"To screen or not to screen": Comparing the health and economic benefits of early peanut introduction strategies in five countries.

BACKGROUND: Early peanut introduction (EPI) in the first year of life is associated with reduced risk of developing peanut allergy in children with either severe eczema and/or egg allergy. However, EPI recommendations differ among countries with formal guidelines. METHODS: Using simulation and Markov modeling over a 20-year horizon to attempt to explore optimal EPI strategies applied to the US population, we compared high-risk infant-specific IgE peanut screening (US/Canadian) with the Australiasian Society for Clinical Immunology and Allergy (Australia/New Zealand) (ASCIA) and the United Kingdom Department of Health (UKDOH)-published EPI approaches. RESULTS: Screening peanut skin testing of all children with early-onset eczema and/or egg allergy before in-office peanut introduction was dominated by a no screening approach, in terms of number of cases of peanut allergy prevented, quality-adjusted life years (QALY), and healthcare costs, although screening resulted in a slightly lower rate of allergic reactions to peanut per patient in high-risk children. Considering costs of peanut allergy in high-risk children, the per-patient cost of early introduction without screening over the model horizon was $6556.69 (95%CI, $6512.76-$6600.62), compared with a cost of $7576.32 (95%CI, $7531.38-$7621.26) for skin test screening prior to introduction. From a US societal perspective, screening prior to introduction cost $654 115 322 and resulted in 3208 additional peanut allergy diagnoses. Both screening and nonscreening approaches dominated deliberately delayed peanut introduction. CONCLUSIONS: A no-screening approach for EPI has superior health and economic benefits in terms of number of peanut allergy cases prevented, QALY, and total healthcare costs compared to screening and in-office peanut introduction.

The urgent need for a harmonized severity scoring system for acute allergic reactions.

The accurate assessment and communication of the severity of acute allergic reactions are important to patients, clinicians, researchers, the food industry, and public health and regulatory authorities. Severity has different meanings to different stakeholders with patients and clinicians rating the significance of particular symptoms very differently. Many severity scoring systems have been generated, most focusing on the severity of reactions following exposure to a limited group of allergens. They are heterogeneous in format, none has used an accepted developmental approach, and none has been validated. Their wide range of outcome formats has led to difficulties with interpretation and application. Therefore, there is a persisting need for an appropriately developed and validated severity scoring system for allergic reactions that work across the range of allergenic triggers and address the needs of different stakeholder groups. We propose a novel approach to develop and then validate a harmonized scoring system for acute allergic reactions, based on a data-driven method that is informed by clinical and patient experience and other stakeholders' perspectives. We envisage two formats: (i) a numerical score giving a continuum from mild to severe reactions that are clinically meaningful and are useful for allergy healthcare professionals and researchers, and (ii) a three-grade-based ordinal format that is simple enough to be used and understood by other professionals and patients. Testing of reliability and validity of the new approach in a range of settings and populations will allow eventual implementation of a standardized scoring system in clinical studies and routine practice.

Treatment of gastric eosinophilia by epicutaneous immunotherapy in piglets sensitized to peanuts.

BACKGROUND: Eosinophilic gastrointestinal disorders (EGIDs) are hypersensitivity disorders frequently triggered by food allergy and manifested by mucosal eosinophilic infiltration at any level of the gastrointestinal tract. This study established a model of gastric eosinophilia in peanut-sensitized piglets to evaluate the efficacy of epicutaneous immunotherapy (EPIT) for its treatment. METHODS: Experiments were carried out in piglets first sensitized by three intra-peritoneal injections of peanut protein extract (PPE) with adjuvant, and then given PPE orally for 10 days, a sequence leading to gastric eosinophilia assessed by endoscopy. For 3 months, eight piglets received active EPIT, using Viaskin® loaded with PPE, applied daily on the ear, while eight received placebo EPIT (Placebo). Piglets were exposed to a second 10-day period of PPE orally. Lesions were scored by endoscopy on the last day of PPE exposure. After killing, all parts of the digestive tract were analysed by a pathologist unaware of the piglets' status. IgE response was measured, and mechanistic parameters were analysed in the spleen. RESULTS: After sensitization, a significant increase of total IgE was observed in sensitized compared to naive animals (61.1 ± 13.3 vs 27.8 ± 6 ng/mL, P < .01). Following oral intake of PPE, sensitized piglets developed moderate gastritis compared to naive piglets (1.5 vs 1.0, median score). After 3 months of immunotherapy, median IgE was significantly reduced in EPIT vs placebo piglets (61.4 ± 16.3 vs 105.9 ± 25.6 ng/mL, P < .01). Active EPIT significantly reduced gastric mucosal lesions induced by PPE oral intake (macroscopic score 0 [0-2] vs 2 [1-3], P < .01, respectively, active vs placebo) and gastric mucosa eosinophils counts (239 eosinophils/mm2 [59-645] vs 2554 eosinophils/mm2 [462-8057], P < .01, respectively active vs placebo). GATA-3, IL-5 and eotaxin mRNA expression decreased significantly after EPIT (P < .05). CONCLUSIONS: This study describes a large animal model of gastric eosinophil in peanut-sensitized piglets. Utilizing this model, we demonstrated the efficacy of EPIT in treating peanut-induced EGIDs.

