Background: This study aims to investigate whether immune dysregulation and gut microbiome alteration are exacerbated in atopic dermatitis (AD) with food allergy (ADFA) and potential treatment strategies. Methods: Total 159 children with AD (tAD) were divided into two groups: AD without-food allergy (ADNFA) and with food allergy (ADFA); 100 children without AD were included as control. Eosinophil counts and total serum IgE levels were measured by routine methods, serum food-specific IgE levels by quantitative fluorescence immunoassay, and serum cytokine levels by multi-microsphere flow immunofluorescence. The intestinal microbiota was evaluated in fecal specimens using metagenomic sequencing. A novel ADFA mouse model was generated to evaluate whether probiotic candidates identified from human fecal samples contributed to the improvement in ADFA pathology. Results: The levels of eosinophils, IgE, IL-2, TNF-α, IL-4, IL-5, IL-6, IL-10, IL-17, IL-12P70 and IFN-α were elevated in tAD compared to normal controls. Compared with ADNFA, the levels of eosinophils, IgE and IL-5 were persistently increased, while IFN-γ was decreased, the species of Lactococcus lactis (L. lactis) was reduced in ADFA. Compared with AD, the ADFA model had more severe skin lesions on the back and significantly higher serum OVA-specific IgE, IL-4 and IL-5. Following oral administration of L. lactis ( L. lactis 1.1936+1.3992), skin lesions in ADFA mice was significantly improved. The levels of OVA-specific IgE, IL-4 and IL-5 decreased in a dose-dependent manner. Conclusions: Food allergy aggravates immune dysregulation and gut microbiome dysbiosis in children with AD. L. lactis could be a candidate probiotic for the treatment of ADFA.

A rare case of wheat-dependentexercise-induced anaphylaxis induced by exercise 5 hours after wheat ingestion.Tomoki Yaguchi1, Katsutoshi Nakano1, Tadayuki Kumagai1Department of Pediatrics, Yaizu City Hospital, Shizuoka, JapanCorresponding authorTomoki Yaguchi, 1000, Dobara, Yaizu-shi, Shizuoka 425-0055, Japan. Phone: +81-54-623-3111, Fax: +81-54-624-9103, E-mail: [email protected] Count for Main Text; 916The number of Table; 1, Figure; 0Keywords：wheat-dependent exercise-induced anaphylaxis, food allergy, aspirin, sensitization, anaphylaxis

Monitoring is a major component of asthma management in children. Regular monitoring allows for diagnosis confirmation, treatment optimization and natural history review. Numerous factors that may affect disease activity and patient wellbeing need to be monitored: response and adherence to treatment, disease control, disease progression, comorbidities, quality of life, medication side-effects, allergen and irritant exposures, diet and more. However, the prioritization of such factors and the selection of relevant assessment tools is an unmet need. Furthermore, rapidly developing technologies promise new opportunities for closer, or even ‘real-time’, monitoring between visits. Following an approach that included needs assessment, evidence appraisal and Delphi consensus, the PeARL Think Tank, in collaboration with major international professional and patient organizations, has developed a set of 24 recommendations on pediatric asthma monitoring, to support healthcare professionals in decision-making and care pathway design.

Background Due to changes in dietary habits tree nuts (TN) are consumed in many households and TN allergy appears to be increasing. One risk factor seems to be allergies to other food such as peanuts. The aim of our study was to investigate, how often peanut-sensitized infants and toddlers are co-sensitized to cashew, hazelnut and walnut and to determine the likelihood of its clinical relevance by their 2S albumin-specific (s)IgE. Methods Sera of 101 peanut-sensitized children, 5 to 24 months of age (median 16 months) were analyzed regarding sIgE to hazelnut, walnut and cashew and to their 2S-albumins Cor a 14, Jug r 1 and Ana o 3 as well as to Ara h 1 and 2, by using the NOVEOS TM immunoanalyzer system. Results 96% of the peanut-sensitized children were co-sensitized to at least one TN with 94.1% to hazelnut, 87.1% to walnut and 84.2% to cashew. More than half (58.4%) of the children were sensitized to at least one 2S albumin with similar rates for infants and toddlers, 26.7% to all three. Moreover, sensitization rates were similar in peanut allergic and tolerant children. Estimating the likelihood of clinical relevance, 15.8% of all peanut-sensitized children had an at least 90% probability to be hazelnut and/or cashew allergic. Conclusion TN sensitization seems to be common among peanut-sensitized infants and toddlers. Many had a high likelihood to be TN allergic. Therefore, it should be considered to determine TN-sIgE in peanut-sensitized children if TN are not consumed so far.

