Background The maturation of innate immune responses in health and atopy is still incompletely understood. Methods We aimed to evaluate age-related trajectories of the TLR3 and TLR7/8 pathways across the lifespan and whether these differ between healthy and atopic individuals. Peripheral blood mononuclear cells (PBMCs) were isolated from 39 otherwise healthy atopic and 39 non-atopic subjects, aged 0-45 years. Selected cytokines involved in antiviral responses were measured by Luminex in culture supernatants of poly(I:C)- and R848-stimulated PBMCs. The non-parametric correlation between age and cytokine expression and differences in developmental trajectories between healthy and atopic were estimated. Patterns of cytokine development were identified with principal component analysis. Results Normal innate immune maturation entails significant and progressive age-related changes in the production of IL-1β, TNF-α, MIP-1β, MCP-3, IP-10, IL-10, IL-12p70 and IFN-γ upon TLR3 and/or TLR7/8 stimulation. Individual cytokines made small contributions to the observed variability; chemokines MCP-3 and IP-10 were key contributors. The development of these pathways deviated in atopic subjects with significant differences observed in the trajectories of IL-1β, MIP-1β and IL-10 synthesis. Conclusion TLR3 and TLR7/8 pathways mature during childhood, while atopy is associated with an abnormal maturation pattern. Suboptimal responses in Th1, inflammatory cytokine and chemokine production may be implicated in poor antiviral immunity in atopics, while deficient maturation of IL-10 producing capacity in the breaking of tolerance.

Background: Although atopic dermatitis (AD) is associated with certain gene variants, the rapidly increasing incidence of AD suggests that environmental factors contribute to disease development. In this study, we investigated the association of AD incidence and phenotype with antibiotic exposure within 6 months of age, considering the dose administered and genetic risk. Methods: This study included 1,637 children from the COCOA birth cohort. Pediatric allergists assessed the presence of AD at each visit and obtained information about antibiotic exposure for more than 3 days. IL-13 (rs20541) polymorphism was genotyped by the TaqMan method. We stratified the AD phenotypes into 4 groups and used multinomial logistic regression models for analysis. Results: Antibiotic exposure within 6 months of age was found to increase the risk of AD within 3 years of life (aOR=1.40, 95%, CI 1.09–1.81) in dose-dependent manner. Antibiotic exposure more than twice increased the risk of the early-persistent AD phenotype (aOR=2.50, 95% CI 1.35–4.63). There was a weak interaction between genetic polymorphisms and environmental factors on the development of AD (p for interaction=0.06). Children with the IL-13 (rs20541) GA+ AA genotype have a higher risk of the early-persistent AD phenotype when exposed to antibiotics more than twice than those with the IL-13 (rs20541) GG genotype and without exposure to antibiotics (aOR=4.73, 2.01–11.14). Conclusion: Antibiotic exposure within 6 months was related to the incidence of early-persistent AD and a dose-dependent increase in the incidence of AD in childhood, whose effect was modified by the IL-13 (rs20541) genotype.

Background: Food allergy is a major health problem that significantly impacts quality of life (QoL). There is growing focus to evaluate food allergy related QoL and treatment value beyond the clinical effectiveness perspective by engaging patients and caregivers. We aimed to identify and prioritize outcomes important to food allergy parents of children and patients allergic to milk, egg, and/or peanut, to guide comparative effectiveness research (CER) that focuses on evaluating food allergy treatment decisions. Methods: We conducted a modified 3-round Delphi study to identify and derive consensus on priority treatment outcomes for parents of children and adult patients with diagnosed allergies to at least one of three major allergenic foods (milk, egg, and peanut) from across the United States. Results: Round 1 yielded 44 statements for round 2, and 39 statements reached the agreement level for round 3 ranking. Statements were organized under 4 sections: 1) food allergy problems, 2) treatment experiences, 3) important treatment outcomes, and 4) value of different treatment options. Conclusion: Food allergy parents and patients face several social, psychological, medical, healthcare, financial, food selection, and awareness challenges. The areas of consensus on important treatment outcomes revealed shared priority for reducing the risk of potentially fatal allergic reactions and having reliable treatments. The most valued treatment options reflect hope for permanent cure and fear of serious allergic reactions.