Invariant natural killer cells change after an oral allergy desensitization protocol for cow's milk.

BACKGROUND: Cow milk (CM) allergy (CMA) affects up to 3% of the paediatric population and recent data suggest that only about 50% will outgrow by age 8. Oral immunotherapy (OIT) is a type of immune-modulating treatment that is able to induce desensitization to food allergens, to increase tolerance threshold, to reduce the risk of anaphylaxis, and to improve the patient's quality of life. The examination of the immunological changes observed during the establishment of food allergy (FA) desensitization in FA patients is a window into the pathogenesis of food allergy and food tolerance development. In this pathway, we have previously found that invariant natural killer T cells (iNKTs) are involved in CM allergy sensitization and now examine their role in OIT. METHODS: In this study, 10 of the 11 children with CM induced anaphylaxis enrolled in a CMA OIT clinical trial and completed the protocol. Peripheral blood iNKTs were quantitatively and qualitatively via flow cytometry characterized ex vivo and after culture with milk lipids before and after completing the OIT protocol. RESULTS: After completing OIT for CM, children were able to reintroduce CM in their diet. For the first time, we demonstrated that OIT induced a significant increase in the peripheral blood iNKT, as well as their switch from a T helper (Th-2; ie IL-4, IL-13) to Th-1 (ie IFN-γ) cytokine profile. CONCLUSIONS AND CLINICAL RELEVANCE: This study confirms the efficacy and safety of CM-OIT as well as the role of iNKT cells in CM allergy.

LEAPing through the looking glass: secondary analysis of the effect of skin test size and age of introduction on peanut tolerance after early peanut introduction.

BACKGROUND: In the Learning Early About Peanut Allergy (LEAP) study, early peanut introduction in high-risk 4- to 11-month-olds was associated with a significantly decreased risk of developing peanut allergy. However, the influences of key baseline high-risk factors on peanut tolerance are poorly understood. METHODS: Secondary analysis was conducted on the publically available LEAP dataset, exploring relationships between peanut tolerance, baseline peanut/egg sensitization, eczema severity/duration, age of introduction, gender, and race. RESULTS: A multiple logistic regression model predicting odds of successful oral food challenge (OFC) at 60 months noted higher odds with early introduction (OR 9.2, P < 0.001, 95% CI 4.2-20.3), white race (OR 2.1, P = 0.04, 95% CI 1.1-3.9), and advancing age (OR 4.8, P = 0.04, 95% CI 1.1-20.8). Odds of peanut tolerance were lower with increasing peanut wheal size (OR 0.58, P < 0.001, 95% CI 0.46-0.74), increased baseline SCORAD score (OR 0.98, P = 0.04, 95% CI 0.97-1), and increased kUA /l of egg serum IgE (sIgE) (OR 0.99, P = 0.04, 95% CI 0.98-1). The probability of peanut tolerance in the early introduction group was 83% vs 43% in the avoidance group with SPT wheal of <4 mm. The probability of a successful OFC was significantly higher with peanut introduction between 6 and 11 months than at 4-6 months. Increasing eczema severity had limited impact on the probability of peanut tolerance in the early introduction arm. CONCLUSION: Increasing peanut wheal size predicted peanut tolerance only in the avoidance arm. Peanut introduction between 6 and 11 months of age was associated with the highest rates of peanut tolerance, questioning the 'urgency' of introduction before 6 months.

Microbiome and its impact on gastrointestinal atopy.

