Basophil activation test as predictor of severity and threshold of allergic reactions to egg.

BACKGROUND: Identifying patients at risk of severe allergic reactions and/or low threshold of reactivity is very important, particularly for staple foods like egg. METHODS: One hundred and fifty children underwent double-blind placebo-controlled food challenge (DBPCFC) to baked egg (BE), skin prick testing and blood collection for serology and basophil activation test (BAT). Patients who passed BE DBPCFC underwent loosely cooked egg (LCE) DBPCFC. Severity of allergic reactions was classified following Practall guidelines and threshold dose was determined during DBPCFC. RESULTS: Sixty out of 150 (40%) children reacted to BE and 16 out of 77 (21%) to LCE on DBPCFC. Considering DBPCFC to BE, 23 children (38%) had severe reactions and 33 (55%) reacted to 0.13 g or less of egg protein (low threshold group). Two children (2 out of 16 = 12%) had severe reactions to LCE. Demographic, clinical and most immunological features were not significantly different between severe/non-severe BE reactors or low/high threshold groups. Severe BE reactors had higher ovomucoid-sIgE (p = .009) and higher BAT to BE (p = .001). Patients with lower threshold to BE had higher IgE-specific activity (p = .027) and BAT to egg (p = .007) but lower severity score (p = .008). Optimal cut-offs for ovomucoid-sIgE had 100% sensitivity, 35% specificity and 60% accuracy and for BAT 76% sensitivity, 74% specificity and 75% accuracy to identify BE severe reactors. Optimal cut-offs for specific activity had 70% sensitivity, 68% specificity and 69% accuracy and for BAT 70% sensitivity, 72% specificity and 71% accuracy to identify low threshold patients. CONCLUSIONS: BAT was the best biomarker to predict severity and threshold of allergic reactions to BE and can be useful when making decisions about management of egg allergy.

Partial Egg Consumption Modifies the Diagnostic Performance of Allergy Tests to Predict Outcome of Double-Blind Placebo-Controlled Food Challenges to Egg.

BACKGROUND: Many children are consuming some egg when they are diagnosed with egg allergy. We hypothesized that egg consumption could modify the diagnostic performance of allergy tests. OBJECTIVE: To stratify diagnostic performance of tests according to egg consumption status. METHODS: The BAT2 study (NCT03309488) participants underwent oral food challenge (OFC), food-frequency questionnaires, skin prick test (SPT), specific immunoglobulin E (sIgE) and specific immunoglobulin G4 (sIgG4) and basophil activation test (BAT). RESULTS: At study entry, 45% of participants reported partial egg consumption ("consumers") and 55% were avoiding egg strictly ("avoiders"). Avoiders had larger SPT (P < .001), higher BAT to egg (P < .001), sIgE to egg white (EW; P = .001) and to ovalbumin (OVA; P = .001), but not to ovomucoid (P = .231). Consumers had higher levels of sIgG4 to all egg allergens (P < .001) than avoiders. In consumers, the test with the best diagnostic performance was BAT (area under the curve [AUC] = .912) followed by SPT to raw egg (AUC = 0.805), EW-sIgE (AUC = 0.738), and OVA-sIgE (AUC = 0.732). In avoiders, the best tests were BAT (AUC = 0.834) and EW-sIgE (AUC = 0.833) followed by OVA-sIgE (AUC = 0.793) and SPT to EW (AUC=0.789). Using 100% sensitivity and 100% specificity cut-offs, the proportion of patients requiring OFC were 33% for BAT, 53% for SPT to raw egg, 61% for OVA-sIgE, and 73% for EW-sIgE for consumers; and 73% for BAT, 79% for EW-sIgE, and 93% for SPT to EW for avoiders. CONCLUSIONS: The diagnostic performance of tests is influenced by the immunomodulatory effect of egg consumption. BAT is the most reliable test and reduced the need for OFC, particularly in partial egg consumers.

