Feast for thought: A comprehensive review of food allergy 2021-2023.

A review of the latest publications in food allergy over the past couple of years confirmed that food allergy is a major public health concern, affecting about 8% of children and 10% of adults in developed countries. The prevalence of food allergy varies around the world, with the increase being driven mainly by environmental factors, possibly together with genetic susceptibility to environmental changes. A precise diagnosis of food allergy is extremely important. Both new tests (eg, the basophil activation test) and improved optimization of information provided by existing tests (eg, the skin prick test and measurement of specific IgE level) can contribute to improving the accuracy and patients' comfort of food allergy diagnosis. Understanding the underlying immune mechanisms is fundamental to designing allergen-specific treatments that can be safe and effective in the long term. New discoveries of the immune response to food allergens, including T-cell and B-cell responses, have emerged. Novel therapeutic approaches are being trialed at various stages of development as attempts to allow for more active intervention to treat food allergy. Prevention is key to reducing the increase in prevalence. Early introduction of allergenic foods seems to be the most effective intervention, but others are being studied, and will, it is hoped, lead to modification of the epidemiologic trajectory of food allergy over time.

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.

Systematic review and meta-analyses on the accuracy of diagnostic tests for IgE-mediated food allergy.

The European Academy of Allergy and Clinical Immunology (EAACI) is updating the Guidelines on Food Allergy Diagnosis. We aimed to undertake a systematic review of the literature with meta-analyses to assess the accuracy of diagnostic tests for IgE-mediated food allergy. We searched three databases (Cochrane CENTRAL (Trials), MEDLINE (OVID) and Embase (OVID)) for diagnostic test accuracy studies published between 1 October 2012 and 30 June 2021 according to a previously published protocol (CRD42021259186). We independently screened abstracts, extracted data from full texts and assessed risk of bias with QUADRAS 2 tool in duplicate. Meta-analyses were undertaken for food-test combinations for which three or more studies were available. A total of 149 studies comprising 24,489 patients met the inclusion criteria and they were generally heterogeneous. 60.4% of studies were in children ≤12 years of age, 54.3% were undertaken in Europe, ≥95% were conducted in a specialized paediatric or allergy clinical setting and all included oral food challenge in at least a percentage of enrolled patients, in 21.5% double-blind placebo-controlled food challenges. Skin prick test (SPT) with fresh cow's milk and raw egg had high sensitivity (90% and 94%) for milk and cooked egg allergies. Specific IgE (sIgE) to individual components had high specificity: Ara h 2-sIgE had 92%, Cor a 14-sIgE 95%, Ana o 3-sIgE 94%, casein-sIgE 93%, ovomucoid-sIgE 92/91% for the diagnosis of peanut, hazelnut, cashew, cow's milk and raw/cooked egg allergies, respectively. The basophil activation test (BAT) was highly specific for the diagnosis of peanut (90%) and sesame (93%) allergies. In conclusion, SPT and specific IgE to extracts had high sensitivity whereas specific IgE to components and BAT had high specificity to support the diagnosis of individual food allergies.

Skin as the target for allergy prevention and treatment.

The fact that genetic and environmental factors could trigger disruption of the epithelial barrier and subsequently initiate a TH2 inflammatory cascade conversely proposes that protecting the same barrier and promoting adequate interactions with other organs, such as the gut, may be crucial for lowering the risk and preventing atopic diseases, particularly, food allergies. In this review, we provide an overview of structural characteristics that support the epithelial barrier hypothesis in patients with atopic dermatitis, including the most relevant filaggrin gene mutations, the recent discovery of the role of the transient receptor potential vanilloid 1, and the role involvement of the microbiome in healthy and damaged skin. We present experimental and human studies that support the mechanisms of allergen penetration, particularly the dual allergen exposure and the outside-in, inside-out, and outside-inside-outside hypotheses. We discuss classic skin-targeted therapies for food allergy prevention, including moisturizers, steroids, and topical calcineurin inhibitors, along with pioneering trials proposed to change their current use (Prevention of Allergy via Cutaneous Intervention and Stopping Eczema and ALlergy). We provide an overview of the novel therapies that enhance the skin barrier, such as probiotics and prebiotics topical application, read-through drugs, direct and indirect FLG replacement, and interleukin and janus kinases inhibitors. Last, we discuss the newer strategies for preventing and treating food allergies in the form of epicutaneous immunotherapy and the experimental use of single-dose of adeno-associated virus vector gene immunotherapy.

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.

The influence of air pollution on gestational age at delivery and birthweight in patients with or without respiratory allergy: A nested case-control study.