Background: Safely liberalizing the diet to include an allergenic food may accelerate resolution of food allergy. The outcome of liberalization, however, varies among patients. Methods: We conducted a prospective observational study to identify factors associated with outcome for egg allergy 1 year after oral food challenge (OFC). We enrolled children < 72 months-old who had egg allergy and underwent OFC for determination of the safe intake quantity of egg allergen. At enrollment, each child’s clinical background was recorded. The Food Allergy Quality of Life Questionnaire–Parent Form (FAQLQ–PF) was administered to the caregivers to assess their children’s QoL. Dietary advice based on the OFC result was then provided to support safe consumption of eggs. At 1 year after OFC, the quantity of egg each child safely consumed in daily life was surveyed. We classified the egg allergy outcome as Outgrowing (Group O) if the quantity increased during the 1 year, or as Non-outgrowing (Group N) if it did not. Factors associated with the outcome were investigated by multivariate logistic regression analysis. Results: A total of 93 children were enrolled, and after 1 year 57 finished in Group O and 36 in Group N. The mean FAQLQ-PF score at baseline was significantly lower (i.e., better QoL) in group O than in group N. Multivariate logistic regression analysis identified comorbid asthma, comorbid atopic dermatitis and a poor QoL as factors predicting an unfavorable outcome. Conclusion: QoL may affect food allergy outcome. Intervention focusing on QoL may promote outgrowing food allergies.

Background: Mutations in the filaggrin gene (FLG) affect epidermal barrier function and increase the risk of atopic dermatitis (AD). We hypothesized that FLG mutations affect immune cell composition in a general pediatric population. Therefore, we investigated if school-aged children with and without FLG mutations have differences in immune cell numbers. Methods: This study was embedded in a population-based prospective cohort study, the Generation R Study, and included 523 children of European genetic ancestry aged 10 years. The most common FLG mutations in the European population (R501X, S1085CfsX36, R2447X and S3247X) were genotyped. Additionally, 11-color flow cytometry was performed on peripheral blood samples to determine helper T (Th), regulatory T (Treg) and CD27+ and CD27- memory B cells. Sensitivity analysis was performed in 102 AD cases, assessed by parental questionnaires. Results: FLG mutations were observed in 8.4% of the total population and in 15.7% of the AD cases. Children with any FLG mutation had higher Th22 cell numbers compared to FLG wild-type children. Children with and without FLG mutations had no difference in Th1, Th2, Th17, Treg or memory B cell numbers. Furthermore, in children with AD, FLG mutation carriership was not associated with differences in T- and B-cells or their subsets. Conclusions: School-aged children with FLG mutations have higher Th22 cell, which might suggest an immunological defense mechanism to an altered skin barrier function. No associations between Th or Treg cells and FLG mutations suggests that FLG mutations do not otherwise affect immune composition in a general pediatric population.

Background: Periostin has emerged as a novel biomarker in the pathogenesis of T helper 2-type allergic diseases in the last years. The aim of this study was to investigate the association of serum periostin levels with clinical features in children with asthma. Methods: Children with physician-diagnosed asthma who attended regularly to an outpatient pediatric allergy and asthma center were enrolled in the study along with control subjects. Asthma severity and control status of the patients were evaluated according to recent GINA guidelines. Results: A total of 158 children (125 with asthma and 33 age and sex-matched control subjects) with a median age of 10.2 years (range 5.9-17.0) were enrolled. Asthma severity was mild in 41 (32.8%), moderate in 63 (50.4%) and severe in 21 (16.8%) children. Children with asthma had significantly higher periostin levels than controls (53.1 ± 13.1 vs 43.0 ± 11.2 ng/mL; p < 0.001). The mean serum periostin levels of children with severe asthma (63.8 ± 10.8) were significantly higher than in children with moderate asthma (53.3 ± 12.7) and mild asthma (47.4 ± 11.1) (p < 0.001). Serum periostin levels were found to be significantly correlated with asthma severity (Spearman’s rho [r]=0.41, p < 0.001). Results of multivariable logistic regression analysis demonstrated an association between serum periostin levels and asthma severity in children (OR, 1.10; 95% CI, 1.04-1.15; p <0.001) Conclusion: Serum periostin levels may serve clinicians in identifying children with severe asthma.