Diagnostic utility of allergy tests to predict baked egg and lightly cooked egg allergies compared to double-blind placebo-controlled food challenges.

BACKGROUND: Double-blind placebo-controlled food challenges (DBPCFC) are the gold-standard to diagnose food allergy. However, they can cause allergic reactions of unpredictable severity. We assessed accuracy of current and new diagnostic tests compared to DBPCFC to baked egg (BE) and to lightly cooked egg (LCE). METHODS: Children aged 6 months to 15 years were assessed for possible egg allergy as part of the BAT2 study (NCT03309488). They underwent clinical assessment, skin prick test (SPT), specific IgE (sIgE) and basophil activation test (BAT). The results of the tests were compared with DBPCFC outcomes to both BE and LCE. RESULTS: A total of 150 children underwent DBPCFC to BE, 60 (40%) reacted to and 85 (57%) tolerated BE and 5 (3%) had inconclusive oral food challenges (OFC). Seventy-seven children tolerant to BE had DBPCFC to LCE and 16 reacted. The test within each modality with the best diagnostic performance for BE allergy was as follows: SPT to egg white (EW) (AUC = 0.726), sIgE to EW (AUC = 0.776) and BAT to egg (AUC = 0.783). BAT (AUC = 0.867) was the best test in the younger than 2 years age group. Applying 100% sensitivity and 100% specificity cut-offs, followed by OFC, resulted in 100% diagnostic accuracy. BAT enabled the greatest reduction in OFC (41%). Using sIgE followed by BAT allowed to reduce the number of BATs performed by about 30% without significantly increasing the number of OFC. CONCLUSIONS: The best diagnostic test was BAT to egg in terms of diagnostic accuracy and reduction in number of OFC. Using sIgE to EW followed by BAT required fewer BATs with sustained OFC reduction and diagnostic accuracy.

Preventing food allergy fatalities.

Fatal anaphylaxis to food is thankfully rare, but every death is a potentially avoidable tragedy. Usually, there will be a coronial inquest to establish the 'how and why' for each death. Reviewing these food allergy-related deaths identifies a number of common themes and risk factors. While some are non-modifiable (such as age, gender and ethnicity), others are and include delayed epinephrine administration and communication difficulties in allergen avoidance. This review highlights the key messages in food allergy-related fatality prevention for healthcare professionals and patients alike, and where available, we explain the evidence behind such recommendations. We describe the data behind the good practice points to facilitate their adoption in routine practice without generating additional anxiety for what is a comparatively rare event. We also propose an information leaflet for patients and carers, developed with patients and endorsed by two major allergy charities, to facilitate dissemination of the recommendations in this review.

Oral Tolerance Induction-Opportunities and Mechanisms.

Oral tolerance is the active absence of response to food allergens, which involves complex mechanisms in the gut-associated lymphoid tissue. Food allergy results from the disruption of such tolerance or the absence of its establishment in the first place. It follows allergic sensitization with the production of allergen-specific IgE and results from the degranulation of basophils and mast cells on subsequent exposure to the allergen. Oral tolerance induction has been explored in the contexts of prevention and treatment of food allergy. Early introduction of allergenic foods (i.e., egg and peanut) in the diet of infants, before allergic sensitization occurs (i.e., via inflamed skin affected with eczema) has shown to be beneficial. Guidelines have changed to recommend the introduction of these allergenic foods by 6 months of age. For food allergic individuals, oral tolerance induction has been attempted using allergen-specific immunotherapy, which involves the administration of an allergen, modified or not, through various possible routes, including oral, sublingual, epicutaneous, and subcutaneous, with or without concomitant administration of antibody-based biologics. Further research into the immune mechanisms of food allergy and oral tolerance can lead to the identification of novel targets to suppress the food allergic response and reverse the current food allergy epidemic.

Improving Diagnostic Accuracy in Food Allergy.

