Application of PLGA-PEG-PLGA Nanoparticles to Percutaneous Immunotherapy for Food Allergy.

Compared with oral or injection administration, percutaneous immunotherapy presents a promising treatment modality for food allergies, providing low invasiveness and safety. This study investigated the efficacy of percutaneous immunotherapy using hen egg lysozyme (HEL)-loaded PLGA-PEG-PLGA nanoparticles (NPs), as an antigen model protein derived from egg white, compared with that of HEL-loaded chitosan hydroxypropyltrimonium chloride (CS)-modified PLGA NPs used in previous research. The intradermal retention of HEL in excised mouse skin was measured using Franz cells, which revealed a 2.1-fold higher retention with PLGA-PEG-PLGA NPs than that with CS-modified PLGA NPs. Observation of skin penetration pathways using fluorescein-4-isothiocyanate (FITC)-labeled HEL demonstrated successful delivery of HEL deep into the hair follicles with PLGA-PEG-PLGA NPs. These findings suggest that after NPs delivery into the skin, PEG prevents protein adhesion and NPs aggregation, facilitating stable delivery deep into the skin. Subsequently, in vivo percutaneous administration experiments in mice, with concurrent iontophoresis, demonstrated a significant increase in serum IgG1 antibody production with PLGA-PEG-PLGA NPs compared with that with CS-PLGA NPs after eight weeks of administration. Furthermore, serum IgE production in each NP administration group significantly decreased compared with that by subcutaneous administration of HEL solution. These results suggest that the combination of PLGA-PEG-PLGA NPs and iontophoresis is an effective percutaneous immunotherapy for food allergies.

'Omics-Based Digital Twins for Personalised Paediatric Healthcare.

Digital twins offer potential to enhance the precision and personalisation of healthcare delivery. As part of a collaborative project between La Trobe University and the Murdoch Children's Research Institute, Melbourne, Australia, multidimensional 'omics-based digital twins of children are being developed. The aim is to explore their application to a range of health contexts in children. A pilot project is commencing that focuses on food allergy diagnosed at one year of age.

Maternal High-Fat Diet Exacerbates Epicutaneous Sensitization and Oral Challenge-Induced Food Allergy to Ovalbumin in Offspring Mice.

Dietary factors have been associated with an increased prevalence of food allergy (FA). However, little is known about how an unhealthy diet in early life affects FA reactions in offspring. The objective of this study is to provide a scientific foundation for developing and promoting healthy dietary patterns in early life. In this study, we found that maternal high-fat diet (HFD) during pregnancy and lactation exacerbates FA (HFD-FA) in offspring mice, leading to increased serum levels of mast cell protease 1. First, we studied the systemic immunity of the HFD-FA mice and observed elevated levels of proinflammatory cytokines (IL-4, IL-6, and IL-1ß) and a reduced frequency of Treg cells in splenocytes. Additionally, the HFD-FA mice showed increased gut permeability, accumulation of intestinal mast cells, and a decrease in the Treg cell frequency in the mesenteric lymph nodes. Furthermore, our findings also indicated a reduction in gut microbial diversity and abundance in HFD-FA mice. Importantly, lipid metabolism profiling revealed unique lipid profiles in the HFD-FA mice, with significant upregulation of triglycerides and downregulation of sphingolipids. Taken together, our results suggest that maternal HFD alters intestinal homeostasis and increases FA susceptibility in offspring mice.

[TWO CASES OF α-GAL SYNDROME CAUSED BY INGESTION OF WILD BOAR MEAT].

α-Gal syndrome (AGS) is an allergic reaction to galactose-α-1,3-galactose (α-gal) found in the salivary glands of ticks, mammalian meat excluding primates, and some antibody preparations, such as cetuximab. We report two cases of AGS diagnosed after ingestion of wild boar meat. Patient 1, a male in his 70s, developed anaphylactic shock about 3 h after eating wild boar meat. He was transported to our acute and critical care center in Nagasaki University Hospital because he had difficulty in moving. Patient 2, a female in her 60s, developed a skin rash about 2.5 h after ingesting wild boar meat. After visiting our department to investigate the cause of the disease, the sera of both patients were found to be positive for α-gal specific IgE antibody and were diagnosed with AGS caused by ingestion of wild boar meat. Reports of AGS diagnosed after ingestion of wild boar meat are rare in Japan. Compared with other prefectures, the consumption of wild boar meat in Nagasaki is relatively high in Japan. In the past 10 years, four cases of AGS were diagnosed at our department, half of which were caused by the ingestion of wild boar meat, the ratio is possibly higher than that in other prefectures in Japan.