INTRODUCTION: Air pollution is a current major health issue. The burden of airborne pollutants and aeroallergen levels varies throughout the year, as well as their interaction and consequences. Prenatal exposure during pregnancy has been associated with adverse perinatal outcomes. The aim of this study was to evaluate the impact of air pollutants on perinatal outcomes in patients with or without respiratory allergy. MATERIAL AND METHODS: Nested case-control retrospective study on 3006 pregnant women. Correlations between concentrations of common pollutants in each trimester of pregnancy and on average during the whole pregnancy and both gestational age at delivery and birthweight were studied. Pearson's correlation coefficient and binary logistic regression were used. RESULTS: In general, pollutants correlated more strongly with birthweight than with gestational age at delivery. Nine-month NO2 , SO2 , CO, and benzene, and second-trimester CO negatively correlated with birthweight, whereas only first-trimester NO2 showed a very mild correlation with gestational age at delivery. Negative correlations between pollutants and birthweight were much stronger in the respiratory allergy group (n = 43; 1.4%) than in the non-allergic group. After adjustments, the most significant predictive pollutant of birthweight was SO2 in both groups. The best predictive model was much stronger in the allergic group for third-trimester SO2 (R2 = 0.12, p = 0.02) than in the non-allergic group for total SO2 (R2 = 0.002, p = 0.02). For each unit that SO2 increased, birthweight reduced by 3.22% vs. 1.28% in each group, respectively. CONCLUSIONS: Air pollutant concentrations, especially SO2 , negatively influenced birthweight. The impact of this association was much stronger and more relevant in the group of women with respiratory allergies.

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.

Follow-up to Adolescence after Early Peanut Introduction for Allergy Prevention.

BACKGROUND: A randomized trial demonstrated consumption of peanut from infancy to age 5 years prevented the development of peanut allergy. An extension of that trial demonstrated the effect persisted after 1 year of peanut avoidance. This follow-up trial examined the durability of peanut tolerance at age 144 months after years of ad libitum peanut consumption. METHODS: Participants from a randomized peanut consumption trial were assessed for peanut allergy following an extended period of eating or avoiding peanuts as desired. The primary end point was the rate of peanut allergy at age 144 months. RESULTS: We enrolled 508 of the original 640 participants (79.4%); 497 had complete primary end point data. At age 144 months, peanut allergy remained significantly more prevalent in participants in the original peanut avoidance group than in the original peanut consumption group (15.4% [38 of 246 participants] vs. 4.4% [11 of 251 participants]; P<0.001). Participants in both groups reported avoiding peanuts for prolonged periods of time between 72 and 144 months. Participants at 144 months in the peanut consumption group had levels of Ara h2-specific immunoglobulin E (a peanut allergen associated with anaphylaxis) of 0.03 ± 3.42 kU/l and levels of peanut-specific immunoglobulin G4 of 535.5 ± 4.98 µg/l, whereas participants in the peanut avoidance group had levels of Ara h2-specific immunoglobulin E of 0.06 ± 11.21 kU/l and levels of peanut-specific immunoglobulin G4 of 209.3 ± 3.84 µg/l. Adverse events were uncommon, and the majority were related to the food challenge. CONCLUSIONS: Peanut consumption, starting in infancy and continuing to age 5 years, provided lasting tolerance to peanut into adolescence irrespective of subsequent peanut consumption, demonstrating that long-term prevention and tolerance can be achieved in food allergy. (Funded by the National Institute of Allergy and Infectious Diseases and others; ITN070AD, ClinicalTrials.gov number, NCT03546413.).

Clinical outcomes of efficacy in food allergen immunotherapy trials.

PURPOSE OF REVIEW: With food allergy affecting millions of children worldwide, the consolidation of food allergen immunotherapy represents an encouraging therapeutic option, that might expand in the next few years to reach greater number of candidates. This review aims at providing a critical overview of the efficacy outcomes employed in food allergen immunotherapy trials (AIT). RECENT FINDINGS: Understanding efficacy endpoints rely on identifying what and how these are being measured. Desensitization, as the efficacy of the therapy to increase the patient's reactivity threshold to the food during therapy, and Sustained Unresponsiveness, withholding such efficacy even if the therapy is withdrawn, are nowadays considered the main parameters of efficacy evaluation. Quality of life is a promising variable to capture food AIT impact from the patient's perspective.There is a relevant degree of heterogeneity across studies in outcomes definitions and also in oral food challenges design, the tool that is more spread to assess results, hampering study comparison. SUMMARY: Interpreting the results of a clinical trial, and comparing data from different studies is an important task, both for the researcher and the clinician, that should be done after a careful analysis of the outcomes and the evaluation tools used.

The effect of maternal obesity and lipid profile on first-trimester serum progesterone levels.

