Amal H. Assa'ad

Work Group report: Oral food challenge testing

Oral food challenges are procedures conducted by allergists/immunologists to make an accurate diagnosis of immediate, and occasionally delayed, adverse reactions to foods. The timing of the challenge is carefully chosen based on the individual patient history and the results of skin prick tests and food specific serum IgE values. The type of the challenge is determined by the history, the age of the patient, and the likelihood of encountering subjective reactions. The food challenge requires preparation of the patient for the procedure and preparation of the office for the organized conduct of the challenge, for a careful assessment of the symptoms and signs and the treatment of reactions. The starting dose, the escalation of the dosing, and the intervals between doses are determined based on experience and the patients history. The interpretation of the results of the challenge and arrangements for follow-up after a challenge are important. A negative oral food challenge result allows introduction of the food into the diet, whereas a positive oral food challenge result provides a sound basis for continued avoidance of the food.

An Antibody Against IL-5 Reduces Numbers of Esophageal Intraepithelial Eosinophils in Children With Eosinophilic Esophagitis

BACKGROUND & AIMS The role of interleukin (IL)-5 in the pathogenesis of eosinophilic esophagitis (EoE) has been established in animal models; anti-IL-5 therapy has been reported to be effective in adults. We investigated whether IL-5 has a role in accumulation of esophageal eosinophils in children with EoE and whether therapy with mepolizumab, an antibody against IL-5, reduces the number of esophageal intraepithelial eosinophils in children with EoE. METHODS We performed an international, multicenter, double-blind, randomized, prospective study of 59 children with EoE, defined as baseline peak count of esophageal intraepithelial eosinophils of ≥ 20 in at least 1 high-power field (hpf). Patients received an infusion every 4 weeks (a total of 3 infusions) of 0.55, 2.5, or 10 mg/kg mepolizumab. No placebo group was used. RESULTS Baseline peak and mean esophageal intraepithelial eosinophil counts were (mean ± SE) 122.5 ± 8.78 and 39.1 ± 3.63 per hpf, respectively. Four weeks after the third infusion, peak eosinophil counts were <5 per hpf in 5 of 57 children (8.8%); we did not observe differences among groups given different doses of mepolizumab. Reduced peak and mean eosinophil counts, to <20 per hpf, were observed in 18 of 57 (31.6%) and 51 of 57 (89.5%) children, respectively. Peak and mean esophageal intraepithelial eosinophil counts decreased significantly to 40.2 ± 5.17 and 9.3 ± 1.25 per hpf, respectively (P < .0001). An analysis to evaluate predictors of response associated a higher mean baseline esophageal intraepithelial eosinophil count with a greater reduction in mean count (P < .0001). CONCLUSIONS IL-5 is involved in the pathogenesis of EoE in children. Mepolizumab, an antibody against IL-5, reduces esophageal eosinophilic inflammation in these patients.

Variants of thymic stromal lymphopoietin and its receptor associate with eosinophilic esophagitis

BACKGROUND The genetic cause 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 patients with EE. In addition, the genetic contributions of other allergy-associated genes to EE risk have not been explored. OBJECTIVE We aimed to delineate single nucleotide polymorphisms (SNPs) that associated with EE apart from allergy. METHODS We used a custom array containing 738 SNPs in 53 genes implicated in allergic responses, immune responses, or both to genotype 220 allergic or 246 nonallergic control subjects and a discovery cohort of 170 patients with EE. 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. RESULTS A single SNP residing in the TSLP gene reached Bonferroni linkage disequilibrium-adjusted significance but only when patients with EE were compared with allergic control subjects (rs10062929; P = 4.11 x 10(-5); odds ratio, 0.35). A nonsynonymous polymorphism in the thymic stromal lymphopoietin receptor (TSLPR) gene on Xp22.3 and Yp11.3 was significantly associated with disease only in male patients with EE. Primary esophageal epithelial cells expressed TSLP mRNA after Toll-like receptor 3 stimulation. CONCLUSION These data collectively identify TSLP as a candidate gene critically involved in EE susceptibility beyond its role in promoting T(H)2 responses.

