Recent developments and highlights in food allergy.
The achievement of long lasting, safe treatments for food allergy is dependent on the understanding of the immunological basis of food allergy. Accurate diagnosis is essential for management. In recent years, data from oral food challenges have revealed that routine allergy testing is poor at predicting clinical allergy for tree nuts, almonds in particular. More advanced antigen-based tests including component resolved diagnostics and epitope reactivity may lead to more accurate diagnosis and selection of therapeutic intervention. Additional diagnostic accuracy may come from cellular tests like the basophil activation test or mast cell approaches. In the context of clinical trials, cellular tests have revealed specific T-cell and B-cell populations that are more abundant in food allergic individuals with distinct mechanistic features. Awareness of clinical markers, such as the ability to eat baked forms of milk and egg, continue to inform the understanding of natural tolerance development. Mouse models have allowed for investigation into multiple mechanisms of food allergy including modification of epithelial metabolism, the induction of regulatory cell subsets and the microbiome. Increasing numbers of children who underwent food immunotherapy enlarged the body of evidence on mechanisms and predictors of treatment success. Experimental immunological markers in conjunction with clinical determinants such as lower age and lower initial specific IgE appear to be of benefit. More research on the optimal dose, preparation, and route of application integrating a high-level safety and efficacy is demanded. Alternatively, biologics blocking TSLP, IL-33, IL4 and IL13, or IgE may help to achieve that.
Clinical Factors Associated with Peanut Allergy in a High Risk Infant Cohort.
BACKGROUND: Prognostication of peanut allergy (PNA) is relevant for early interventions. We aimed to determine baseline parameters associated with development of PNA in 3-15 month olds with likely egg and/or milk allergy, and/or moderate-severe atopic dermatitis (AD) and a positive egg/milk skin prick test (SPT), but no known PNA. METHODS: The primary endpoint was PNA [confirmed/convincing diagnosis or last classified as serologic PNA (<2 yrs, ≥5 kUA/L, otherwise ≥14 kUA/L, peanut-IgE)] among 511 participants (median follow-up, 7.3 years). Associations were explored with univariate logistic regression; factors with p<0.15 were analyzed by stepwise multiple logistic regression, using data stratified by PNA status and randomly assigned to development and validation datasets. RESULTS: 205/511 (40.1%) had PNA. Univariate factors associated with PNA (p<0.01) included: increased AD severity, larger egg and peanut SPT, greater egg, milk, peanut, Ara h1-h3 IgE, higher peanut IgG and IgG4, and increased pregnancy peanut consumption. P-values were between 0.01 and 0.05 for younger age, non-white race, lack of breastfeeding, and increased lactation peanut consumption. Using a development dataset, the multivariate model identified younger age at enrollment, greater peanut and Ara h2 IgE, and lack of breastfeeding as prognosticators. The final model predicted 79% in the development and 75% in the validation dataset (AUC=0.83 for both). Models using stricter or less strict PNA criteria both found Ara h2 as predictive. CONCLUSIONS: Key factors associated with PNA in this high risk population included lack of breastfeeding, age, and greater Ara h2 and peanut-specific IgE, which can be used to prognosticate outcomes.
Food allergy endotype with high risk of severe anaphylaxis in children-Monosensitization to cashew 2S albumin Ana o 3.
BACKGROUND: Food allergy in children can be life-threatening. Component-resolved diagnostics approach to food anaphylaxis is rarely assessed in children. The aim of the study was to identify the food allergen components as the triggers responsible for severe anaphylaxis, with regard to characteristics and associated risks, among children in a large, population-based setting. METHODS: Two hundred and seventy-one children who were hospitalized due to systemic allergic reaction (SAR) and food anaphylaxis were recruited. Medical history was assessed, and culprit allergen source and anaphylaxis severity grade were established. Specific IgE to 112 allergen components using multiplex ImmunoCAP ISAC immunoassay and specific IgE to hazelnut, Cor a 14, and cashew, Ana o 3, using singleplex ImmunoCAP immunoassay were determined. RESULTS: We analyzed data from 237 SAR/anaphylaxis in 237 children. Trigger at allergen component level was defined for every episode. The most common triggers of SAR/anaphylaxis were seeds (50.6%), among them, the storage proteins. Anaphylaxis triggered by Ana o 3, 2S albumin from cashews (aOR = 15.0; 95% CI: 3.27 to 73.47); Tri a 19 from wheat (aOR = 9.93; 95% CI: 1.73 to 56.97); and Cor a 9 from hazelnut (aOR = 6.53; 95% CI: 1.16 to 36.72) had the worst clinical presentation including cardiovascular and severe respiratory symptoms (grade IV-V vs I-III in Cox scale). Thirteen out of 237 (5.5%) SAR/anaphylaxis patients were triggered by Ana o 3. Almost 82% of patients with severe Ana o 3 anaphylaxis were sensitized only to this component and had no concomitant food sensitization. CONCLUSION: Monosensitization to Ana o 3 is, irrespective of other parameters, connected with high risk of severe anaphylaxis.
