Contributions of the early-life microbiome to childhood atopy and asthma development.

The rapid rise in atopy and asthma in industrialized nations has led to the identification of early life environmental factors that promote these conditions and spurred research into how such exposures may mediate the trajectory to childhood disease development. Over the past decade, the human microbiome has emerged as a key determinant of human health. This is largely due to the increasing appreciation for the myriad of non-mutually exclusive mechanisms by which microbes tune and train host immunity. Microbiomes, particularly those in early life, are shaped by extrinsic and intrinsic factors, including many of the exposures known to influence allergy and asthma risk. This has led to the over-arching hypothesis that such exposures mediate their effect on childhood atopy and asthma by altering the functions and metabolic productivity of microbiomes that shape immune function during this critical developmental period. The capacity to study microbiomes at the genetic and molecular level in humans from the pre-natal period into childhood with well-defined clinical outcomes, offers an unprecedented opportunity to identify early-life and inter-generational determinants of atopy and asthma outcomes. Moreover, such studies provide an integrative microbiome research framework that can be applied to other chronic inflammatory conditions. This review attempts to capture key studies in the field that offer insights into the developmental origins of childhood atopy and asthma, providing novel insights into microbial mediators of maladaptive immunity and chronic inflammatory disease in childhood.

Early-life nasal microbiota dynamics relate to longitudinal respiratory phenotypes in urban children.

BACKGROUND: Five distinct respiratory phenotypes based on latent classes of longitudinal patterns of wheezing, allergic sensitization. and pulmonary function measured in urban children from ages from 0 to 7 years have previously been described. OBJECTIVE: Our aim was to determine whether distinct respiratory phenotypes are associated with early-life upper respiratory microbiota development and environmental microbial exposures. METHODS: Microbiota profiling was performed using 16S ribosomal RNA-based sequencing of nasal samples collected at age 12 months (n = 120) or age 36 months (n = 142) and paired house dust samples collected at 3 months (12-month, n = 73; 36-month, n = 90) from all 4 centers in the Urban Environment and Childhood Asthma (URECA) cohort. RESULTS: In these high-risk urban children, nasal microbiota increased in diversity between ages 12 and 36 months (ß = 2.04; P = .006). Age-related changes in microbiota evenness differed significantly by respiratory phenotypes (interaction P = .0007), increasing most in the transient wheeze group. At age 12 months, respiratory illness (R2 = 0.055; P = .0001) and dominant bacterial genus (R2 = 0.59; P = .0001) explained variance in nasal microbiota composition, and enrichment of Moraxella and Haemophilus members was associated with both transient and high-wheeze respiratory phenotypes. By age 36 months, nasal microbiota was significantly associated with respiratory phenotypes (R2 = 0.019; P = .0376), and Moraxella-dominated microbiota was associated specifically with atopy-associated phenotypes. Analysis of paired house dust and nasal samples indicated that 12 month olds with low wheeze and atopy incidence exhibited the largest number of shared bacterial taxa with their environment. CONCLUSION: Nasal microbiota development over the course of early childhood and composition at age 3 years are associated with longitudinal respiratory phenotypes. These data provide evidence supporting an early-life window of airway microbiota development that is influenced by environmental microbial exposures in infancy and associates with wheeze- and atopy-associated respiratory phenotypes through age 7 years.

Untargeted metabolomic profiling in children identifies novel pathways in asthma and atopy.

BACKGROUND: Asthma and other atopic disorders can present with varying clinical phenotypes marked by differential metabolomic manifestations and enriched biological pathways. OBJECTIVE: We sought to identify these unique metabolomic profiles in atopy and asthma. METHODS: We analyzed baseline nonfasted plasma samples from a large multisite pediatric population of 470 children aged <13 years from 3 different sites in the United States and France. Atopy positivity (At+) was defined as skin prick test result of ≥3 mm and/or specific IgE ≥ 0.35 IU/mL and/or total IgE ≥ 173 IU/mL. Asthma positivity (As+) was based on physician diagnosis. The cohort was divided into 4 groups of varying combinations of asthma and atopy, and 6 pairwise analyses were conducted to best assess the differential metabolomic profiles between groups. RESULTS: Two hundred ten children were classified as At-As-, 42 as At+As-, 74 as At-As+, and 144 as At+As+. Untargeted global metabolomic profiles were generated through ultra-high-performance liquid chromatography-tandem mass spectroscopy. We applied 2 independent machine learning classifiers and short-listed 362 metabolites as discriminant features. Our analysis showed the most diverse metabolomic profile in the At+As+/At-As- comparison, followed by the At-As+/At-As- comparison, indicating that asthma is the most discriminant condition associated with metabolomic changes. At+As+ metabolomic profiles were characterized by higher levels of bile acids, sphingolipids, and phospholipids, and lower levels of polyamine, tryptophan, and gamma-glutamyl amino acids. CONCLUSION: The At+As+ phenotype displays a distinct metabolomic profile suggesting underlying mechanisms such as modulation of host-pathogen and gut microbiota interactions, epigenetic changes in T-cell differentiation, and lower antioxidant properties of the airway epithelium.