Primary prevention of allergic disease through nutritional interventions

With the rising prevalence of atopic disease, primary prevention may play a role in reducing its burden, especially in high-risk infants. With this in mind, the Adverse Reactions to Foods Committee of the American Academy of Allergy, Asthma & Immunology was charged with the task of developing recommendations for primary care physicians and specialists about the primary prevention of allergic disease through nutritional interventions according to current available literature and expert opinion. Recommendations that are supported by data are as follows. Avoidance diets during pregnancy and lactation are not recommended at this time, but more research is necessary for peanut. Exclusive breast-feeding for at least 4 and up to 6 months is endorsed. For high-risk infants who cannot be exclusively breast-fed, hydrolyzed formula appears to offer advantages to prevent allergic disease and cows milk allergy. Complementary foods can be introduced between 4 and 6 months of age. Because no formal recommendations have been previously provided about how and when to introduce the main allergenic foods (cows milk, egg, soy, wheat, peanut, tree nuts, fish, shellfish), these are now provided, and reasons to consider allergy consultation for development of a personalized plan for food introduction are also presented.

Intrinsically defective skin barrier function in children with atopic dermatitis correlates with disease severity

BACKGROUND Recent genetic evidence supports that an underlying defect in skin barrier function contributes to the pathogenesis of atopic dermatitis (AD). The integrity of the skin barrier can be assessed objectively by measuring transepidermal water loss (TEWL). Previous investigations of TEWL as a biomarker of skin barrier function have been limited by small sample size, and studies including African American subjects are lacking. OBJECTIVE We sought to determine whether children with AD have inherently altered skin barrier function by comparing TEWL as a measure of skin barrier function in African American and white children with AD with that in control subjects without AD. METHODS TEWL was measured on nonlesional normal-appearing skin at 4 sites (the volar forearm, dorsal arm, lower leg, and cheek) in (1) children with AD (cases), (2) children with asthma or allergic rhinitis but without AD (allergic control subjects), and (3) nonatopic control subjects. AD severity was assessed by using the objective SCORAD index. RESULTS TEWL was increased in children with AD compared with that seen in both control groups at most of the anatomic sites tested (P < .05). TEWL also correlated with objective SCORAD score. The presence of allergic sensitization or other allergic conditions did not affect TEWL among children with AD. TEWL was higher in white than in African American children. CONCLUSION Skin barrier function as assessed by TEWL is intrinsically compromised in children with AD but not in children with other allergic conditions. The magnitude of skin barrier dysfunction correlates with AD disease severity.

Anti-IL-5 (mepolizumab) therapy reduces eosinophil activation ex vivo and increases IL-5 and IL-5 receptor levels.

BACKGROUND Anti-IL-5 might be a useful therapeutic agent for eosinophilic disorders, yet its immunologic consequences have not been well characterized. OBJECTIVE We sought to characterize the hematologic and immunologic effects of anti-IL-5 in human subjects. METHODS 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. RESULTS 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 in 76% 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 alpha 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. CONCLUSIONS 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 alpha and lymphocyte IL-5 production after anti-IL-5 therapy suggest an endogenous IL-5 autoregulatory pathway.

NIAID-Sponsored 2010 Guidelines for Managing Food Allergy: Applications in the Pediatric Population

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 patients 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.

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.

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-α (IL-5Rα), and intracellular lymphocyte expression of IL-4, IL-5, IL-13, interferon-γ, and tumor necrosis factor-α. 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.

Addendum guidelines for the prevention of peanut allergy in the United States: Report of the National Institute of Allergy and Infectious Diseases–sponsored expert panel

Background: Food allergy is an important public health problem because it affects children and adults, can be severe and even life‐threatening, and may be increasing in prevalence. Beginning in 2008, the National Institute of Allergy and Infectious Diseases, working with other organizations and advocacy groups, led the development of the first clinical guidelines for the diagnosis and management of food allergy. A recent landmark clinical trial and other emerging data suggest that peanut allergy can be prevented through introduction of peanut‐containing foods beginning in infancy. Objectives: Prompted by these findings, along with 25 professional organizations, federal agencies, and patient advocacy groups, the National Institute of Allergy and Infectious Diseases facilitated development of addendum guidelines to specifically address the prevention of peanut allergy. Results: The addendum provides 3 separate guidelines for infants at various risk levels for the development of peanut allergy and is intended for use by a wide variety of health care providers. Topics addressed include the definition of risk categories, appropriate use of testing (specific IgE measurement, skin prick tests, and oral food challenges), and the timing and approaches for introduction of peanut‐containing foods in the health care providers office or at home. The addendum guidelines provide the background, rationale, and strength of evidence for each recommendation. Conclusions: Guidelines have been developed for early introduction of peanut‐containing foods into the diets of infants at various risk levels for peanut allergy.