Poppy Seed Allergy: Molecular Diagnosis and Cross-Reactivity With Tree Nuts.

BACKGROUND: Poppy seed (PS) can be a cause of severe allergic reactions, especially in individuals with concurrent allergy to tree nuts and other seeds, but diagnostic criteria and sensitization patterns are lacking. OBJECTIVE: To assess the role of PS extract and individual allergens in diagnosing PS allergy and their cross-reactivities with tree nuts and buckwheat. METHODS: Our retrospective study included 36 PS-sensitized patients; 10 with a positive and 26 with a negative oral food challenge (OFC). We identified individual PS allergens and compared the diagnostic performance of specific IgE (sIgE) to PS extract with its allergens. Cross-reactivities between PS and related allergens from other seeds were assessed by a competitive enzyme-linked immunosorbent assay. RESULTS: We identified 4 novel PS allergens: Pap s 1 (vicilin), Pap s 1 (27-424) (α-hairpinin), Pap s 2 (legumin), and Pap s 3 (small hydrophilic seed protein). A positive OFC correlated with higher PS-sIgE levels and elevated sIgE levels for the PS allergens, except for Pap s 3. PS and α-hairpinin-sIgE effectively differentiated allergic from tolerant patients, with area under the curve values of 0.95 and 0.94. PS-sIgE >10.00 kUA/L exhibited 90% sensitivity and 73% specificity, whereas α-hairpinin-sIgE >2.60 kUA/L showed 100% sensitivity and 77% specificity. PS vicilin and legumin highly cross-reacted with hazelnut and buckwheat homologs, whereas α-hairpinin-sIgE cross-reacted with the related almond allergen. CONCLUSIONS: This is the most extensive study on PS allergy to date. PS and α-hairpinin-sIgE are highly sensitive indicators of clinical reactivity to PS, whereas vicilin and legumin-sIgE contribute to concurrent sensitization to hazelnut and buckwheat.

Clinical performance of AI-integrated risk assessment pooling reveals cost savings even at high prevalence of COVID-19.

Individual testing of samples is time- and cost-intensive, particularly during an ongoing pandemic. Better practical alternatives to individual testing can significantly decrease the burden of disease on the healthcare system. Herein, we presented the clinical validation of Segtnan™ on 3929 patients. Segtnan™ is available as a mobile application entailing an AI-integrated personalized risk assessment approach with a novel data-driven equation for pooling of biological samples. The AI was selected from a comparison between 15 machine learning classifiers (highest accuracy = 80.14%) and a feed-forward neural network with an accuracy of 81.38% in predicting the rRT-PCR test results based on a designed survey with minimal clinical questions. Furthermore, we derived a novel pool-size equation from the pooling data of 54 published original studies. The results demonstrated testing capacity increase of 750%, 60%, and 5% at prevalence rates of 0.05%, 22%, and 50%, respectively. Compared to Dorfman's method, our novel equation saved more tests significantly at high prevalence, i.e., 28% (p = 0.006), 40% (p = 0.00001), and 66% (p = 0.02). Lastly, we illustrated the feasibility of the Segtnan™ usage in clinically complex settings like emergency and psychiatric departments.

A concept for integrated care pathways for atopic dermatitis-A GA2 LEN ADCARE initiative.

INTRODUCTION: The integrated care pathways for atopic dermatitis (AD-ICPs) aim to bridge the gap between existing AD treatment evidence-based guidelines and expert opinion based on daily practice by offering a structured multidisciplinary plan for patient management of AD. ICPs have the potential to enhance guideline recommendations by combining interventions and aspects from different guidelines, integrating quality assurance, and describing co-ordination of care. Most importantly, patients can enter the ICPs at any level depending on AD severity, resources available in their country, and economic factors such as differences in insurance reimbursement systems. METHODS: The GA2 LEN ADCARE network and partners as well as all stakeholders, abbreviated as the AD-ICPs working group, were involved in the discussion and preparation of the AD ICPs during a series of subgroup workshops and meetings in years 2020 and 2021, after which the document was circulated within all GAL2 EN ADCARE centres. RESULTS: The AD-ICPs outline the diagnostic procedures, possible co-morbidities, different available treatment options including differential approaches for the pediatric population, and the role of the pharmacists and other stakeholders, as well as remaining unmet needs in the management of AD. CONCLUSION: The AD-ICPs provide a multidisciplinary plan for improved diagnosis, treatment, and patient feedback in AD management, as well as addressing critical unmet needs, including improved access to care, training specialists, implementation of educational programs, assessment on the impact of climate change, and fostering a personalised treatment approach. By focusing on these key areas, the initiative aims to pave the way for a brighter future in the management of AD.