The diagnosis of food allergy can have a major impact on the lives of patients and families, imposing dietary restrictions and limitations on social activities. On the other hand, misdiagnosis can place the patient at risk of a potentially severe allergic reaction. Therefore, an accurate diagnosis of food allergy is of utmost importance. The diagnosis of food allergy is often established by the combination of the clinical history and allergen-specific IgE; however, without a clear history of an allergic reaction, the interpretation of IgE sensitization tests can be difficult. There are also rare cases of clinical food allergy in the absence of IgE sensitization. For that reason, testing for suspected food allergy ideally requires access to oral food challenges (OFCs), which are currently the gold standard tests to diagnose food allergy. As OFCs are time consuming and involve the risk of acute allergic reactions of unpredictable severity, the question remains: how can we improve the accuracy of diagnosis before referring the patient for an OFC? Herein, we review the predictive value of different tests used to support the diagnosis of food allergy, discuss implications for therapy and prognosis, and propose a diagnostic approach to be applied in clinical practice.

The Challenge of Home Allergen Re-introductions Using the Ladder Approach in Children With Non-IgE Mediated Gastrointestinal Food Allergy.

Background: Oral food challenges remain the most reliable method for allergy confirmation. Although consensus guidelines have been published to unify Immunoglobulin E (IgE)-mediated challenges, this does not exist for non-IgE mediated gastrointestinal allergies outside of Food Protein Induced Enterocolitis Syndrome. We therefore set out to establish the use of home introduction protocols (HIP) for confirmation of food allergy for milk, soya, egg and wheat using a ladder approach in children with non-IgE mediated allergy. Materials and Methods: Patients with suspected non-IgE mediated gastrointestinal allergies (0-16 years) were recruited following symptom improvement on an elimination diet. All children had skin prick or specific IgE tests to rule out IgE-mediated allergies prior to suggestion the HIP. Number of trials and outcome was documented. HIPs were developed using a published ladder approach for cow's milk as baseline and final dose was calculated based on guidelines for food protein induced enterocolitis syndrome and portions for age from the National Diet and Nutrition Survey. First foods were baked/highly processed and every 4th day patients moved to a more unprocessed/unheated food. Results: From 131 recruited patients, 117 (89.3%) followed the HIP for food allergens. No adverse events were documented. In more than 50% of cases one attempt at the HIP was sufficient to establish allergy status, but many required 2-5 attempts before the outcome was clear. About half of the children were fully tolerant to foods they initially eliminated: 36, 26 and 30% were partially tolerant to milk, soya, and egg and only 15% achieved partial tolerance to wheat. Wheat was the allergen introduced earliest, followed by soya, cow's milk and egg. Conclusions: This study indicates that home HIPs are safe in non-IgE mediated gastrointestinal food allergy and that the ladder approach may be useful in re-introducing allergens in children at home with non-IgE mediated gastrointestinal allergies. From this study we can also conclude that tolerance to processed/baked allergens was observed in many children. Further studies should be performed on the HIP and ideally reintroduction should occur pre-defined time intervals.

Biomarkers of diagnosis and resolution of food allergy.

Food allergy is increasing in prevalence, affecting up to 10% of children in developed countries. Food allergy can significantly affect the quality of life and well-being of patients and their families; therefore, an accurate diagnosis is of extreme importance. Some food allergies can spontaneously resolve in 50%-60% of cow's milk and egg-allergic, 20% of peanut-allergic and 9% of tree nut-allergic children by school age. For that reason, food-allergic status should be monitored over time to determine when to reintroduce the food back into the child's diet. The gold-standard to confirm the diagnosis and the resolution of food allergy is an oral food challenge; however, this involves the risk of causing an acute-allergic reaction and requires clinical experience and resources to treat allergic reactions of any degree of severity. In the clinical setting, biomarkers have been used and validated to enable an accurate diagnosis when combined with the clinical history, deferring the oral food challenge, whenever possible. In this review, we cover the tools available to support the diagnosis of food allergies and to predict food allergy resolution over time. We review the latest evidence on different testing modalities and how effective they are in guiding clinical decision making in practice. We also evaluate predictive test cut-offs for the more common food allergens to try and provide guidance on when challenges might be most successful in determining oral tolerance in children.