The prevalence of allergic conditions has continuously increased in the last few decades in Westernized countries. A dysbiotic gut microbiome may play an important role in the development of allergic diseases. Genetic, environmental, and dietary factors may alter the commensal microbiota leading to inflammatory dysregulation of homeostasis. Murine and human studies have begun to elucidate the role of the microbiota in the pathogenesis of atopic diseases including asthma, atopic dermatitis, and food allergies. However, the role of the microbiome in most eosinophilic gastrointestinal diseases (EGIDs) is not yet known. This review provides an overview of what is currently known about the development of tolerance from both molecular and clinical standpoints. We also look at the gut-specific microbiome and its role in atopic conditions with the hope of applying this knowledge to the understanding, prevention, and treatment of EGIDs, particularly EoE.

Eosinophilic esophagitis is characterized by a non-IgE-mediated food hypersensitivity.

Eosinophilic esophagitis (EoE) is a chronic disease characterized clinically by symptoms of esophageal dysfunction and histologically by eosinophil-predominant inflammation. EoE is frequently associated with concomitant atopic diseases and immunoglobulin E (IgE) sensitization to food allergens in children as well as to aeroallergens and cross-reactive plant allergen components in adults. Patients with EoE respond well to elemental and empirical food elimination diets. Recent research has, however, indicated that the pathogenesis of EoE is distinct from IgE-mediated food allergy. In this review, we discuss the individual roles of epithelial barrier defects, dysregulated innate and adaptive immune responses, and of microbiota in the pathogenesis of EoE. Although food has been recognized as a trigger factor of EoE, the mechanism by which it initiates or facilitates eosinophilic inflammation appears to be largely independent of IgE and needs to be further investigated. Understanding the pathogenic role of food in EoE is a prerequisite for the development of specific diagnostic tools and targeted therapeutic procedures.

Omalizumab therapy is associated with reduced circulating basophil populations in asthmatic children.

Basophils have been implicated in promoting the early development of TH 2 cell responses in some murine models of TH 2 cytokine-associated inflammation. However, the specific role of basophils in allergic asthma remains an active area of research. Recent studies in animal models and human subjects suggest that IgE may regulate the homeostasis of human basophil populations. Here, we examine basophil populations in children with severe asthma before and during therapy with the IgE-directed monoclonal antibody omalizumab. Omalizumab therapy was associated with a significant reduction in circulating basophil numbers, a finding that was concurrent with improved clinical outcomes. The observation that circulating basophils are reduced following omalizumab therapy supports a mechanistic link between IgE levels and circulating basophil populations, and may provide new insights into one mechanism by which omalizumab improves asthma symptoms.

Invariant natural killer T cells in children with eosinophilic esophagitis.

BACKGROUND: Eosinophilic esophagitis (EoE) is an atopic disease characterized by eosinophilic inflammation in which dietary antigens (in particular, milk) play a major role. EoE is most likely a mixed IgE and non-IgE food-mediated reaction in which overexpression of Th2 cytokines, particularly IL-13, play a major role; however, the cells responsible for IL-13 overexpression remain elusive. Th2-cytokines are secreted following the ligation of invariant natural killer T cell receptors to sphingolipids (SLs). Sphingolipids (SLs) are presented via the CD1d molecule on the INKTs surface. Cow's milk-derived SL has been shown to activate iNKTs from children with IgE-mediated food allergies to milk (FA-MA) to produce Th2 cytokines. The role of iNKTs and milk-SL in EoE pathogenesis is currently unknown. OBJECTIVE: The aim of this study was to investigate the role of iNKTs and milk-SL in EoE. METHODS: Peripheral blood mononuclear cells (PBMCs) from 10 children with active EoE (EoE-A), 10 children with controlled EoE (EoE-C) and 16 healthy controls (non-EoE) were measured ex vivo and then incubated with α-galactosylceramide (αGal) and milk-SL. INKTs from peripheral blood (PB) and oesophageal biopsies were studied. RESULTS: EoE-A children had significantly fewer peripheral blood iNKTs with a greater Th2-response to αGal and milk-SM compared with iNKTs of EoE-C and non-EoE children. Additionally, EoE-A children had increased iNKT levels in oesophageal biopsies compared with EoE-C children. CONCLUSION: Milk-SLs are able to activate peripheral blood iNKTs in EoE-A children to produce Th2 cytokines. Additionally, iNKT levels are higher at the site of active oesophageal eosinophilic inflammation. CLINICAL RELEVANCE: This study suggests that sphingolipids (SLs) contained in milk may drive the development of EoE by promoting an iNKT-cell-mediated Th2-type cytokine response that facilitates eosinophil-mediated allergic inflammation.