Challenge-verified thresholds for allergens mandatory for labeling: How little is too much for the most sensitive patient?

BACKGROUND: It is mandatory to label food products with the 14 main allergens in the EU. Reasonable allergen labeling requires knowledge of population-based thresholds derived from food challenges. The aim of this study was to evaluate the threshold-distribution in clinically verified food allergic patients for allergens mandatory for labeling. METHODS: All positive open oral food challenges and double-blind placebo-controlled food challenges (DBPCFC) performed at the Allergy Center, Odense University Hospital, Denmark (2000-2022) were included. For each included challenge, the cumulative threshold (LOAEL) was obtained and NOAEL estimated. Data were modelled as an interval censored log-normal distribution. RESULTS: Overall, 38 of all 2612 challenges (1.5%) in 1229 patients (717 male, 986 children) reacted to <5 mg protein. The majority of the most sensitive patients reacted with a Sampson severity score of 2-3. Using interval censored log-normal models only five groups (hens´ egg, fish, peanut, milk, tree-nuts) elicited reactions after ingestion of 0.5 mg protein and in low frequencies of the population. Hen's egg was the most potent allergen, with reactivity to <0.5 mg protein in 0.24% [0.13-0.44%] of egg allergic patients while the estimated fraction of allergic patients reacting to a eliciting dose on 0.5 mg protein for most other allergens were below 0.04%. CONCLUSION: Our data demonstrates that the majority of food allergic patients as expected tolerating traces of allergenic foods without developing severe allergic symptoms and signs. Hen's egg appears to be the food most likely to elicit reactions in the most sensitive individuals at very low doses.

A comparison of double-blind, placebo-controlled food challenge and open food challenge.

BACKGROUND: Double-blind, placebo-controlled food challenge (DBPCFC) remains the gold standard for diagnosing food allergy, despite sparse comparisons to open food challenges (OpenFCs). The objective of this retrospective study was to compare severity of symptoms and threshold values (cumulative dose of food allergen eliciting a clinical reaction) in children and adults with peanut allergy, challenged in an open and/or double-blind, placebo-controlled protocol. METHODS: This study included patients from the Allergy Centre, Odense University Hospital with a positive oral food challenge, defined as strict objective signs, with peanut during the period 2001-2022. Severity of symptoms was graded using the Sampson's severity score. Distribution models of threshold values were calculated using log-normal interval-censored survival analysis, and the number of placebo reactions was evaluated. RESULTS: In total, 318 positive OpenFCs and 86 DBPCFCs were included. There was no difference in severity of symptoms nor threshold values comparing the two challenge types, neither when stratified for age groups. However, a higher proportion of children experienced Grade 3 symptoms in the double-blind group. Only one patient had a positive reaction to a placebo challenge. CONCLUSION: Our findings do not advocate for DBPCFC being superior to OpenFC, if the latter is performed with strict objective stop criteria by trained staff.

Detection of Circulating Peanut Components in Serum after Ingestion.

INTRODUCTION: Detection of specific food allergens brought into circulation following ingestion is complicated by the minute amounts present in serum. We therefore aimed to assess the utility of selective removal of IgE against peanut components using ImmunoCAP combined with the basophil histamine release (HR) assay (BHRA) to identify the absorbed allergen components after ingestion of peanut. METHODS: Serum from six healthy individuals was drawn before and 1 h after ingestion of 100 g peanut. Serum from two peanut allergic patients was depleted for IgE against single allergen components by incubation with ImmunoCAPs coupled with either Ara h 1; 2; 3 or 6 before donor basophils were passively sensitized with the serum preparations. The sensitized cells were challenged with serum obtained from the six individuals before and after ingestion of peanut, and HR was measured after serum provocation. RESULTS: Ara h 2 and Ara h 6 were detected in serum 1 h after ingestion in 6/6 individuals by negative selection. Depletion of specific IgE against Ara h 2 or Ara h 6 almost completely abolished the response to serum provocation, indicating a sequence homology between the two allergen components in serum. Ara h 1 was demonstrated in 5/6 sera and Ara h 3 in 1/6 sera. CONCLUSION: This study is a proof of concept showing that passive sensitization of basophils with sera depleted of component-specific IgE can be used to identify food allergen components present in serum after ingestion.