Indoor allergen exposure and its association to upper respiratory infections and pulmonary outcomes among children with asthma.

BACKGROUND: Certain environmental allergen exposures are more common in disadvantaged communities and may contribute to differences in susceptibility to upper respiratory infections (URIs). OBJECTIVES: We examined associations between indoor allergens and: (1) URI; (2) URI + cold symptoms; (3) URI + cold symptoms + pulmonary eosinophilic inflammation (fraction of exhaled nitric oxide ≥20 ppb); and (4) URI + cold symptoms + reduced lung function (percent predicted forced expiratory volume in 1 second of <80%). METHODS: We used data from the Environmental Control as Add-on Therapy for Childhood Asthma (ECATCh) study. Allergen concentrations were measured in air (mouse) and settled dust (mouse, cockroach, dog, and cat). URI was determined by testing nasal mucus for upper respiratory viruses. We evaluated associations between allergen concentrations and URI-associated outcomes accounting for age, sex, study month, season, health insurance, and household size. RESULTS: Ninety participants (92% Black, 92% public insurance) with 192 observations were included; 52 (27%) of observations were positive for URI. A doubling in cockroach allergen concentration increased the odds of a URI with cold symptoms by 18% (odds ratio [OR] = 1.18, 95% confidence interval [CI], 0.99-1.40), the odds of a URI + cold symptoms + pulmonary eosinophilic inflammation by 31% (OR = 1.31, 95% CI, 1.10-1.57), and the odds of a URI + cold symptoms + reduced lung function by 45% (OR = 1.45, 95% CI, 1.13-1.85). Mouse allergen concentrations were positively associated with all outcomes. Associations were suggestively stronger among children sensitized to pest allergens. CONCLUSIONS: Cockroach and mouse, but not dog or cat, allergen exposure may predispose children with asthma to URIs with colds and lower respiratory outcomes.

TH2-driven manifestations of inborn errors of immunity.

Monogenic lesions in pathways critical for effector functions responsible for immune surveillance, protection against autoinflammation, and appropriate responses to allergens and microorganisms underlie the pathophysiology of inborn errors of immunity (IEI). Variants in cytokine production, cytokine signaling, epithelial barrier function, antigen presentation, receptor signaling, and cellular processes and metabolism can drive autoimmunity, immunodeficiency, and/or allergic inflammation. Identification of these variants has improved our understanding of the role that many of these proteins play in skewing toward TH2-related allergic inflammation. Early-onset or atypical atopic disease, often in conjunction with immunodeficiency and/or autoimmunity, should raise suspicion for an IEI. This becomes a diagnostic dilemma if the initial clinical presentation is solely allergic inflammation, especially when the prevalence of allergic diseases is becoming more common. Genetic sequencing is necessary for IEI diagnosis and is helpful for early recognition and implementation of targeted treatment, if available. Although genetic evaluation is not feasible for all patients with atopy, identifying atopic patients with molecular immune abnormalities may be helpful for diagnostic, therapeutic, and prognostic purposes. In this review, we focus on IEI associated with TH2-driven allergic manifestations and classify them on the basis of the affected molecular pathways and predominant clinical manifestations.

Atopic Dermatitis in Early Childhood and Risk of Inflammatory Bowel Disease: A Scandinavian Birth Cohort Study.

OBJECTIVE: To examine the association between early-life atopic manifestations and later risk of inflammatory bowel disease (IBD), for which prospective data are scarce. STUDY DESIGN: The population-based All Babies in Southeast Sweden (ABIS) and Norwegian Mother, Father, and Child (MoBa) cohorts follow children from birth (ABIS 1997-1999; MoBa 2000-2009) to the end of 2021. Based on validated questionnaires, parents prospectively reported information on asthma, food-related allergic symptoms, atopic dermatitis, and allergic rhinitis by age 3. IBD was defined by ≥ 2 diagnostic records in the national health registries. Cox regression estimated hazard ratios adjusted (aHRs) for parental IBD, atopy, education level, smoking habits, and national origin. Cohort-specific estimates were pooled using a random-effects model. RESULTS: We compiled data on 83 311 children (ABIS, n = 9041; MoBa, n = 74 270). In over 1 174 756 person-years of follow-up, 301 participants were diagnosed with IBD. Children with atopic dermatitis at age 3 had an increased risk of IBD (pooled aHR = 1.46 [95% CI = 1.13-1.88]), Crohn's disease (pooled aHR = 1.53 [95%CI = 1.04-2.26]), and ulcerative colitis (pooled aHR = 1.78 [95%CI = 1.15-2.75]). Conversely, any atopic manifestation by age 3 was not associated with IBD (pooled aHR = 1.20 [95%CI = 0.95-1.52]), nor were analyses specifically focused on early-life food-related allergic symptoms, asthma, and allergic rhinitis. CONCLUSION: While atopic manifestations in early childhood were overall not associated with IBD, children with atopic dermatitis specifically were at increased risk of developing IBD, suggesting shared etiologic traits; these findings might be useful in identifying at-risk individuals for IBD.