This review summarises recent advances in characterising the transcriptional pathways associated with outcomes following Oral Immunotherapy. Recent technological advances including single-cell sequencing are transforming the ways in which the transcriptional landscape is understood. The application of these technologies is still in its infancy in food allergy but here we summarise current understanding of gene expression changes following oral immunotherapy for food allergy and specific signatures underpinning the different clinical outcomes of desensitisation and remission (sustained unresponsiveness). T helper 2A cells have been identified as a cell type which correlates with disease activity and is modified by treatment. Molecular features at study entry may differentiate individuals who achieve more positive outcomes during OIT. Recent findings point to T cell anergy and Type 1 interferon pathways as potential mechanisms supporting redirection of the allergen-specific immune response away from allergy towards remission. Despite these developments in our understanding of immune mechanisms following OIT, there are still significant gaps. Additional studies examining immune signatures associated with long term and well-defined clinical outcomes are required to gain a more complete understanding of the pathways leading to remission of allergy, in order to optimise treatments and gain improved outcomes for patients.

Background Oral immunotherapy (OIT) is increasingly used for the treatment of childhood food allergies, with limited data available on cashew nut allergy OIT. This study investigated the safety and feasibility of cashew nut OIT, comparing it with peanut OIT. Methods We retrospectively analyzed cashew nut (n=24) and peanut (n=38) OIT cases initiated between 2018 and 2022. Two different starting protocols were used, and nut intake was then incrementally increased by 20-30% every two weeks to reach a maintenance dose of 1 g of nut protein. After consuming the maintenance dose regularly for 18-24 months, a second oral food challenge was performed. Patients who passed this challenge were considered desensitized. The safety of the therapy was evaluated based on the frequency and severity of adverse reactions during the up-dosing phase. Results Over the study period, 33% of cashew nut-allergic and 63% of peanut-allergic patients experienced mild to moderate side effects. Severe reactions occurred in five peanut-allergic children with high initial IgE levels. Six patients with peanut and none with cashew nut OIT, were discontinued due to side effects. The mean duration to reach the maintenance phase was longer for children with asthma or another food allergy. Among children undergoing the second challenge, desensitization was achieved in 88% of cashew nut and 69% of peanut-allergic patients. Conclusion Cashew nut OIT had a low frequency of adverse effects and was generally well tolerated. However, patient characteristics influenced side effect risk and treatment duration, emphasizing the need for individualized OIT plans.

Background Asthma during pregnancy is associated with a range of adverse perinatal outcomes. It is also linked to increased rates of neurodevelopmental conditions the offspring. We aimed to assess whether fractional exhaled nitric oxide (F ENO)-based asthma management during pregnancy improves child developmental and behavioural outcomes compared to usual care. Methods The Breathing for Life Trial was a randomised controlled trial that compared F ENO-based asthma management during pregnancy to usual care. Participants were invited to the developmental follow-up, the Breathing for Life Trial – Infant Development study, which followed up infants at 6 weeks, 6 months, and 12 months. The primary outcomes were measured in infants at 12-months using the Bayley-III: Cognitive, Language, and Motor composite scores. Secondary outcomes included Bayley-III social-emotional and adaptive behaviour scores, autism likelihood, and sensory and temperament outcomes. The exposure of interest was the randomised intervention group. Results 220 infants and their 217 participating mothers were recruited to the follow-up; 107 mothers were in the intervention group and 113 were in the control group. There was no evidence of an intervention effect for the primary outcomes: Bayley-III cognitive (Mean=108.9 control, 108.5 intervention, p=0.93), language (Mean=95.9 control, 95.6 intervention, p=0.87) and motor composite scores (Mean=97.2 control, 97.9 intervention, p=0.25). Mean scores for secondary outcomes were also similar among infants born to control and F ENO group mothers, with few results reaching p<0.05. Conclusion In this sample, F ENO-guided asthma treatment during pregnancy did not improve infant developmental outcomes in the first year of life.