The influence of acetylsalicylic acid and alcohol on absorption kinetics of hen´s egg white in a human passive cutaneous anaphylaxis model.

Background: Despite the well-known fact that acetylsalicylic acid (ASA) can induce anaphylaxis in patients susceptible to wheat-dependent exercise-induced anaphylaxis, few studies have sought to investigate the effects of cofactors on type-1 food allergy and none with ASA and hen's egg and hen's egg and alcohol combined. Methods and results: We applied the experimental model of 'passive cutaneous anaphylaxis' in humans to study whether the absorption kinetics of egg white is altered while being treated with ASA or under the influence of alcohol. Donor sera from four egg allergic patients with specific immunoglobulin E (s-IgE) to ovalbumin (0.1-8.87-19.5-170 kUA/L) were injected intracutaneously into the forearm of 12 healthy volunteers who were then challenged separately to: 1) egg white 2) egg white + ASA and 3) egg white + alcohol. 'Time to wheal' and 'wheal size' were compared among the three experiments.We saw that 'time to wheal' with both ASA (P = 0.001) and alcohol (P = 0.019) added as cofactor significantly decreased compared with baseline. Conclusion: In this passive cutaneous anaphylaxis model, ASA and alcohol affected both reaction time and size of reactions elicited after egg ingestion. This suggests that patients with egg allergy could have faster and more severe reactions during ASA treatment or under alcohol influence.

The quest for ingested peanut protein in human serum.

BACKGROUND: There is mounting evidence that systemic uptake of food allergens is key to triggering anaphylaxis. However, direct proof for this theory is still lacking. The purpose of this study was to quantify the absorption and to determine the absorption kinetics of immunoreactive peanut protein in relation to the allergic response in human. METHODS: Quantitative protein assays including mass spectrometry, dot blots and Western blotting were developed to determine the level of Ara h 2 absorption in human serum. The double monoclonal sandwich ELISA was applied to quantify absorbed Ara h 2 and 6, and the basophil histamine release assay and the human passive cutaneous anaphylaxis test were utilized to study the absorption kinetics of immunologically intact peanut proteins. RESULTS: The protein assays worked but were not sensitive enough to trace the minute amounts of absorbed Ara h 2 in human serum. The level of Ara h 6 in serum was found to be up to 0.2 ng/mL, but Ara h 2 could not be detected with the ELISA. Both the in vivo and the in vitro methods were successful in demonstrating that: immunoreactive peanut protein was absorbed shortly after ingestion (≤5 minutes); the peanut protein concentration peaks between 1 and 4 hours; and peanut proteins can circulate for at least 48 hours in the bloodstream. CONCLUSION: Ingested peanut protein is absorbed systemically and retains its immunoreactive capacity in human serum. However, the precise quantities and the implication for the elicitation of anaphylaxis remains to be elucidated.

Clinical and serological follow-up of patients with WDEIA.

The clinical threshold in wheat-dependent, exercise-induced anaphylaxis seems to be lowered in patients on wheat free diet, whereas the opposite is seen in patients on regular wheat intake. Therefore, a recommendation of wheat consumption, if considered safe to the patient based on case-history and challenge results, could be advised.

Wheat-Dependent Cofactor-Augmented Anaphylaxis: A Prospective Study of Exercise, Aspirin, and Alcohol Efficacy as Cofactors.

BACKGROUND: Wheat-dependent exercise-induced anaphylaxis (WDEIA) is a severe and potentially life-threatening allergy caused by wheat ingestion and most commonly in combination with exercise. OBJECTIVE: To investigate the role and impact of different cofactors (exercise, aspirin, and alcohol) in patients with WDEIA. METHODS: We studied 25 adult patients with WDEIA. Diagnostic workup included specific IgE to omega-5 gliadin and skin prick test with wheat flour and gluten. Titrated oral challenge was performed with gluten at rest, combined with treadmill exercise, aspirin, alcohol, or a combination of exercise and aspirin. RESULTS: A positive challenge to gluten was found at rest (without cofactors) in 48% (12 of 25), with exercise in 92% (23 of 25), with aspirin in 84% (21 of 25), with alcohol in 56% (9 of 19), and with a combination of exercise and aspirin in 82% (18 of 22) of the patients. With exercise as a cofactor, the median threshold was 24 g (range, 4.8-80 g), with aspirin 8 g (range, 2.4-80 g), and with alcohol 28 g (range, 0-45 g). The combination of 2 cofactors (exercise and aspirin) resulted in a median threshold of 4.3 g (range, 1.1-48 g). The threshold for the clinical reaction was lowered by 63%, 83%, 36%, and 87%, respectively, compared with at rest. The mean severity grade (scale 0-5) according to the Sampson severity score at rest was 0.8 (range, 0-2), and when combined with exercise 2.1 (range, 0-5), with aspirin 1.9 (range, 0-5), with alcohol 0.8 (range, 0-2), and with the combination of exercise and aspirin 1.5 (range, 0-2). CONCLUSION: Our results demonstrate that exercise and aspirin augment clinical reactions in WDEIA by lowering the threshold and increase the severity of the allergic reaction, whereas alcohol gives ambiguous results. Furthermore, a combination of 2 cofactors (exercise and aspirin) increases the risk of reactions.