The functional biology of peanut allergens and possible links to their allergenicity
Peanut is one of the most common food triggers of fatal anaphylaxis worldwide although peanut allergy affects only 1-2% of the general population. Peanuts are the source of highly potent allergenic proteins. It is emerging that the allergenicity of certain proteins is linked to their biological function. Peanut is an unusual crop in that it flowers above ground but produces its seed-containing pods underground. This so called geocarpic fruiting habit exposes pods and seeds during their development to soilborne pathogens and pests. Pest damage can also open routes of entry for opportunistic fungi such as Aspergillus. Although seed proteins have primary functions in nutrient reservoirs, lipid storage bodies, or the cytoskeleton, they have also evolved to act as part of the plant's defense system to enhance fitness and survival of the species. When interacting with pathogens or pests, these proteins modify and damage cells' membranes, interact with immune receptors and modulate signaling pathways. Moreover, following exposure, the immune system of predisposed individuals reacts to these proteins with the production of specific IgE. This review explores the evolutionary biology of peanut and its seed proteins and highlights possible links between the proteins' biological function and their allergenicity.
Chemically modified peanut extract shows increased safety while maintaining immunogenicity.
BACKGROUND: Peanuts are most responsible for food-induced anaphylaxis in adults in developed countries. An effective and safe immunotherapy is urgently needed. The aim of this study was to investigate the immunogenicity, allergenicity and immunotherapeutic efficacy of a well characterized chemically modified peanut extract (MPE) adsorbed to Al(OH)3. METHODS: Peanut extract (PE) was modified by reduction and alkylation. Using sera of peanut allergic patients, competitive IgE-binding assays and mediator release assays were performed. The immunogenicity of MPE was evaluated by measuring activation of human PE-specific T-cell lines and the induction of PE-specific IgG in mice. The safety and efficacy of MPE adsorbed to Al(OH)3 was tested in two mouse models by measuring allergic manifestations upon peanut challenge in peanut allergic mice. RESULTS: Compared to PE, the IgE-binding and capacity to induce allergic symptoms of MPE was lower in all patients. PE and MPE displayed similar immunogenicity in vivo and in vitro. In mice sensitized to PE, the threshold for anaphylaxis (drop in BT) upon subcutaneous challenge with PE was 0.01 mg, while at 0.3 mg MPE no allergic reaction occurred. Anaphylaxis was not observed when PE and MPE were fully adsorbed to Al(OH)3 . Both PE and MPE + Al(OH)3 showed to be efficacious in a model for immunotherapy. CONCLUSION: In our studies an Al(OH)3 adsorbed MPE showed reduced allergenicity compared to unmodified PE, while the efficacy of immunotherapy is maintained. The preclinical data presented in this study supports further development of modified peanut allergens for IT.
Oral peanut immunotherapy‐How much is too much? How much is enough?.
Efficacy of Food allergy immunotherapy (FA-AIT) for cow's milk, hen's egg and peanut at the level of desensitization is established via several small placebo-controlled trials and a number of open label trials1 . First approved treatments for peanut allergy are projected to become available soon including oral immunotherapy (OIT). But there is still a discussion which group of patients might profit most of OIT and what amount of maintenance dose to apply.
Peanut allergy–individual molecules as a key to precision medicine.
Peanut allergy is one of the most severe food allergies affecting millions of individuals worldwide. In German-speaking countries, peanutallergy is the most important cause of anaphylaxis in children and adolescents. This Editorial highlights the impact of individual peanutallergens on the severity of symptoms and summarizes the allergens' biological characteristics and usefulness as tools for precision diagnostic tests.