Food-dependent exercise-induced anaphylaxis.

PURPOSE OF REVIEW: The following article provides an overview of food-dependent exercise-induced anaphylaxis (FD-EIAn). The review focuses on the epidemiology, pathophysiology, and clinical findings of FD-EIAn and details current practice in terms of the investigation, management, and treatment options available. RECENT FINDINGS: The management of FD-EIAn has not changed significantly over the last few years and still requires careful investigation by an experienced clinician to ensure that the correct diagnosis is made and appropriate treatment is given. Although new therapies such as synthetic prostaglandin E1 analogs and IgE monoclonal antibodies have been trialed as treatment options for FD-EIAn, the mainstay of treatment remains the graded reintroduction to exercise in a supervised setting. SUMMARY: FD-EIAn is a rare but serious condition that can have a significant impact on patients' lives. This review aims to discuss new relevant research into this field to help guide clinicians in managing this condition.

Mini Review - Asthma and Food Allergy.

BACKGROUND: It is well known that there is a common interplay between atopic conditions and that having one atopic condition can predispose to the development of others. The link between asthma and food allergy has been well researched over the years; although the exact interplay between the two atopic conditions is yet to be fully described. Research suggests that children who have both asthma and food allergy are at greater risk of more severe asthmatic episodes. CONCLUSION: They are also at risk of food allergen triggered asthmatic episodes as well as foodallergen induced anaphylaxis. Therefore, it is important for clinicians to understand and recognise the association between these two atopic conditions to provide children and their families with the correct treatment and management to avoid potentially life-threatening events related to their disease.

Immune mechanisms of food allergy and its prevention by early intervention.

The environmental factors driving the increase in food allergies are unclear and possibly involve dual exposure to allergens, microbiome-driven effects or other mechanisms. Until they can be better understood, early intervention aiming at establishing oral tolerance provides an effective way to decrease the window-of-risk when children may develop allergic sensitisation to foods due to the absence of a protective immune response. Thus, the recent LEAP (Learning Early About Peanut allergy) and LEAP-On studies achieved a high level of peanut allergy prevention by early introduction of peanuts in the infants diet and conveyed more information regarding the evolution of IgE and IgG4 antibody responses to food antigens over time.

Asthma, Food Allergy, and How They Relate to Each Other.

The association between atopic diseases is well known, and previous research has shown that having one atopic disease can predispose to having another. The link between asthma and food allergy has been well researched, but the exact relationship between the two atopic conditions is not fully understood. Food allergic infants are at increased risk for the development of asthma and are at risk of food-induced asthmatic episodes and also anaphylaxis. Having a diagnosis of both food allergy and asthma has also been shown to have an effect on the severity of a patient's disease including being at greater risk of severe asthmatic episodes. Therefore, understanding the relationship between these two conditions in order to treat and manage these children safely is crucial to clinicians.

The impact on quality of life on families of children on an elimination diet for Non-immunoglobulin E mediated gastrointestinal food allergies.

BACKGROUND: The impact on health related quality of life (HRQL) has been well studied in children with Immunoglobulin E (IgE)-mediated food allergy. However limited data exists on related quality of life (QOL) of families who have a child suffering from food protein induced non-IgE mediated gastrointestinal allergies. We aimed to establish the QOL of families with children at the beginning of following an elimination diet for non-IgE mediated gastrointestinal food allergies. METHODS: A prospective, observational study was performed. Parents of children aged 4 weeks-16 years who improved after 4-8 weeks of following an elimination diet for suspected non-IgE mediated allergies were included. The Family Impact Module (FIM) of the Pediatric Quality of Life (PedsQL™) was used and we compared our data to two historical cohorts: one with sickle cell disease and another with intestinal failure. RESULTS: One hundred and twenty three children with a median age of 20 months were included (84 boys). The total FIM Score was 57.43 (SD 22.27) and particularly low for daily activities and worry. Factors that impacted significantly included age (p < 0.0001), number of foods excluded (p = 0.008), symptom severity (p = 0.041) and chronic nasal congestion (p = 0.012). Children with non-IgE mediated food allergies had worse scores in all domains (p < 0.0001) compared to sickle cell disease and worse physical (p = 0.04), emotional (p = 0.04) and worry (p = 0.01) domains compared to intestinal failure. CONCLUSIONS: This study found that parent QOL and family functioning was worse in those families who had a child on an elimination diet for non-IgE mediated allergies compared to those with sickle cell disease and intestinal failure, highlighting the impact this disease has on families.

