without EE. Flow cytometry was used to measure eosinophil expression of chemokine receptor 3 (CCR3) and interleukin-5 receptor-alpha (IL-5Ralpha), and intracellular lymphocyte expression of IL-4, IL-5, IL-13, interferon-gamma, and tumor necrosis factor-alpha. Eosinophil numbers and eotaxin-3 mRNA levels were quantitated in esophageal biopsy specimens. RESULTS: Compared with nonatopic control children, EE patients with active disease had increased peripheral blood eosinophil percentages, mean channel of fluorescence (MCF) of CCR3 on eosinophils, and percentage of CD4+ T cells expressing IL-5. Notably, these parameters positively correlated with esophageal eosinophil numbers. Eotaxin-3 tissue expression positively correlated with esophageal eosinophil numbers and peripheral blood eosinophil CCR3 MCF. The percentage of peripheral blood eosinophils, eosinophil CCR3 MCF, and CD4+ T cell expression of IL-5 were lower in EE patients in disease remission than in patients with active disease. CONCLUSIONS: Collectively, these studies demonstrate cooperation between systemic CD4+ Th2-cell-mediated immunity and an enhanced eosinophil-CCR3/eotaxin-3 pathway in EE pathogenesis. Furthermore, the imbalanced Th2 immunity and increased CCR3 expression are reversible with disease remission.

Anti-IL-5 (mepolizumab) therapy for eosinophilic esophagitis.

BACKGROUND: Eosinophilic esophagitis (EE) is characterized by high numbers of eosinophils in the esophagus and epithelial hyperplasia, and is being increasingly recognized. IL-5 promotes eosinophil trafficking to the esophagus, and positively regulates eosinophil growth, activation, survival, and tissue recruitment. OBJECTIVE: We hypothesized that the humanized monoclonal IgG(1) antibody against human IL-5 (mepolizumab) may be useful in the control of EE. METHODS: An open-label phase I/II safety and efficacy study of anti-IL-5 in 4 adult patients with EE and longstanding dysphagia and esophageal strictures was conducted. Patients received 3 infusions of anti-IL-5 (750 mg intravenously monthly) without change in their current therapy. The levels of plasma IL-5, peripheral blood eosinophils, and CCR3+ cells in blood, quality of life measurements, and histological analysis of esophageal biopsies were determined before and 1 month after treatment. RESULTS: Peripheral blood eosinophilia and percent of CCR3+ cells decreased by 6.4-fold and 7.9-fold (P < .05), respectively, after anti-IL-5 treatment. Notably, mean and maximal esophageal eosinophilia decreased from 46 to 6 and from 153 to 28 eosinophils/high-power field (x400; average, 8.9-fold, P < .001, and 6-fold, P < .05), respectively. Patients reported a better clinical outcome and improved quality of life (P = .03). Therapy was generally well tolerated, and responsiveness to anti-IL-5 therapy did not correlate with plasma IL-5 levels. CONCLUSION: Anti-IL-5 therapy is associated with marked decreases in peripheral blood and esophageal eosinophilia (including the number of CCR3+ blood cells) in patients with EE and improved clinical outcomes. CLINICAL IMPLICATIONS: Anti-IL-5 is a promising therapeutic intervention for EE.

Eotaxin-3 and a uniquely conserved gene-expression profile in eosinophilic esophagitis.

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.

Anti-IL-5 and hypereosinophilic syndromes.

Hypereosinophilic syndromes represent a heterogeneous group of disorders characterized by peripheral eosinophilia and end-organ damage associated with eosinophil infiltrations. In many instances, the eosinophilia is refractory to standard therapies and clinicians rely on potentially toxic alternatives. This group of disorders has recently gained attention with the description of patients that harbor a genetic rearrangement that produces a constitutively active tyrosine kinase, often responsive to anti-tyrosine kinase therapy. In addition, the recent expansion in our understanding of the mechanisms by which eosinophils develop and become activated, involving the cytokine interleukin-5 (IL-5), has led to advances in therapeutic options. A new therapy currently in clinical trials is the humanized monoclonal antibody against IL-5. This review will discuss the etiology, classification, and treatment options for the hypereosinophilic syndromes, with particular emphasis on anti-interleukin-5 therapy.

Clinical and immunopathologic effects of swallowed fluticasone for eosinophilic esophagitis.

BACKGROUND & AIMS: Eosinophilic esophagitis (EE) is a recently recognized clinical disorder that is understood poorly. We aimed to determine the efficacy of swallowed fluticasone propionate on the immunopathologic features associated with EE. METHODS: A retrospective analysis was performed on 20 pediatric patients with EE. Inclusion criteria specified a peak eosinophil density of > or =24 cells per 400x field in the esophagus and treatment with swallowed fluticasone between 2 endoscopic assessments. Histologic specimens were examined for eosinophil and CD8(+) lymphocyte infiltration, papillary lengthening, and proliferation of the basal layer as determined by monoclonal anti-Ki-67 (MIB-1) antibody staining. RESULTS: The mean time interval between endoscopic assessments was 4.8 months. The patients were divided equally between allergic and nonallergic groups based on the results of skin-prick testing. All of the nonallergic patients responded to fluticasone propionate. The endoscopic appearance of the mucosa improved and microscopic evaluation showed markedly reduced eosinophil infiltration, reduced basal layer hyperplasia documented by a reduced number of MIB-1(+) cells, and a reduced number of CD8(+) lymphocytes. However, allergic patients were relatively refractory to therapy; 20% had a partial response, whereas 20% had no detectable improvement. Esophageal eosinophil levels before and after therapy in all patients strongly correlated with the level of epithelial cell proliferation as measured by MIB-1 staining. CONCLUSIONS: Collectively, these results suggest that patients treated with swallowed fluticasone have improved endoscopic, histologic, and immunologic parameters associated with EE. However, patients with identifiable allergies who fail dietary elimination may have a blunted response to treatment.

Anti-interleukin-5 (mepolizumab) therapy for hypereosinophilic syndromes.

BACKGROUND: IL-5 is a cytokine critically involved in regulating several aspects of eosinophils including their production, activation, and tissue recruitment. As such, IL-5 may be involved in the pathogenesis of hypereosinophilic syndromes, a group of poorly treated diverse disorders characterized by sustained peripheral blood and/or tissue eosinophilia. OBJECTIVE: We aimed to assess the safety and efficacy of a humanized blocking monoclonal antibody against IL-5 (mepolizumab) in patients with several forms of hyper-eosinophilic syndromes. METHODS: We performed an open-label trial of anti-IL-5 in which 3 intravenous doses (10 mg/kg, maximum 750 mg) were administered at 4-week intervals to 4 patients with hypereosinophilic syndromes (defined by peripheral blood and/or tissue eosinophilia). The effects of treatment on safety, eosinophil levels (in peripheral blood and/or diseased tissue), pulmonary function, and quality of life were measured over a 28-week period. RESULTS: Anti-IL-5 was well tolerated in all patients and lowered peripheral blood eosinophil counts despite ongoing systemic glucocorticoid therapy. The decline in circulating eosinophil counts was sustained for at least 12 weeks after the last dose of anti-IL-5. In addition, anti-IL-5 improved clinical and quality of life measurements. In one patient with striking tissue eosinophilia (eosinophilic esophagitis), anti-IL-5 resulted in a 10-fold reduction in tissue eosinophil levels. CONCLUSIONS: These results suggest that anti-IL-5 is safe, effective in lowering eosinophil levels, and has potential glucocorticoid-sparing effects in patients with a variety of hyper-eosinophilic syndromes. As such, anti-IL-5 may have significant therapeutic potential for hypereosinophilic syndromes.