Abstract Background: Ataxia-telangiectasia (A-T) is a rare genetic disorder characterized by a distinct range of clinical manifestations, including progressive ataxia, immunodeficiency, and radiosensitivity. Methods: Clinical data, laboratory results, and genetic data were collected from forty-three A-T patients. Whole exome sequencing and Sanger sequencing were done for the patients clinically diagnosed as suffering from A-T. Based on the phenotype severity of the disease, patients were divided into severe and mild sub-groups. Results: The median (IQR) age of diagnosis in this cohort was 5 (3-7) years and various types of clinical manifestations, including fever (p= 0.005), lower respiratory tract infection (p= 0.033), diarrhea (p= 0.014), and hepatosplenomegaly (p= 0.032) were significantly higher amongst patients diagnosed with the severe phenotype. Our results showed a strong correlation between phenotype severity and mutation type. The chance of having severe phenotype in patients who have severe mutations, including frameshift and nonsense, was 7.3 times higher compared to patients who were categorized in the mild genotype group (odds ratio= 7.3, p= 0.006). Thirty-four types of mutations including 9 novel mutations, were observed in our study. Conclusion: Molecular analysis provides the opportunity for accurate diagnosis and timely management in A-T patients with chronic progressive disease, especially infections and the risk of malignancies. This study characterizes for the first time, the broad spectrum of mutations and phenotypes in Iranian A-T patients which are required for carrier detection and reducing the burden of disease in future using the patients’ families and for the public health care system. Keywords: Ataxia-telangiectasia (A-T), ATM, Whole-exome sequencing, Class switching recombination (CSR), phenotype severity.

Background: H1-antihistamines (AHs) are widely used for the treatment of allergic diseases, being one of the most commonly prescribed classes of medications in Pediatrics. Newer-generation AHs are associated with fewer adverse effects compared to first-generation. However, their relative harms in the pediatric population still need scrutiny. Methods: We performed a systematic review of randomized controlled trials (RCTs) which included comparisons of safety parameters between an orally administered newer-generation AH with another AH (first- or second- generation), montelukast or placebo in children aged≤12 years. We searched MEDLINE and CENTRAL, independently extracted data on study population, interventions, adverse events (AEs) and treatment discontinuations, and assessed the methodological quality of the included RCTs using the Cochrane’s risk of bias tool. Results: Fourty-five RCTs published between 1989 and 2017 met eligibility criteria. The majority of RCTs included school-aged children with allergic rhinitis and had a follow-up period of up to a month. Four RCTs reported serious AEs in patients receiving a newer-generation AH, but only two patients experienced a possibly drug-related serious AE. The occurrence of AEs, drug-related AEs and treatment discontinuations due to AEs varied between RCTs. Most AEs reported were of mild intensity. Indirect evidence indicates that cetirizine is more sedating than the other newer-generation AHs. Conclusion: Our findings confirm that newer-generation AHs have a favorable safety and tolerability profile. However, we could not draw firm conclusions regarding the comparative safety profile of the newer-generation AHs due to the paucity of head-to-head RCTs, variation in definitions and reporting of AEs, and short follow-up duration.

Introduction: Children with allergy may increase a chance to sensitize the allergic pollens with several environmental changes. Purpose of this study was to investigate the correlation with alternation of pollination associated with meteorological changes and increased sensitization rate of pollen allergens of children in Seoul metropolitan area, Korea. Methods: There were recruited 8,295 children who visited the pediatric allergic clinics at Hanyang University Seoul and Guri Hospital for allergy symptoms from January 1st, 1998 to December 31st, 2019. The pollen was collected by Burkard 7 days-sampler in 2 hospitals during the study. Meteorological data was investigated from Korea Meteorological Administration. Results: Allergic sensitization of oak, hazel, and alder pollens had the highest rate of increase among major tree pollens, an increase of 0.28% annually. The sensitization rate to pollen was increased with younger age group yearly. The duration of pollen season was 98 days in 1998, but 140 days in 2019. The duration of the pollen seasons and pollen sensitization rate to trees were positively correlated. The relationship between the sensitization rate to pollens and accumulated temperature were also correlated, positively. Conclusions: This study demonstrates the correlation between the weather changes and consequent changes of pollen seasons with increasing the sensitization rate to allergic pollens in children in Seoul metropolitan area. In addition, there was an increase in the sensitization rate in younger age group from year to year. Continuous changes in distribution of pollens raised from meteorological changes are expected from now on.