Ultra-processed foods, allergy outcomes and underlying mechanisms in children: An EAACI task force report.

BACKGROUND: Consumption of ultra-processed foods [UPFs] may be associated with negative health outcomes. Limited data exist regarding the potential role of UPFs in the occurrence of allergic diseases. The underlying mechanisms underpinning any such associations are also poorly elucidated. METHODS: We performed a systematic review and narrative evidence synthesis of the available literature to assess associations between UPF consumption and pediatric allergy outcomes (n = 26 papers), including data on the association seen with the gut microbiome (n = 16 papers) or immune system (n = 3 papers) structure and function following PRISMA guidelines. RESULTS: Dietary exposure to fructose, carbonated soft drinks, and sugar intake was associated with an increased risk of asthma, allergic rhinitis, and food allergies in children. Commercial baby food intake was associated with childhood food allergy. Childhood intake of fructose, fruit juices, sugar-sweetened beverages, high carbohydrate UPFs, monosodium glutamate, UPFs, and advanced glycated end-products (AGEs) was associated with the occurrence of allergic diseases. Exposure to UPFs and common ingredients in UPFs seem to be associated with increased occurrence of allergic diseases such as asthma, wheezing, food allergies, atopic dermatitis, and allergic rhinitis, in many, but not all studies. CONCLUSION: More preclinical and clinical studies are required to better define the link between UPF consumption and the risk of allergies and asthma. These observational studies ideally require supporting data with clearly defined UPF consumption, validated dietary measures, and mechanistic assessments to definitively link UPFs with the risk of allergies and asthma.

Higher maternal bread and thiamine intakes are associated with increased infant allergic disease.

BACKGROUND: A mother's diet during pregnancy may influence her infant's immune development. However, as potential interactions between components of our dietary intakes can make any nutritional analysis complex, here we took a multi-component dietary analysis approach. METHODS: Nutritional intake data was collected from 639 pregnant women using a validated semi-quantitative food frequency questionnaire to reflect their dietary intakes during 32-36 weeks of gestation. To investigate their dietary intake pattern, we calculated Dietary Inflammatory Index scores. Maternal consumption of 12 food groups, 20 individual whole foods, and 18 specific nutrient intakes, along with any vitamin and mineral supplementation, were determined. Infant outcomes included eczema, allergen sensitization, and IgE-mediated food allergy. Regression-based analyses with covariates adjustment were applied. RESULTS: Women with higher white bread consumption were more likely to have an infant with doctor-diagnosed eczema (adjusted relative risk [aRR] 1.16; 95% CI 1.08, 1.24; p < .001) and IgE-mediated food allergy (aRR 1.14; 95% CI 1.02, 1.28; p = .02). Higher maternal intakes of fiber-rich bread (aRR 1.14; 95% CI 1.04, 1.25; p = .01) and legumes (aRR 1.11; 95% CI 1.02, 1.21; p = .02) were also associated with infant doctor-diagnosed eczema. Higher maternal thiamine intakes were associated with increased parent-reported infant eczema (aRR 1.08; 95% CI 1.03, 1.12; p < .001). CONCLUSION: In Australia, where bread flour is fortified with thiamine, we identified consistent links between higher maternal thiamine-rich diets and increased risk of infant eczema and food allergy. Our results highlight a need for further investigation of potential effects of high thiamine exposures on immune development, especially in-utero.

A case report of diet elimination guided by food specific IgG4 achieved clinical cure for eczematous external otitis with finger paronychia.

RATIONALE: Eczematous external otitis (EEO) is the most difficult-to-treat otitis externa, and characterized by the symptoms of inflammation with hypersensitivity of the external ear canal skin. It is acknowledged as a chronic skin inflammation primarily caused by dermatological and allergic reactions. Food allergens are also considered a cause to induce the inflammation. However, the role of food specific IgG4 in this disease is unclear yet. PATIENT CONCERNS: A 54-year-old woman complained of recurrent itching of the external auditory meatus for 3 years and nails chapping of hands for 2 years. DIAGNOSES AND INTERVENTIONS: She was diagnosed with EEO and underwent the therapeutic strategy as food elimination of egg, milk and wheat, guided by the result of food specific IgG4 together with probiotics on the basis of previous symptom controlling therapy. OUTCOMES: After 17 months' treatment, she was finally free of all the symptoms and the serum IgG4 specific to all foods are under normal limit. LESSONS: To the best of our knowledge, it is the first report revealing the clinical significance of food specific IgG4 in EEO, and the successful treatment with diet elimination guided by food specific IgG4 threw a new light on the clinical management of refractory EEO.