The role of dietary interventions in the prevention of IgE-mediated food allergy in children.

Over the last 30 years, the prevalence of food allergy has been on the rise and remains a disease that can have a significant impact on the quality of life of children and their families. There are several hypotheses that have been suggested to account for the increasing prevalence, but this review will focus on the impact that dietary factors have on food allergy development. In the past food allergy, prevalence has largely focused on allergen avoidance; however, there is increasing evidence from interventional studies that have shown that early introduction to potential food allergens may have a beneficial role in allergy prevention. This review aims to look at the evidence in support of early introduction of allergens into infant diets to prevent against the development of food allergy.

Establishing the prevalence of low vitamin D in non-immunoglobulin-E mediated gastrointestinal food allergic children in a tertiary centre.

BACKGROUND: There is no data on the prevalence of vitamin D deficiency in children with non-immunoglobulin-E (IgE) mediated gastrointestinal food allergy. The aims of our study were to understand the prevalence of vitamin D insufficiency and deficiency in children with non-IgE mediated gastrointestinal food allergy and identify predisposing factors. METHODS: This was a retrospective study which looked at data from Great Ormond Street Hospital from January 2002 to September 2015. Children 0-18 years old with a confirmed diagnosis of non-IgE mediated gastrointestinal food allergy who had a vitamin D level measured during the course of their disease were included. Low vitamin D levels were defined as <50 nmol/L; insufficient levels were defined as 25-50 nmol/L and deficient levels as <25 nmol/L. Patient characteristics and clinical factors were also recorded. RESULTS: Ninety-two patients met the study criteria; 49% were female and median age was 10 years 2 months [IQR: 4 years 8 months to 13 years 7 months]. Of the cohort, 26% (24/92) had low vitamin D levels; 16% had insufficient vitamin D levels and 10% had vitamin D deficiency. Gender (p = 0.043) and age (p = 0.035) were significantly associated with low vitamin D levels. Twelve percent of children who were on an amino acid formula (AAF) had low vitamin D compared to 31% of children who were not (p = 0.06). No other clinical factors were found to be significantly associated with low vitamin D levels. CONCLUSIONS: Children with non-IgE mediated gastrointestinal food allergy are at risk of vitamin D insufficiency and deficiency. Further prospective studies need to be performed in all children with non-IgE mediated gastrointestinal food allergies. TRIAL REGISTRATION: The study was registered with the GOSH Research & Development department as a retrospective case note review. The Health Research Authority confirmed that NHS Research and Ethics Committee approval was not required; thus there is no trial registration number.

Prevention of food allergy - Early dietary interventions.

The prevalence of food allergy has increased over the last 30 years and remains a disease, which significantly impacts on the quality of life of children and their families. Several hypotheses have been formulated to explain the increasing prevalence; this review will focus on the hypothesis that dietary factors may influence the development of food allergy. Historically, the prevention of food allergy has focused on allergen avoidance. However, recent findings from interventional studies have prompted a shift in the mind set from avoidance to early introduction of potentially allergenic foods. This review aims to facilitate a better understanding of contemporary research studies that make use of early introduction of common allergenic foods into infant diets as a preventative strategy against the development of food allergy.