Exercise-induced anaphylaxis: causes, consequences, and management recommendations.

INTRODUCTION: Exercise-induced anaphylaxis (EIA) denotes a range of disorders where anaphylaxis occurs in relation to physical exercise. Typical symptoms include flushing, pruritus, urticaria, angioedema, respiratory symptoms, gastrointestinal symptoms, hypotension, and collapse during or after exercise. The far best described entity within EIA is food-dependent exercise-induced anaphylaxis (FDEIA), where symptoms only occur in combination with food intake. Frequency and predictability of symptoms vary, and some patients experience symptoms only if exercise is accompanied by other co-factors Areas covered: In the present review, we aimed to provide an overview of EIA, diagnostic workup, causes, management and discuss areas in need of further research. Expert opinion: Though rare, EIA is an entity that all allergists and practicing physicians should recognize. The pathophysiological and immunological mechanisms of EIA are largely unknown. Management is centered upon avoidance of eliciting factors, where emergency plans are individualized, except a mandatory prescription of an adrenaline auto-injector.

Integrating Clinical and Epidemiologic Data on Allergic Diseases Across Birth Cohorts: A Harmonization Study in the Mechanisms of the Development of Allergy Project.

The numbers of international collaborations among birth cohort studies designed to better understand asthma and allergies have increased in the last several years. However, differences in definitions and methods preclude direct pooling of original data on individual participants. As part of the Mechanisms of the Development of Allergy (MeDALL) Project, we harmonized data from 14 birth cohort studies (each with 3-20 follow-up periods) carried out in 9 European countries during 1990-1998 or 2003-2009. The harmonization process followed 6 steps: 1) organization of the harmonization panel; 2) identification of variables relevant to MeDALL objectives (candidate variables); 3) proposal of a definition for each candidate variable (reference definition); 4) assessment of the compatibility of each cohort variable with its reference definition (inferential equivalence) and classification of this inferential equivalence as complete, partial, or impossible; 5) convocation of a workshop to agree on the reference definitions and classifications of inferential equivalence; and 6) preparation and delivery of data through a knowledge management portal. We agreed on 137 reference definitions. The inferential equivalence of 3,551 cohort variables to their corresponding reference definitions was classified as complete, partial, and impossible for 70%, 15%, and 15% of the variables, respectively. A harmonized database was delivered to MeDALL investigators. In asthma and allergy birth cohorts, the harmonization of data for pooled analyses is feasible, and high inferential comparability may be achieved. The MeDALL harmonization approach can be used in other collaborative projects.

Ratios of specific IgG4 over IgE antibodies do not improve prediction of peanut allergy nor of its severity compared to specific IgE alone.

BACKGROUND: IgG4 antibodies have been suggested to play a protective role in the translation of peanut sensitization into peanut allergy. Whether they have added value as diagnostic read-out has not yet been reported. OBJECTIVE: To evaluate whether (a) peanut-specific IgG, IgG4 and/or IgA antibodies are associated with tolerance and/or less severe reactions and (b) they can improve IgE-based diagnostic tests. METHODS: Sera of 137 patients with challenge-proven peanut allergy and of 25 subjects that tolerated peanut, both with known IgE profiles to peanut extract and five individual peanut allergens, were analyzed for specific IgG and IgG4 . Antibody levels and ratios thereof were associated with challenge outcome including symptom severity grades. For comparison of the discriminative performance, receiver operating characteristic curve (ROC) analysis was used. RESULTS: IgE against Ara h 2 was significantly higher in allergic than in tolerant patients and associated with severity of reactions (P < 0.001) with substantial diagnostic capability (AUC 0.91, 95%CI 0.87-0.96 and 0.80, 95%CI 0.73-0.87, respectively). IgG and IgG4 were also positively associated albeit significantly weaker (AUCs from 0.65 to 0.72). On the other hand, ratios of IgG and IgG4 over IgE were greater in patients that were tolerant or had mild symptoms as compared to severe patients but they did not predict challenge outcomes better than IgE alone (AUCs from 0.54 to 0.89). CONCLUSION: IgE against Ara h 2 is the best biomarker for predicting peanut challenge outcomes including severity and IgG and IgG4 antibody ratios over IgE do not improve these outcomes.