Racial and Ethnic Representation in Food Allergen Immunotherapy Trial Participants: A Systematic Review.

Importance: The lack of inclusion of diverse population samples in food allergy immunotherapy clinical trials not only leads to decreased applicability to the general population in terms of results and treatments but can also be seen as a broader social injustice contributing to inequity within the health care system. Objectives: To investigate the racial and ethnic distribution of participants included in food allergy immunotherapy clinical trials, and determine whether the racial and ethnic representation in trials accurately reflects the patients who experience food allergy. Evidence Review: Data were collected from articles found on PubMed and ClinicalTrials.gov using key terms of food hypersensitivity, food allergy, and immunotherapy, while also incorporating specific criteria such as clinical trials conducted within the last 5 years with children aged from birth to 18 years old. Articles were selected based on their relevance to the research question. Main outcomes were totals and percentages of trial participants by race and ethnicity, stratified by pediatric trials, site of study, and National Institutes of Health funding. Findings: Thirty-five articles were initially identified, of which 34 were classified as human clinical trials. Of these trials, 26 met criteria of an original randomized clinical trial and included racial and ethnic demographics for analysis in the study. Among trials included, the majority of the 3689 participants identified as White (2640 participants [72.0%]), followed by Black or African American (293 participants [8.0%]), Asian (239 participants [6.0%]), multiple races or other (210 participants [6.0%]), Hispanic or Latino (96 participants [3.0%]), American Indian (3 participants [<1.0%]), and Native American or Pacific Islander (3 participants [<1.0%]). We observed differences in racial and ethnic inclusion by study site (US vs external to US) and funding support (National Institutes of Health vs industry or other non-National Institutes of Health sources). Conclusions and Relevance: In this systematic review of racial and ethnic diversity in food allergy immunotherapy trials, there was a lack of diversity relative to the overall food allergy burden among Black and Hispanic patients, indicating important gaps in the conduct of pediatric clinical trials, especially for treatments that are meant for use in broad populations where significant race- and ethnicity-related disparities exist. Working to correct this disparity will not only increase the usefulness of future clinical trial data but can further assist in alleviating public health inequities.

Pollen-Food Allergy Syndrome: From Food Avoidance to Deciphering the Potential Cross-Reactivity between Pru p 3 and Ole e 7.

BACKGROUND: Cross-reactivity between nonspecific lipid transfer proteins could cause anaphylaxis, further influencing food avoidance and nutrient deficiencies. The one affecting olive pollen (Ole e 7) and peach (Pru p 3) may underlie a variety of pollen-food syndromes, though a deep molecular analysis is necessary. METHODS: Three Ole e 7-monosensitised patients (MON_OLE), three Pru p 3-monosensitised patients (MON_PRU) and three bisensitised patients (BI) were selected. For epitope mapping, both digested proteins were incubated with patient sera, and the captured IgE-bound peptides were characterised by LC-MS. RESULTS: The analysis revealed two Ole e 7 epitopes and the three Pru p 3 epitopes previously described. Interestingly, the "KSALALVGNKV" Ole e 7 peptide was recognised by MON_OLE, BI and MON_PRU patients. Conversely, all patients recognised the "ISASTNCATVK" Pru p 3 peptide. Although complete sequence alignment between both proteins revealed 32.6% identity, local alignment considering seven residue fragments showed 50 and 57% identity when comparing "ISASTNCATVK" with Ole e 7 and "KSALALVGNKV" with Pru p 3. CONCLUSIONS: This study mapped sIgE-Ole e 7-binding epitopes, paving the way for more precise diagnostic tools. Assuming non-significant sequence similarity, structural homology and shared key residues may underlie the potential cross-reactivity between Ole e 7 and Pru p 3 nsLTPs.

Food-Protein-Induced Proctocolitis in Pre-Term Newborns with Bloody Stools in a Neonatal Intensive Care Unit.