Background: Accidental allergic reactions (AAR) in children are under-studied, especially with precise pediatrician-based exact diagnoses and follow-ups. This study aimed to assess the prevalence and risk factors for AAR in Japanese children with immediate-type food allergies. Methods: This single-center study included children with immediate-type hen’s egg (HE), cow’s milk (CM), wheat, or peanut allergy who had been followed-up regularly at a national center specialized for allergy in Japan. Low-dose reactivity was defined as allergic reactions to a low dose of ≤250, ≤102, ≤53, or ≤133 mg HE, CM, wheat, or peanut protein, respectively. From January to December 2020, pediatricians followed the AAR experience every 2–4 months. Risk factors for AAR were analyzed using multiple logistic regression. Results: Of the 1096 participants, 609, 457, 138, and 90 had HE, CM, wheat, and peanut allergies, respectively. In this cohort, the median age was 5.0 years, 39% had completely eliminated allergenic food, and 24% had low-dose reactivity. The annual AAR rate was 0.130 in all sub-cohorts. Moderate and severe symptoms occurred in 50% and 0.7%, respectively, of children who experienced AAR. Multiple logistic regression revealed that low-dose reactivity was a significant risk factor for AAR in the overall, HE, and CM cohorts, respectively ( p <0.001, p = 0.029 and 0.036). Conclusion: In Japanese children with immediate-type food allergies, the annualized rate of AAR was relatively low; however, half of the participants with AAR had moderate to severe symptoms. Children, especially those with low-dose reactivity, would require careful risk management of AAR.

Background: There has been increasing interest in elucidating the relationship between adenoid hypertrophy (AH) and allergic rhinitis (AR). However, the impact of aeroallergen sensitization patterns on children concurrently experiencing AH and AR remains unclear. Methods: Patients aged 2-8 years (January 2019 to December 2022) with nasal symptoms were assessed for allergies, adenoid size and respiratory viral infection history. The levels of serum total immunoglobulin E (IgE) and specific IgE and flexible nasal endoscopy were performed. We analyzed the relationship between AH and sensitization patterns and lymphocyte subpopulations in adenoid samples using flow cytometry. Results: 5281 children were enrolled in our cohort. 56.5% of children was diagnosed with AR and 48.6% with AH. AR was more prevalent in AH children compared to nAR. Compared to non-sensitized, those with AR polysensitized to molds had a higher prevalence of AH (adjusted OR 1.61, 95%CI 1.32-1.96) and a greater occurrence of two or more respiratory viral infections, particularly in cases with adenoidectomy. In AH-AR children, adenoid tissues showed reduced frequencies and corrected absolute counts of regulatory T cells (Tregs), activated Tregs, class-switched memory B cells (CSMB), natural killer (NK) T cells and NK subpopulations compared to AH-nAR children. Polysensitization in AH-AR children correlated with lower CSMB frequencies. Conclusion: Polysensitivity to molds significantly increased the risk of AH in children with AR. Adenoids of AR children demonstrated less number of B cells, NK cells and Treg cells with an effector/memory phenotype, which was closely linked to sensitization models and respiratory viral infection, particularly concerning CSMB.

Background: Food allergies, particularly their severe and persistent forms, have a significant impact on children’s quality of life (QoL). Understanding and enhancing QoL is a crucial component of food allergy management. This study aimed to evaluate the QoL of Turkish children aged 0-12 years with IgE-mediated tree nut allergies (TNA) and explore influential factors, including parental anxiety. Methods: Primary caregiver-parents of children diagnosed with TNA completed the valid and reliable Food Allergy Quality of Life Questionnaire-Parent Form (FAQLQ-PF) and State-Trait Anxiety Inventory (STAI) to assess QoL and parental anxiety, respectively. Results: The study included 88 parents, predominantly mothers (83%). The children had a median age of 12 months (IQR 7.25-19.5). The mean FAQLQ-PF score was 3.55±1.34 without a statistical significance between age groups (0-3 years 3.15±1.28; 4-6 years 3.76±1.42; 7-12 years 3.73±1.19). Parents reported significantly worse FAQLQ-PF scores for children with hazelnut allergy, with a history of anaphylaxis, and who had to use an adrenaline autoinjector. State and trait anxiety scores were strongly correlated (r=0.584, p<0.001). There was significant but weak correlations between FAQLQ-PF and STAI domains. The multivariate linear regression analysis revealed that having a hazelnut allergy, a history of anaphylaxis, and higher parental state anxiety were all associated with poorer FAQLQ-PF scores, but, fathers tended to report better level of QoL. Conclusions: The QoL of Turkish children with TNA, as reported by parents, is influenced by various factors. Understanding and addressing these factors are crucial for a deeper understanding of how to enhance the accuracy of QoL assessment.