BACKGROUND: Prepregnancy overweight increases the risk of adverse perinatal outcomes. Maternal lipid profile plays a key role in the production of pregnancy hormones. The influence that obesity has on the specific mechanisms that may be involved and the potential associations with abnormal conditions in pregnancy are still poorly understood. OBJECTIVE: This study aimed to evaluate the effect of maternal body mass index and lipid profile on first-trimester serum progesterone levels. STUDY DESIGN: This was a prospective cohort study including 734 pregnant people. First-trimester maternal serum progesterone, cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and triglycerides were measured between 9 and 11 weeks' gestation. Free ß-hCG, PAPP-A, age, body mass index, smoking status, gestational age at delivery, fetal sex, and birthweight were also recorded. Pregnant people were classified according to their body mass index into underweight (n=21), normal weight (n=395), overweight (n=221), obesity class I (n=64), and obesity class II/III (n=33) groups. RESULTS: Gestational age at sampling was 10.0 4±1.12 weeks. Serum progesterone levels decreased as maternal body mass index increased (35.84±12.00 ng/mL, 33.08±11.27 ng/mL, 28.04±8.91 ng/mL, 24.37±8.56 ng/mL, and 19.87±11.00 mL for underweight, normal weight, overweight, obesity class I, and obesity class II/III groups, respectively; P<.000001). There were statistically significant negative correlations between maternal progesterone and body mass index, triglycerides, and cholesterol/high-density lipoprotein cholesterol ratio, and positive correlations with gestational age at sampling, maternal age, cholesterol, high-density lipoprotein cholesterol, crown-rump length, free ß-hCG, and PAPP-A. Linear regression showed that the only independent predictor variables for progesterone levels were body mass index (P<.0001), PAPP-A (P<.0001), high-density lipoprotein cholesterol (P<.0001), and free ß-hCG (P<.0001) (R2=0.33; P<.0000001). CONCLUSION: First-trimester serum progesterone levels were lower in overweight pregnant people and markedly decreased in those with obesity, especially obesity class II/III. Maternal high-density lipoprotein cholesterol was independently related to progesterone levels as a protective factor. Benefits of progesterone supplementation in pregnant people with obesity need further evaluation.

The influence of maternal respiratory allergy on obstetrics and perinatal outcomes: A nested case-control study.

OBJECTIVE: To evaluate the influence of respiratory allergy on obstetrics and perinatal outcomes. METHODS: A nested case-control retrospective study on 41 035 pregnant women. Obstetrics and perinatal outcomes of women with or without respiratory allergy were compared. Rates of preterm delivery (<37 weeks of gestation), low birth weight (<2500 g), neonatal acidosis (pH < 7.20), low 5-min APGAR score (<7), cesarean section rate and indications, and perinatal morbidity and mortality were analyzed. Results are expressed as number and percentages. χ2 and Fisher exact tests were used for comparisons. Logistic regression was used. Statistical significance was set at 95% level (P < 0.05). RESULTS: A total of 724 (1.8%) patients had respiratory allergy, and their rates of preterm delivery and low birth weight were significantly higher than those of control women (both P < 0.001). Nevertheless, analyzing the causes, multiple gestation rate was significantly higher in this group, and adjusting by this, no statistical difference was found in any of the perinatal outcomes studied. In addition, in vitro fertilization and sterility were also significantly higher in the respiratory allergy group (both P < 0.001). CONCLUSION: Women with respiratory allergy are at higher risks of prematurity and low birth weight but these results are mediated by sterility, in vitro fertilization, and multiple gestation rate. Nonetheless, participation of inflammatory mechanisms should be further studied.

IgE-Mediated Shellfish Allergy in Children.

Shellfish, including various species of mollusks (e.g., mussels, clams, and oysters) and crustaceans (e.g., shrimp, prawn, lobster, and crab), have been a keystone of healthy dietary recommendations due to their valuable protein content. In parallel with their consumption, allergic reactions related to shellfish may be increasing. Adverse reactions to shellfish are classified into different groups: (1) Immunological reactions, including IgE and non-IgE allergic reactions; (2) non-immunological reactions, including toxic reactions and food intolerance. The IgE-mediated reactions occur within about two hours after ingestion of the shellfish and range from urticaria, angioedema, nausea, and vomiting to respiratory signs and symptoms such as bronchospasm, laryngeal oedema, and anaphylaxis. The most common allergenic proteins involved in IgE-mediated allergic reactions to shellfish include tropomyosin, arginine kinase, myosin light chain, sarcoplasmic calcium-binding protein, troponin c, and triosephosphate isomerase. Over the past decades, the knowledge gained on the identification of the molecular features of different shellfish allergens improved the diagnosis and the potential design of allergen immunotherapy for shellfish allergy. Unfortunately, immunotherapeutic studies and some diagnostic tools are still restricted in a research context and need to be validated before being implemented into clinical practice. However, they seem promising for improving management strategies for shellfish allergy. In this review, epidemiology, pathogenesis, clinical features, diagnosis, and management of shellfish allergies in children are presented. The cross-reactivity among different forms of shellfish and immunotherapeutic approaches, including unmodified allergens, hypoallergens, peptide-based, and DNA-based vaccines, are also addressed.