The bloody stools of newborns may be a clue for several clinical entities of varying severity, ranging from idiopathic neonatal transient colitis to food-protein-induced allergic proctocolitis (FPIAP) or necrotizing enterocolitis (NEC). Distinguishing among them at an early stage is challenging but crucial, as the treatments and prognoses are different. We conducted a monocentric retrospective study including all pre-term infants with bloody stools admitted to the Neonatal Intensive Care Unit (NICU) of the Vittore Buzzi Children's Hospital (Milan) from December 2022 to May 2024. Patients diagnosed with NEC exhibited significantly lower eosinophil counts and higher procalcitonin levels than both patients with FPIAP and patients with idiopathic neonatal transient colitis, as well as a statistically significant increase in pathological features from abdomen ultrasounds and abdominal X-rays. In contrast, no lab markers or imaging techniques have been demonstrated to be useful in distinguishing between idiopathic neonatal transient colitis and FPIAP. Thus, after excluding a diagnosis of NEC, the only way to confirm FPIAP is through the oral food challenge, which can be performed in premature newborns presenting with bloody stools who are otherwise healthy and under medical supervision, in order to identify infants who may benefit from a cow's-milk-free diet.

Development and Management of Avoidant/Restrictive Food Intake Disorder and Food Neophobia in Pediatric Patients with Food Allergy: A Comprehensive Review.

Avoidant/Restrictive Food Intake Disorder (ARFID) and food neophobia present significant challenges in pediatric healthcare, particularly among children with food allergies (FAs). These eating disorders, characterized by the persistent avoidance or restriction of food, can lead to severe nutritional deficiencies and psychosocial impairments. The presence of FAs further complicates these eating behaviors, as the fear of allergic reactions exacerbates avoidance and restrictive patterns. This comprehensive review synthesizes current knowledge on ARFID and food neophobia, focusing on their definitions, characteristics, and the unique challenges they present in the context of FAs. The review explores the critical role of healthcare professionals, especially nurses, in integrating psychological and clinical care to improve outcomes for affected children. A multidisciplinary approach, including Cognitive Behavioral Therapy (CBT) and Family-Based Therapy (FBT), is emphasized as essential in addressing the complex needs of these patients. The review also highlights the need for standardized treatment protocols and further research on the long-term outcomes of these disorders, aiming to enhance therapeutic strategies and family support systems. Effective management of ARFID and food neophobia in the context of FAs requires a holistic and integrated approach to mitigate the profound impacts on a child's growth, development, and overall well-being.

The Role of Food Allergy in Atopic Dermatitis.

Atopic dermatitis (AD) and food allergies are 2 atopic conditions that tend to develop early in life. Their interrelationship has been a topic of controversy and many studies. The presence of atopic dermatitis in infancy and early childhood, particularly if severe, is a risk factor for the development of immunoglobulin E (IgE) -mediated food allergies. While it is common for children with AD to demonstrate extensive sensitization to foods, serum IgE testing is not always indicative of clinical allergy.

Timing of Food Introduction and Allergy Prevention: An Update.

Recommendations about allergy prevention through diet are rapidly changing. In just the past several years, multiple organizations have provided updated guidance and recommendations about infant feeding based on recent studies and meta-analyses. In addition to the increased number of studies supporting the benefit of early introduction of allergenic foods, in particular peanut and egg, recent studies demonstrate that infant and maternal diet diversity may also reduce risk of food allergy and atopy. Skin emollients have not been found to be helpful in prevention of food allergy, and more evidence is needed to determine if emollients play a role in prevention of atopic dermatitis.

Characteristics of childhood anaphylaxis in different age groups.

BACKGROUND: Anaphylaxis is a severe systemic hypersensitivity reaction that usually has a rapid onset and can be fatal. Presentations of childhood anaphylaxis vary widely in accordance with the triggers and the patient's age, geographical region and dietary and lifestyle habits. METHODS: The medical records of 177 paediatric patients diagnosed with anaphylaxis between January 2021 and January 2024, whose disease progression was monitored at a single tertiary care centre, were reviewed retrospectively. RESULTS: The study included 177 patients diagnosed with anaphylaxis (107 males and 70 females with a median age of 48 months). The most common allergen responsible was food (53.7%). Egg allergy was the most common source of anaphylaxis, afflicting 35 patients (19.3%), while beta-lactam provoked the most common drug allergy, affecting 24 patients (13.6%). The most common organ involved was the skin (92.7%). When the patients were analysed by age group, there were more males in the infancy, preschool and school age groups, while there were more females in the adolescent group (p = 0.44). Food-induced anaphylaxis became less common with increasing age, whereas the rate of drug-induced anaphylaxis increased (p = 0.01 and p = 0.01, respectively). Cardiovascular system findings were observed more frequently in adolescents compared to other age groups (p = 0.003). Most cases stemming from a food allergy were mild, whereas most drug-induced cases were moderate or severe (p < 0.05). When severity was analysed by age group, mild cases in infants were more common than moderate to severe cases. CONCLUSION: The aetiological and clinical manifestations of childhood anaphylaxis vary among different age groups.