The natural history of eosinophilic oesophagitis in the transition from childhood to adulthood.

BACKGROUND: Eosinophilic oesophagitis (EoE) is a chronic inflammatory condition affecting both children and adults. Little is known about the natural history of EoE in the transition from childhood into adulthood. AIM: To determine the prevalence of EoE symptoms and impact of EoE on quality of life among adults diagnosed with EoE during childhood. METHODS: This is a cross-sectional study of EoE patients from the Children's Hospital of Philadelphia EoE registry. Patients ≥18 years diagnosed with EoE during childhood were administered validated dysphagia [Mayo Dysphagia Questionnaire (MDQ)-30] and Quality of Life (PAGI-QOL) questionnaires. Ongoing EoE treatments were ascertained. RESULTS: A total of 140 EoE patients ≥18 years were identified; 53 completed all questions. Only 6 (11%) subjects had positive (n = 2) or indeterminate (n = 4) dysphagia scores. However, of 47 patients with negative scores, 18 (37%) reported ongoing difficulty swallowing. The mean PAGI-QOL score was 4.58/5. The dietary dimension score was 3.73/5. Current pharmacological EoE treatments were topical steroids (3/53) and interleukin-5 antagonists (3/53). Additionally, 26/53 (49%) were on PPI therapy and 40/53 (76%) were following allergy directed diets. CONCLUSIONS: The majority of young adults diagnosed with EoE during childhood continue to require pharmacological treatment and/or dietary modification for EoE. A substantial proportion of this population experiences ongoing swallowing difficulties that a standard dysphagia questionnaire fails to capture. Dietary quality of life, but not total quality of life, appears to be adversely affected. These data suggest that EoE diagnosed during childhood remains a significant medical issue during early adulthood, and that better EoE symptom measurement instruments are needed.

Addition of topical pimecrolimus to once-daily mid-potent steroid confers no short-term therapeutic benefit in the treatment of severe atopic dermatitis; a randomized controlled trial.

BACKGROUND: Combination therapy with pimecrolimus cream 1%, a topical calcineurin inhibitor (TCI), and fluticasone propionate cream 0.05% (FP), a mid-potency topical corticosteroid, may have a synergistic effect for treatment of atopic dermatitis (AD) because their mechanism of action differs. OBJECTIVES: To assess the efficacy of concomitant pimecrolimus twice daily/FP once daily vs. vehicle twice daily/FP once daily in patients with severe AD. METHODS: An exploratory, 2-week, double-blind, randomized, within-patient study was conducted (n = 45). Two target areas of similar severity, size and location were assessed. Assessments included the modified Eczema Area and Severity Index (0-12 scale) (primary variable), localized investigator global assessment (0-4 scale) and Patients' Self-Assessment of Disease Severity (0-4 scale). RESULTS: Data for all variables were similar for the TCI/FP and vehicle/FP treatments. CONCLUSIONS: The efficacy observed for treatment of severe AD flares with this TCI/FP combination regimen was equivalent to that of vehicle/FP.

Diagnosis and treatment of atopic dermatitis in children and adults: European Academy of Allergology and Clinical Immunology/American Academy of Allergy, Asthma and Immunology/PRACTALL Consensus Report.

There are remarkable differences in the diagnostic and therapeutic management of atopic dermatitis practiced by dermatologists and pediatricians in different countries. Therefore, the European Academy of Allergy and Clinical Immunology and the American Academy of Allergy, Asthma and Immunology nominated expert teams who were given the task of finding a consensus to serve as a guideline for clinical practice in Europe as well as in North America. The consensus report is part of the PRACTALL initiative, which is endorsed by both academies.

Natural history of peanut allergy.

Peanut allergy raises major concerns and requires diligence in families because of the possibility of severe reactions, the perceived inability to outgrow peanut allergy, and the widespread availability of peanuts in the Western diet. However, studies in the past year have shown that a subset of patients with peanut allergy can become tolerant to peanut. The patients with the milder reactions on presentation have a better chance to develop tolerance to peanuts than the patients whose first reaction is anaphylaxis. This review will focus on the mechanism of allergic sensitization to peanuts and the natural history of peanut allergy as it is currently evolving. The effects of cooking and altering peanut allergens are discussed as are potential treatment modalities.

An obligate role for T-cell receptor alphabeta+ T cells but not T-cell receptor gammadelta+ T cells, B cells, or CD40/CD40L interactions in a mouse model of atopic dermatitis.