Background: Tree nut allergy is usually life-long and potentially life-threatening. Standard of care consists of strict avoidance of the culprit nut and symptomatic treatment of accidental reactions. Objective: To evaluate the potential therapeutic options for desensitization of patients with IgE-mediated tree nut allergy, focusing on, but not limited to, immunotherapy. Methods: We systematically searched three bibliographic databases for studies published until July 2022 for active treatments of IgE-mediated allergy to tree nuts (walnut, hazelnut, pistachio, cashew, and almond) with allergen-specific immunotherapy (AIT) using oral (OIT), sublingual (SLIT), epicutaneous (EPIT) or subcutaneous (SCIT) delivery, or with other disease-modifying treatments. Results: We included 17 studies (three randomized, double-blinded, placebo-controlled, five quasi-experimental prospective cohorts, five prospective cohorts, two retrospective cohorts, and two case reports. Three studies investigated sublingual immunotherapy, five investigated oral immunotherapy to a single tree nut, and six used multi-food oral immunotherapy with (four) or without (two) omalizumab. The remaining studies investigated the effectiveness of monoclonal antibodies in multi-food allergic patients, including patients with a tree nut allergy. The heterogeneity of the studies prevented pooling and meta-analysis. Conclusion: Even though strict avoidance remains the standard of care for patients with tree nut allergy, alternative approaches have been tested in clinical trials and real-life studies. These new concepts require further investigation with more well-designed studies including well-characterized nut allergic patients before implementing them in daily clinical practice.

Background: The role of Component Resolved Diagnostics (CRD) in the diagnosis of cow’s milk allergy (CMA) remains highly controversial. In this systematic review, we aimed to evaluate the accuracy of CRD in diagnosing CMA in children. Methods: We searched four electronic databases (EMBASE, PubMed, the Cochrane Library, and Web of Science) from January 1, 2000, to March 27, 2023, for studies that utilized milk composition and oral food challenges (OFC) as a reference standard in patients with suspected milk allergy. The quality of the included studies was assessed using QUADAS-2. Due to the heterogeneity of the studies, a meta-analysis could not be performed, and a narrative synthesis of the findings was conducted. Results: Our analysis included 5 prospective studies, 2 retrospective studies, and 2 case-control studies, with a total of 958 children. The sensitivity of Bos d 4 ranged from 0.50 to 0.82, and specificity from 0.78 to 0.98. Bos d 5 sensitivity 0.24-1.0, and specificity 0.58-0.98. Bos d 6 sensitivity 0.09, and specificity 0.94. Bos d 8 sensitivity 0.34-0.90, specificity 0.79-0.98. CONCLUSION: The specific IgE (sIgE) of the Bos d 4, Bos d 6, and Bos d 8 components of milk is highly specific but not sensitive in diagnosing cow’s milk allergy in children. The use of CRD for the diagnosis of CMA in children may reduce the need for OFC.

Prolonged drug provocation with an initial full therapeutic dose to diagnose serum sickness-like reactions (SSLR) to β-lactams in childrenMarcel M Bergmanna,b,c, Eva Gomesd, Natalia Blanca-Lópeze, Jean-Christoph Caubeta, Philippe A Eigenmanna , Giulia Liccioli f, Francesca Morif, Marina Atanaskovic Markovicga Pediatric allergy unit, Department of women, children and adolescents, University Hospitals of Geneva, Geneva, Switzerlandb Centro Pediatrico del Mendrisiotto, Mendrisio, Switzerlandc Faculty of Biomedical Science, Università della Svizzera Italiana (USI), Lugano, Switzerlandd Serviço de Imunoalergologia, Centro Hospitalar Universitário do Porto, Porto, Portugale Servicio de Alergia, Laboratorio de Investigación, Hospital Universitario Infanta Leonor, Madrid, Spainf Allergy Unit, Meyer Children’s University Hospital, IRCCS, Florence, Italyg University of Belgrade Faculty of Medicine, University Children’s Hospital, Belgrade, Serbia

Background: Approximately 50–90% of children with immediate-type cow’s milk allergy (CMA) acquire tolerance by pre-school age. We aimed to investigate the tolerance acquisition rate of CMA in children aged 6–12 years. Methods: Children with CMA that persisted until 6 years of age were included. Tolerance acquisition was defined as either passing an oral food challenge with 200 mL of unheated cow’s milk (CM) or consuming CM of any quantity without symptoms. Persistent CMA was defined as fulfilling neither of these criteria by 12 years of age. Children undergoing oral immunotherapy were defined as having persistent CMA. Risk factors associated with persistent CMA were assessed using Cox regression analysis. Results: Of the 123 children analyzed, 60 (49%) had previous CM anaphylaxis, 82 (67%) eliminated CM from their diet, and the median CM-specific immunoglobulin E (sIgE) level was 23.3 kU A/L at 6 years of age. Twenty-five children (20%) acquired tolerance by 9 years of age, and 46 (37%) by age 12. At baseline, higher CM-sIgE levels (hazard ratio: 2.58 [95% confidence interval: 1.62–4.12], optimal cutoff level: 34.4 kU A/L), previous CM anaphylaxis (2.42 [1.24–4.69]), and complete CM elimination (5.18 [2.45–10.99]) were associated with persistent CMA. None of the children with CMA who had all three risk factors (n = 26) acquired tolerance. Conclusion: At least one-third of the children with CMA at 6 years of age acquired tolerance by 12 years of age. Children with CMA who have the risk factors are less likely to acquire tolerance.