A document by Josefina Cernadas. Click on the document to view its contents.

Background: Phthalates can cause respiratory and immunological disorders. However, little is known about the role of serum periostin and YKL-40 levels in mediating the effects of phthalates. We investigated the mediating role of these biomarkers in the relationship between phthalates and airway dysfunction. Methods: A total of 487 children (aged 10 to 12 years-old) were examined. Four high-molecular-weight phthalate (HMWP) [Σ4HMWP] metabolites and 3 low-molecular-weight phthalate (LMWP) [Σ3LMWP] metabolites in urine samples were measured. Serum periostin and YKL-40 levels were measured. Airway function was measured using impulse oscillometry. A mediation model was used to quantify the mediating effects of periostin and YKL-40 on airway dysfunction. Results: After adjustment for height, gender, BMI z-score, aeroallergen sensitization, secondary smoking, and vitamin D level, the level of urinary Σ3LMWP metabolites was significantly associated with respiratory system resistance at 5 Hz (Rrs5; adjusted β: 0.020, 95% CI: 0.005 to 0.034; P = .010). The levels of urinary Σ4HMWP and Σ3LMWP metabolites were significantly associated with periostin level, but not with YKL-40 level. In addition, the periostin level was associated with Rrs5 (adjusted β: 0.048, 95% CI: 0.015 to 0.081; P = .005) and Rrs20-5 (adjusted β: 0.040, 95% CI: 0.011 to 0.069; P =.007). Serum periostin level had a significant effect in mediating the relationship between Σ3LMWP and Rrs5 (13.9%, 95% CI: 10.7 to 77.0; P < .001). Conclusion: Exposure to LMWPs was significantly associated with airway dysfunction, and this effect was partially attributable to increased serum periostin level.

A document by Marisol Perez-Toledo. Click on the document to view its contents.

A document by Ailish Breathnach. Click on the document to view its contents.

Objetives: The rate of eosinophilic esophagitis (EoE) diagnosis is increasing. This study aims to determine the incidence of EoE in the paediatric population residing in the southwestern Madrid and to analyse whether absolute monthly pollen counts, modified or not by the principal atmospheric pollutants, are associated with it. Methods: A prospective observational study was designed to calculate the incidence of EoE in children aged under 15 years who were diagnosed between September 2014 and August 2016 in twelve area hospitals. We collected clinical data, date of endoscopic diagnosis and the number of first-time endoscopies performed. Relative risk estimation was performed to assess the association between the incidence of diagnosis and monthly pollen counts and levels of atmospheric pollutants. Results: One hundred forty-eight patients were included. The most frequent symptoms were abdominal pain 42.57%, dysphagia 42.57% and impaction 39-86%. The average overall monthly incidence was 1.27 (0.41-2.67) cases/100,000 children and the annual average was 15.2. The overall analysis of the relationship between incidence and absolute monthly counts and air pollutants, corrected for the number of first-time endoscopies performed, revealed no statistically significant association. There was a higher frequency of diagnosis during the pollination period of Cupressaceae and during February and November (relative risk 1.67; p<0.01). Conclusions: This study confirms the high incidence of eosinophilic esophagitis and also suggest a period of higher incidence of diagnosis in the months of February and November as well as in the period of high pollination of Cupressaceae.

Background: Antiepileptic drugs (AEDs) are widely used for the treatment of epilepsy, but they can be associated with the development of mainly delayed/non-immediate hypersensitivity reactions (HRs). Although these reactions are usually cutaneous, self-limited and spontaneously resolve within days after drug discontinuation, sometime HRs reactions to AEDs can be severe and life threatening. Aim: This paper seeks to show examples on practical management of AEDs HRs in children starting from a review of what it is already known in literature. Results: Risk factors include age, history of previous AEDs reactions, viral infections, concomitant medications and genetic factors. The diagnosis work-up consists of in vivo (Intradermal testing and Patch testing) and in vitro tests [serological investigation to exclude the role of viral infection, lymphocyte transformation test (LTT), cytokine detection in ELISpot assays and granulysin (Grl) in flow cytometry]. Treatment is based on a prompt drug discontinuation and mainly on the use of glucocorticoids. Conclusion: Dealing with AEDs HRs is challenging. The primary goal in the diagnosis and management of HRs to AEDs should be trying to accurately identify the causal trigger and simultaneously identify a safe and effective alternate anticonvulsant. There is therefore an ongoing need to improve our knowledge of HS reactions due to AED medications and in particular to improve our diagnostic capabilities.