BACKGROUND: We recently described a murine model of atopic dermatitis (AD) elicited by epicutaneous sensitization with ovalbumin (OVA). The skin lesions in these mice were characterized by a dermal infiltrate consisting of eosinophils and T cells and by increased expression of the TH2 cytokines IL-4 and IL-5. Epicutaneous sensitization induces a rise in the levels of serum total IgE and OVA-specific antibodies, further indicating that it elicits a predominantly TH2 response. OBJECTIVE: This study was undertaken to assess the roles of T cells, B cells, and CD40L-CD40 interactions in AD. METHODS: Mice with targeted gene deletions were sensitized with OVA. Histologic and immunohistochemical examinations, as well as measurements of IL-4 mRNA, were performed on OVA-sensitized skin. Total and antigen-specific serum IgE levels were determined. RESULTS: RAG2(-/-) mice, which lack both T and B cells, did not exhibit cellular infiltration, induction of dermal IL-4 mRNA, or elevation of serum IgE after OVA sensitization; all of these features were present in B-cell-deficient IgH(-/-) mice. T-cell receptor alpha(-/-) mice did not display cellular infiltration, IL-4 mRNA expression, or increased IgE levels after OVA sensitization, but these responses were elicited in T-cell receptor delta(-/-) mice after sensitization. Absence of CD40 had no effect on these responses. CONCLUSION: These results suggest that alphabeta T cells, but not gammadelta T cells, B cells, or CD40L-CD40 interactions, are critical for skin inflammation and the TH2 response in AD.

Anaphylaxis to raw potato.

BACKGROUND: Potato allergy has been described rarely, generally in relation to the Oral Allergy Syndrome (OAS). Adults with seasonal allergic rhinitis have been reported in whom peeling of raw potatoes causes oculonasal symptoms, wheezing, and contact urticaria. Skin testing with fresh fruits and vegetables has been recommended in cases of OAS, although the sensitivity of commercial potato extract is reportedly equal to that of fresh potato. CASE REPORT: This report describes a 4-year-old with raw potato-induced anaphylaxis. He rapidly developed urticaria, angioedema, respiratory distress, vomiting and diarrhea after biting into a raw potato that was being used for painting in preschool. Review of systems is significant for viral-induced wheezing, but no symptoms suggestive of seasonal allergic rhinitis were evident. His mother has a history of seasonal allergic rhinitis and contact urticaria with raw potato. Skin testing to commercial potato extract was negative and skin testing to fresh potato by the prick + prick method was markedly positive. Skin testing to birch tree was negative. An open challenge to a small amount of cooked potato was negative. Food challenge to raw potato was not considered indicated in this case of immediate anaphylaxis to a single food. CONCLUSIONS: This patient had clinical and skin test reactivity to raw and uncooked potato in the absence of OAS. The patient will be followed for the development of seasonal allergic rhinitis.

Resolution of childhood peanut allergy.

BACKGROUND: Peanut allergy creates great fear in many families because it is one of the leading causes of fatal and near-fatal food-induced allergies. Earlier reports suggested that peanut allergy was life-long, but a recent study described resolution of peanut allergy in some children. OBJECTIVE: Tolerance to peanut allergy in childhood was studied. Examination of the natural history of childhood peanut allergy was explored. METHODS: A retrospective review of all children with peanut allergy seen at the Children's Hospital of Philadelphia in a 3-year period (n = 293). Children with histories of peanut allergy were challenged at the mean age [3.8 years; range 1.5 to 8 year] which was 1.8 years [range: 0.5 to 6.8 years], following their last known clinical reaction. Food allergy or tolerance was confirmed by open challenges. RESULTS: Thirty-three patients with histories of peanut allergy and a positive skin test to peanut underwent oral challenges. Not one patient (n = 5) with a history of peanut anaphylaxis developed tolerance to peanuts. In comparison, 9 of 17 patients with history of urticaria upon ingestion to peanuts developed tolerance. Also, 4 of 10 patients with flaring of their atopic dermatitis upon ingestion to peanuts developed tolerance. The 14 patients with a negative challenge to peanut had a significantly smaller wheal and flare reaction than the 19 patients with positive challenges. Tolerance to peanut was documented by a positive challenge reverting to a negative challenge in one patient. Oral challenge of 13 additional patients with positive skin tests and histories of only refusing to eat peanut resulted in 5 (39%) positive challenges. CONCLUSION: A selected group of peanut-allergic children, who do not have a history anaphylaxis to peanut, may develop tolerance to peanuts.