Background: A proportion of the convalescent SARS-CoV-2 pediatric population presents nonspecific symptoms, mental health problems and a reduction in quality of life similar to myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and long COVID-19 symptomatic. However, data regarding its clinical manifestation and immune mechanisms are currently scarce. Methods: In this study, we perform a comprehensive clinical and immunological profiling of 17 convalescent COVID-19 children with post-acute COVID-19 sequelae (PASC) manifestation and 13 convalescent children without PASC manifestation. A detailed medical history, blood and instrumental tests and physical examination were obtained from all patients. SARS-CoV-2 reactive T cell response was analyzed via multiparametric flowcytometry and the humoral immunity was addressed via pseudovirus neutralization and ELISA assay. Results: The most common PASC symptoms were shortness of breath/exercise intolerance, paresthesia, smell/taste disturbance, chest pain, dyspnea, headache and lack of concentration. Blood count and clinical chemistry showed no statistical differences among the study groups. We detected higher frequencies of spike (S) reactive CD4+ and CD8+ T cells among the PASC study group, characterized by TNFα and IFNγ production and low functional avidity. CRP levels are positively correlated with IFNγ producing reactive CD8+ T cells. Conclusions: Our data might indicate a possible involvement of a persistent cellular inflammatory response triggered by SARS-CoV-2 in the development of the observed sequelae in pediatric PASC. These results may have implications on future therapeutic and prevention strategies.

Background: Several recent studies have investigated the association between maternal diet during pregnancy and asthma in children. However, whether a specific dietary pattern during pregnancy protects children from asthma remains unclear. This study investigated the association between a healthy diet, dietary inflammation potential during pregnancy, and the risk for wheezing and atopic eczema in children. Methods: This study included 1330 mother-child pairs who attended the Kuopio Birth Cohort (KuBiCo) study and had dietary information during the last trimester and information on children’s health in the first year of life. The Alternative Healthy Eating Index for Pregnancy (AHEI-P) and Dietary Inflammatory Index (DII) indicate a healthy diet and dietary inflammation potential during pregnancy. The AHEI-P and DII were compared with reported wheezing and doctor-diagnosed atopic eczema in children during the first year of life. Results: Neither the AHEI-P nor the DII was associated with wheezing or atopic eczema in children when analyzed by continuous variables or tertiles. The odds ratio for AHEI-P and wheezing was 0.99 (0.98–1.01); for AHEI-P and atopic eczema was 1.01 (0.99–1.02); for DII and wheezing was 1.02 (0.95–1.09), and for DII and atopic eczema was 0.97 (0.91–1.04). Conclusion: In this cohort study, a maternal healthy or anti-inflammatory diet during pregnancy was not associated with wheezing or atopic eczema in the first year of life. Interventions in the overall dietary pattern during pregnancy might not effectively prevent atopic diseases in children.

Coronaviruses are important human and animal pathogens. We will show that probably antibodies don’t have essential role in immunity against COVID-19 in long term, but a type of white globules named T cells may have critical role in immunity against COVID-19. T cells have long time memory to remain in blood. The most important point for investigation of such issue is mild effection of children to COVID-19. While the milder COVID-19 disease in children is remained secretly till this paper, but its understanding will provide important information about the disease. It may also suggest important protective mechanisms and targets for future therapies. Then a main factor in producing a vaccine for COVID-19 maybe consideration of mild infection report of children by COVID-19 comparing adults’ infection that causes conclusion of higher resistance of immune system of children comparing adults. We identified this could be because immunity of children is based on innate immunity (phagocytes) while adults are based on antibodies. Our results show innate immune system including phagocytes contribute severely to the elimination of COVID-19 in both mouse model and human. Our results also show the elimination of COVID-19 required the activation of B cells by CD4+ T cells. CD4+ T cells play an important role in elimination of COVID-19 in primary effection. We measured IgM and IgG in human patients including adults and kids and found that IgM and IgG in kids’ patients are much higher than other adults patients.