Allergic Rhinitis and its Impact on Asthma (ARIA) Phase 4 (2018): Change management in allergic rhinitis and asthma multimorbidity using mobile technology.

Allergic Rhinitis and its Impact on Asthma (ARIA) has evolved from a guideline by using the best approach to integrated care pathways using mobile technology in patients with allergic rhinitis (AR) and asthma multimorbidity. The proposed next phase of ARIA is change management, with the aim of providing an active and healthy life to patients with rhinitis and to those with asthma multimorbidity across the lifecycle irrespective of their sex or socioeconomic status to reduce health and social inequities incurred by the disease. ARIA has followed the 8-step model of Kotter to assess and implement the effect of rhinitis on asthma multimorbidity and to propose multimorbid guidelines. A second change management strategy is proposed by ARIA Phase 4 to increase self-medication and shared decision making in rhinitis and asthma multimorbidity. An innovation of ARIA has been the development and validation of information technology evidence-based tools (Mobile Airways Sentinel Network [MASK]) that can inform patient decisions on the basis of a self-care plan proposed by the health care professional.

Does early onset asthma increase childhood obesity risk? A pooled analysis of 16 European cohorts.

The parallel epidemics of childhood asthma and obesity over the past few decades have spurred research into obesity as a risk factor for asthma. However, little is known regarding the role of asthma in obesity incidence. We examined whether early-onset asthma and related phenotypes are associated with the risk of developing obesity in childhood.This study includes 21 130 children born from 1990 to 2008 in Denmark, France, Germany, Greece, Italy, The Netherlands, Spain, Sweden and the UK. We followed non-obese children at 3-4 years of age for incident obesity up to 8 years of age. Physician-diagnosed asthma, wheezing and allergic rhinitis were assessed up to 3-4 years of age.Children with physician-diagnosed asthma had a higher risk for incident obesity than those without asthma (adjusted hazard ratio (aHR) 1.66, 95% CI 1.18-2.33). Children with active asthma (wheeze in the last 12 months and physician-diagnosed asthma) exhibited a higher risk for obesity (aHR 1.98, 95% CI 1.31-3.00) than those without wheeze and asthma. Persistent wheezing was associated with increased risk for incident obesity compared to never wheezers (aHR 1.51, 95% CI 1.08-2.09).Early-onset asthma and wheezing may contribute to an increased risk of developing obesity in later childhood.

Assessing severity of anaphylaxis: a data-driven comparison of 23 instruments.

BACKGROUD: The severity of an allergic reaction can range from mild local symptoms to anaphylactic shock. To score this, a number of instruments have been developed, although heterogeneous in design and purpose. Severity scoring algorithms are therefore difficult to compare, but are frequently used beyond their initial purpose. Our objective was to compare the most used severity scoring instruments by a data-driven approach on both milder reactions and anaphylaxis. METHODS: All positive challenges to foods or drugs (n = 2828) including anaphylaxis (n = 616) at Odense University Hospital, Denmark from 1998 to 2016 were included and severity was scored according to Sampson5. Based on recommendations from an expert group, the symptoms and values from Sampson5 were for all reactions and anaphylaxis only translated and compared by kappa statistics with 22 instruments, ranging from 3 to 6 steps. RESULTS: For milder reactions, there was a significant correlation between the number of steps in an instrument and the number of challenges that could be translated, whereas all instruments were good to identify food anaphylaxis. Some instruments scored reactions more severely than Sampson5, other scored them milder and some scored food and drug challenges differently. Instruments for hymenoptera reactions were difficult to apply on food and drug reactions, and thus distributed severity differently. Algorithms hampered the translation between instruments, and 7 instruments were poor concerning drug anaphylaxis, including the only instrument developed specifically for drug reactions. CONCLUSION: The distributions of severity differed between the 23 instruments in both food and drug allergy, and thus rendering translation especially between scoring systems with 3 and 5 grades difficult. Fine-graded and simple instruments are preferred for comparison especially among milder reactions, and instruments applied to non-intended situations may not reflect a true severity picture.