Feasibility of desensitizing children highly allergic to peanut by high‐dose oral immunotherapy.
BACKGROUND: There is limited data on feasibility, efficacy and safety of high-dose oral immunotherapy (OIT) in children highly allergic to peanuts. OBJECTIVE: In children highly allergic to peanut, we primarily aimed to determine the feasibility of reaching the maximum maintenance dose (MMD) of 5000 mg peanut protein or alternatively, a lower individual maintenance dose (IMD), by OIT up-dosing. Secondarily, we aimed to identify adverse events (AEs), and determine factors associated with reaching a maintenance dose. METHODS: The TAKE-AWAY peanut OIT trial enrolled 77 children 5-15 years -old, with a positive oral peanut challenge. Fifty-seven were randomized to OIT with bi-weekly dose step-up until reaching MMD or IMD, and 20 to observation only. Demographic and biological characteristics, AEs, medication and protocol-deviations were explored for associations with reaching maintenance dose. RESULTS: All children had anaphylaxis defined by objective symptoms in minimum two organ systems during baseline challenge. The MMD was reached by 21.1%, while 54.4% reached an IMD of median (minimum, maximum) 2700 (250, 4000) mg peanut protein, whereas 24.5% discontinued OIT. During up-dosing, 19.4% experienced anaphylaxis. Not reaching the MMD was caused by distaste for peanuts (66.7%), unacceptable AEs (26.7%) and social reasons (6.7%). Increased peanut s-IgG₄/s-IgE ratio (OR (95% CI)) 1.02 (1.00, 1.04) was associated with reaching MMD. CONCLUSION: Although 75.5% of children with peanut anaphylaxis reached a maintenance dose of 0.25 - 5 g, only 21.1% reached the MMD. Distaste for peanuts and AEs, including high risk of anaphylaxis, limited feasibility of reaching MMD.
" 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-screen approach, in terms of number of cases of peanut allergy prevented, QALY's, and healthcare costs, though 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 $6,556.69 (95%CI, $6,512.76-$6,600.62), compared with a cost of $7,576.32 (95%CI, $7,531.38-$7,621.26) for skin test screening prior to introduction. From a US societal perspective, screening prior to introduction cost $654,115,322 and resulted in 3,208 additional peanut allergy diagnoses. Both screening and non-screening 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's, and total health care costs compared to screening and in-office peanut introduction.
Diagnostic accuracy, risk assessment, and cost‐effectiveness of component‐resolved diagnostics for food allergy: a systematic review.
BACKGROUND: Component-resolved diagnostics (CRD) are promising tools for diagnosing food allergy, offering the potential to determine specific phenotypes and to develop patient-tailored risk profiles. Nevertheless, the diagnostic accuracy of these tests varies across studies; thus, their clinical utility remains unclear. Therefore, we synthesized the evidence from studies investigating the diagnostic accuracy, risk assessment ability, and cost-effectiveness of CRD for food allergy. METHODS: We systematically searched 10 electronic databases and four clinical trial registries for studies published January 2000-February 2017. The quality of included studies was assessed using QUADAS-2. Due to heterogeneity, we narratively synthesized the evidence. RESULTS: Eleven studies met inclusion criteria, altogether recruiting 1,098 participants. The food allergies investigated were cow's milk, hen's egg, peanut, hazelnut, and shrimp. The components with the highest diagnostic accuracy for each allergen, along with their sensitivity-specificity pairs, were: Bos d 4 for cow's milk (62.0% and 87.5%), Gal d 1 for hen's egg (84.2% and 89.8% for heated egg, and 60.6% and 97.1% for raw egg), Ara h 2 for peanut (80.3% and 95.1%), Cor a 14 for hazelnut (100% and 93.8%), and Lit v 1 for shrimp (82.8% and 56.3%) allergy. CONCLUSION: Selected components of cow's milk, hen's egg, peanut, hazelnut, and shrimp allergen showed high specificity, but lower sensitivity. However, few studies exist for each component, and studies vary widely regarding the cut-off values used, making it challenging to synthesize findings across studies. Further research is needed to determine clinically appropriate cut-off values, risk assessment abilities, and cost-effectiveness of CRD approaches.