From triggers to treatment: An epidemiological exploration of anaphylaxis in a lower middle-income area in Colombia.

In this cross-sectional, descriptive, and observational study conducted at Fundación Valle del Lili in Colombia, the clinical and sociodemographic characteristics of anaphylaxis were investigated in a cohort of 80 patients who sought medical care between January 2021 and December 2022. With a median age of 16 years and a notable prevalence among individuals aged below 18 years, the study revealed that 63.8% of patients had concomitant allergic diseases. Medications emerged as the primary triggers for anaphylaxis, followed by food. The mucocutaneous system was predominantly affected in 55% of cases, with respiratory involvement observed in 37.5%. Alarmingly, anaphylactic shock occurred in 17.5%, and 7.5% experienced biphasic anaphylaxis. Intramuscular adrenaline was administered in 88.8% of cases, with 75% of patients not receiving an allergy consultation upon discharge, and 52.5% lacking follow-up for allergy care. Considering that in Colombia epidemiological data on the clinical and sociodemographic aspects of anaphylaxis remain largely unknown, this study documents the features of anaphylaxis in both adult and pediatric populations and highlights the urgent need for improved awareness, timely evaluation by allergists, and comprehensive follow-up care for individuals experiencing anaphylaxis.

Formononetin inhibits IgE by huPlasma/PBMCs and mast cells/basophil activation via JAK/STAT/PI3-Akt pathways.

Rationale: Food allergy is a prevalent disease in the U.S., affecting nearly 30 million people. The primary management strategy for this condition is food avoidance, as limited treatment options are available. The elevation of pathologic IgE and over-reactive mast cells/basophils is a central factor in food allergy anaphylaxis. This study aims to comprehensively evaluate the potential therapeutic mechanisms of a small molecule compound called formononetin in regulating IgE and mast cell activation. Methods: In this study, we determined the inhibitory effect of formononetin on the production of human IgE from peripheral blood mononuclear cells of food-allergic patients using ELISA. We also measured formononetin's effect on preventing mast cell degranulation in RBL-2H3 and KU812 cells using beta-hexosaminidase assay. To identify potential targets of formononetin in IgE-mediated diseases, mast cell disorders, and food allergies, we utilized computational modeling to analyze mechanistic targets of formononetin from various databases, including SEA, Swiss Target Prediction, PubChem, Gene Cards, and Mala Cards. We generated a KEGG pathway, Gene Ontology, and Compound Target Pathway Disease Network using these targets. Finally, we used qRT-PCR to measure the gene expression of selected targets in KU812 and U266 cell lines. Results: Formononetin significantly decreased IgE production in IgE-producing human myeloma cells and PBMCs from food-allergic patients in a dose-dependent manner without cytotoxicity. Formononetin decreased beta-hexosaminidase release in RBL-2H3 cells and KU812 cells. Formononetin regulates 25 targets in food allergy, 51 in IgE diseases, and 19 in mast cell diseases. KEGG pathway and gene ontology analysis of targets showed that formononetin regulated disease pathways, primary immunodeficiency, Epstein-Barr Virus, and pathways in cancer. The biological processes regulated by formononetin include B cell proliferation, differentiation, immune response, and activation processes. Compound target pathway disease network identified NFKB1, NFKBIA, STAT1, STAT3, CCND1, TP53, TYK2, and CASP8 as the top targets regulated at a high degree by formononetin. TP53, STAT3, PTPRC, IL2, and CD19 were identified as the proteins mostly targeted by formononetin. qPCR validated genes of Formononetin molecular targets of IgE regulation in U266 cells and KU812 cells. In U266 cells, formononetin was found to significantly increase the gene expression of NFKBIA, TP53, and BCL-2 while decreasing the gene expression of BTK TYK, CASP8, STAT3, CCND1, STAT1, NFKB1, IL7R. In basophils KU812 cells, formononetin significantly increased the gene expression of NFKBIA, TP53, and BCL-2 while decreasing the gene expression of BTK, TYK, CASP8, STAT3, CCND1, STAT1, NFKB1, IL7R. Conclusion: These findings comprehensively present formononetin's mechanisms in regulating IgE production in plasma cells and degranulation in mast cells.