Background: Various studies have assessed omalizumab outcomes in the clinical practice setting but follow-up and/or number of patients included were limited. We aim to describe the long-term outcomes of pediatric patients with severe persistent allergic asthma receiving omalizumab in the largest real-life cohort reported to date. Methods: ANCHORS was a multicenter, observational, retrospective cohort study conducted in 25 Pediatric Allergy and Pulmonology units in Spain. We collected data of patients <18 years and initiating omalizumab between 2006-2018, from the year prior to omalizumab initiation to discontinuation or last available follow-up. The primary outcome was the evolution of the annual number of moderate-to-severe exacerbations compared to the baseline period. Results: Of the 484 patients included, 101 (20.9%) reached six years of treatment. The mean±standard deviation number of exacerbations decreased during the first year of treatment (7.9±6.6 to 1.1±2.0, p<0.001) and remained likewise for up to six years. The other clinical parameters assessed also improved significantly during the first year and stabilized or continued to improve thereafter. The percentage of patients experiencing adverse events was consistently low, and the main reason for discontinuation was good disease evolution. Conclusion: In this large, long-term, observational study, moderate-to-severe exacerbations decreased significantly from the first year of treatment with omalizumab. The beneficial effect was maintained in the long-term, along with a good safety profile. Our results position omalizumab as an effective long-term treatment in pediatric patients with severe persistent allergic asthma.

Background: allergic rhinitis is a common childhood disease responsible for a major impact on quality of life and health care resources. Many hypotheses have been proposed to explain the link between allergy and otitis media, although a definitive mechanism has not been identified yet. One of the major critical points is that authors failed in distinguishing among different phenotypes of middle ear inflammation. This review pointed out evidence from the laboratory and clinical experience to link allergy to different phenotypes of otitis media in children. Methods: we performed a systematic review in accordance with the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) process. Our search yielded 3010 articles that were finally screened. This resulted in 20 publications of which the full texts included for the qualitative analysis based on different phenotypes of otitis media. Results: clinical evidences and analyses of biomarkers suggested that allergy may be linked to some phenotypes of otitis media and, in particular, to otitis media with effusion and acute re-exacerbations in children with middle ear effusion. It was not possible to perform the analysis for allergy and acute and chronic otitis media because of paucity and heterogeneity of data. Conclusion: Allergy should be considered in the diagnostic work up of different phenotypes of otitis media. Clinicians should evaluate prompt and accurate treatment of allergy in improving outcomes, although futures studies are required to increase evidence supporting that anti-allergy treatment may be effective in the recovery and outcome of otitis media with effusion.

Background: Children with allergic symptoms tend to have behavioral or emotional problems. However, previous studies on this association did not control for factors such as parenting stress, demographic characteristics, or allergy presentation. This study aimed to investigate the relationship between childhood allergic symptoms and behavioral problems, adjusted for confounders such as demographic characteristics, parenting stress, and allergy-related variables. Methods: We conducted an online cross-sectional survey among caregivers of children aged 2-6 years (n=633). The Strengths and Difficulties Questionnaire (SDQ) score was used as the primary measure of children’s behavioral characteristics. Data on history of wheezing, eczema, and rhinitis were collected from the children’s caregivers, using a standardized questionnaire, based on the International Study of Asthma and Allergies in Childhood. Associations were estimated using logistic regression analyses with propensity score to adjust for confounding factors. Results: Univariate analyses showed that history of wheezing was associated with conduct problems, a behavioral component of the SDQ. History of eczema was also associated with hyperactivity. Furthermore, nose symptoms were associated with conduct and emotional problems. After adjusting for potential confounders, history of wheezing (adjusted odds ratio [OR]=1.69, 95% confidence interval [CI]: 1.04-2.75) and nose symptoms (adjusted OR=1.56, 95% CI: 1.05-2.34) remained associated with increased risk of conduct problems. Conclusions: This study revealed that history of wheezing and rhinitis in children are associated with increased risk of behavioral problems, in particular, that of conduct problems. This evidence may inform future research into childhood allergy symptoms and their behavioral problems.