Amal Assa’ad

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.

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.

Combined Immune Deficiency in a Patient with a Novel NFKB2 Mutation

NFKB2 encodes the p100/p52 protein, a critical mediator of the canonical and noncanonical NFkB signaling pathways. Here we report the comprehensive immune evaluation of a child with a novel NFKB2 mutation and provide evidence that aberrant NFKB2 signaling not only causes humoral immune deficiency, but also interferes with the TCR-mediated proliferation of T cells. These observations expand the known phenotype associated with NFKB2 mutations.

Effect of varying doses of epicutaneous immunotherapy vs placebo on reaction to peanut protein exposure among patients with peanut sensitivity : A randomized clinical trial

Importance Epicutaneous immunotherapy may have potential for treating peanut allergy but has been assessed only in preclinical and early human trials. Objective To determine the optimal dose, adverse events (AEs), and efficacy of a peanut patch for peanut allergy treatment. Design, Setting, and Participants Phase 2b double-blind, placebo-controlled, dose-ranging trial of a peanut patch in peanut-allergic patients (6-55 years) from 22 centers, with a 2-year, open-label extension (July 31, 2012-July 31, 2014; extension completed September 29, 2016). Patients (n = 221) had peanut sensitivity and positive double-blind, placebo-controlled food challenges to an eliciting dose of 300 mg or less of peanut protein. Interventions Randomly assigned patients (1:1:1:1) received an epicutaneous peanut patch containing 50 &mgr;g (n = 53), 100 &mgr;g (n = 56), or 250 &mgr;g (n = 56) of peanut protein or a placebo patch (n = 56). Following daily patch application for 12 months, patients underwent a double-blind, placebo-controlled food challenge to establish changes in eliciting dose. Main Outcomes and Measures The primary efficacy end point was percentage of treatment responders (eliciting dose: ≥10-times increase and/or reaching ≥1000 mg of peanut protein) in each group vs placebo patch after 12 months. Secondary end points included percentage of responders by age strata and treatment-emergent adverse events (TEAEs). Results Of 221 patients randomized (median age, 11 years [quartile 1, quartile 3: 8, 16]; 37.6% female), 93.7% completed the trial. A significant absolute difference in response rates was observed at month 12 between the 250-&mgr;g (n = 28; 50.0%) and placebo (n = 14; 25.0%) patches (difference, 25.0%; 95% CI, 7.7%-42.3%; P = .01). No significant difference was seen between the placebo patch vs the 100-&mgr;g patch. Because of statistical testing hierarchical rules, the 50-&mgr;g patch was not compared with placebo. Interaction by age group was only significant for the 250-&mgr;g patch (P = .04). In the 6- to 11-year stratum, the response rate difference between the 250-&mgr;g (n = 15; 53.6%) and placebo (n = 6; 19.4%) patches was 34.2% (95% CI, 11.1%-57.3%; P = .008); adolescents/adults showed no difference between the 250-&mgr;g (n = 13; 46.4%) and placebo (n = 8; 32.0%) patches: 14.4% (95% CI, −11.6% to 40.4%; P = .40). No dose-related serious AEs were observed. The percentage of patients with 1 or more TEAEs (largely local skin reactions) was similar across all groups in year 1: 50-&mgr;g patch = 100%, 100-&mgr;g patch = 98.2%, 250-&mgr;g patch = 100%, and placebo patch = 92.9%. The overall median adherence was 97.6% after 1 year; the dropout rate for treatment-related AEs was 0.9%. Conclusions and Relevance In this dose-ranging trial of peanut-allergic patients, the 250-&mgr;g peanut patch resulted in significant treatment response vs placebo patch following 12 months of therapy. These findings warrant a phase 3 trial. Trial Registration clinicaltrials.gov Identifier: NCT01675882

Efficacy and Safety of Benralizumab, a Monoclonal Antibody against IL-5Rα, in Uncontrolled Eosinophilic Asthma

Nonresponders to maximal guideline-based therapies of asthma account for most of the morbidity, mortality, and economic burden of the disease. Because eosinophils are key effector cells in asthmatic airway inflammation, blocking IL-5, the main cytokine responsible for its survival and activation, seems to be a rational strategy. While previous monoclonal antibodies against the IL-5 ligand resulted in inconsistent improvements in asthma outcomes, benralizumab has shown promise. Benralizumab is a monoclonal antibody against IL-5 receptor, and has an enhanced antibody dependent cell-mediated cytotoxicity function. In this article, we review the theoretical advantages of benralizumab compared to previous compounds, as well as current status of the clinical development of benralizumab in asthma. Lastly, we briefly discuss the potential role of benralizumab in chronic obstructive pulmonary disease.

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

BackgroundFood 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.ObjectivesPrompted 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.ResultsThe 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 provider’s office or at home. The addendum guidelines provide the background, rationale, and strength of evidence for each recommendation.ConclusionsGuidelines have been developed for early introduction of peanut-containing foods into the diets of infants at various risk levels for peanut allergy.

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

BackgroundFood 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.ObjectivesPrompted 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.ResultsThe 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 provider’s office or at home. The addendum guidelines provide the background, rationale, and strength of evidence for each recommendation.ConclusionsGuidelines have been developed for early introduction of peanut-containing foods into the diets of infants at various risk levels for peanut allergy.

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.

Caustic Ingestions Mimicking Anaphylaxis: Case Studies and Literature Review

Anaphylaxis presents in children with rapid involvement of typically 2 or more organ systems including cutaneous, gastrointestinal, and respiratory. Caustic ingestions (CI) may also present with acute involvement of cutaneous, gastrointestinal, and respiratory systems. We present 2 cases of “missed diagnosis” that illustrate how CI presenting with respiratory symptoms can be mistaken for anaphylaxis owing to these similarities. Both of these patients had delay in appropriate care for CI as a result. These cases demonstrate the importance of considering CI in children who have gastrointestinal symptoms, respiratory distress, and oropharyngeal edema.

The global impact of the DRACMA guidelines cow’s milk allergy clinical practice

BackgroundThe 2010 Diagnosis and Rationale for Action against Cow’s Milk Allergy (DRACMA) guidelines are the only Grading of Recommendations Assessment, Development and Evaluation (GRADE) guidelines for cow’s milk allergy (CMA). They indicate oral food challenge (OFC) as the reference test for diagnosis, and suggest the choice of specific alternative formula in different clinical conditions. Their recommendations are flexible, both in diagnosis and in treatment.Objectives & methodsUsing the Scopus citation records, we evaluated the influence of the DRACMA guidelines on milk allergy literature. We also reviewed their impact on successive food allergy and CMA guidelines at national and international level. We describe some economic consequences of their application.ResultsDRACMA are the most cited CMA guidelines, and the second cited guidelines on food allergy. Many subsequent guidelines took stock of DRACMA’s metanalyses adapting recommendations to the local context. Some of these chose not to consider OFC as an absolute requirement for the diagnosis of CMA. Studies on their implementation show that in this case, the treatment costs may increase and there is a risk of overdiagnosis. Interestingly, we observed a reduction in the cost of alternative formulas following the publication of the DRACMA guidelines.ConclusionsDRACMA reconciled international differences in the diagnosis and management of CMA. They promoted a cultural debate, improved clinician’s knowledge of CMA, improved the quality of diagnosis and care, reduced inappropriate practices, fostered the efficient use of resources, empowered patients, and influenced some public policies. The accruing evidence on diagnosis and treatment of CMA necessitates their update in the near future.