Genetic association between atopic disease and osteoarthritis.

OBJECTIVES: To evaluate the association between genetically determined risk for atopic disease and osteoarthritis (OA). METHODS: We performed linkage disequilibrium (LD) score regression using 1000 Genomes Project European samples as a reference for patterns of genome-wide LD. Summary statistics for atopic disease traits were obtained from the UK Biobank. We generated a pairwise genetic correlation between OA and traits for atopic disease to estimate the genetic correlation between traits (rg) and heritability for each trait. The association between atopy-related traits and OA was examined using Mendelian randomization (MR) on summary statistics; we reported inverse-variance weighted (IVW), MR-Egger, maximum likelihood estimation, weighted median, and weighted mode. RESULTS: There was a significant positive correlation between the genome-wide genetic architecture of asthma and all OA traits. Using the IVW (random effects), there was a significant association between asthma and knee OA ((odds ratio) OR = 1.04, 95% (confidence interval) CI 1.01-1.08, p = 0.0169). Using IVW (fixed effects), significant associations were identified between knee OA and allergic disease (OR = 1.07, 95% CI 1.01-1.14, p = 0.0342), allergic rhinitis (OR = 1.07, 95% CI 1.00-1.13, p = 0.0368), and asthma (OR = 1.04, 95% CI 1.01-1.07, p = 0.0139), as well as for OA at any site and asthma (OR = 1.02, 95% CI 1.00-1.04, p = 0.0166). CONCLUSIONS: We found a significant correlation between the overall genetic architecture of asthma and OA, as well as an increased risk of developing OA in patients with genetic variants associated with asthma and allergic rhinitis; predominately, this risk was for the development of knee OA. These results support a causal relationship between asthma and/or allergic rhinitis and knee OA.

AllergoOncology: Biomarkers and refined classification for research in the allergy and glioma nexus-A joint EAACI-EANO position paper.

Epidemiological studies have explored the relationship between allergic diseases and cancer risk or prognosis in AllergoOncology. Some studies suggest an inverse association, but uncertainties remain, including in IgE-mediated diseases and glioma. Allergic disease stems from a Th2-biased immune response to allergens in predisposed atopic individuals. Allergic disorders vary in phenotype, genotype and endotype, affecting their pathophysiology. Beyond clinical manifestation and commonly used clinical markers, there is ongoing research to identify novel biomarkers for allergy diagnosis, monitoring, severity assessment and treatment. Gliomas, the most common and diverse brain tumours, have in parallel undergone changes in classification over time, with specific molecular biomarkers defining glioma subtypes. Gliomas exhibit a complex tumour-immune interphase and distinct immune microenvironment features. Immunotherapy and targeted therapy hold promise for primary brain tumour treatment, but require more specific and effective approaches. Animal studies indicate allergic airway inflammation may delay glioma progression. This collaborative European Academy of Allergy and Clinical Immunology (EAACI) and European Association of Neuro-Oncology (EANO) Position Paper summarizes recent advances and emerging biomarkers for refined allergy and adult-type diffuse glioma classification to inform future epidemiological and clinical studies. Future research is needed to enhance our understanding of immune-glioma interactions to ultimately improve patient prognosis and survival.

Alopecia areata exhibits cutaneous and systemic OX40 activation across atopic backgrounds.

BACKGROUND: Alopecia areata (AA) is a chronic, nonscarring hair-loss disorder associated with significant quality-of-life impairment and limited treatment options. AA has been recently linked to atopy and shown to exhibit both Th1- and Th2-driven inflammation. However, a comprehensive molecular and cellular characterization across blood and scalp compartments in both atopic and nonatopic patients is lacking. METHODS: Lesional and nonlesional scalp biopsies obtained from AA patients with (n = 16) or without (n = 20) atopic history, and 17 demographically matched healthy controls were analyzed with RNA-seq, RT-PCR, and immunohistochemistry. Flow cytometry was also performed on peripheral blood mononuclear cells (PBMCs) from a subset of patients. Differential expression was defined using |fold-change| > 1.5 and false-discovery rate <0.05. RESULTS: AA scalp exhibited robust upregulation of Th1- (IFNG, CXCL9, CXCL10, CXCL11) and Th2-related products (CCL26, CCR4, IL10, IL13, TSLP, TNFRSF4/OX40) and shared downregulation of hair keratins, regardless of atopic background, with variable Th17/Th22 modulation. AA patients with atopy exhibited greater inflammatory tone and Th2-skewing (IL10, IL13, IL33, CCR4, CCL26). Disease severity correlated significantly with immune and hair keratin biomarkers and with perifollicular cellular infiltrates. Cutaneous OX40/OX40L upregulation was paralleled by increases in circulating OX40+ and OX40L+ leukocytes, regardless of atopic background. CONCLUSION: Our results suggest some atopy-associated immune differences in AA and highlight the OX40 axis as a potential novel therapeutic target that may broadly benefit AA patients.

Atopy Does Not Influence the Clinical Outcome of Acute Urticaria: A Retrospective Study.

BACKGROUND: Acute urticaria (AU) may be associated with atopy, but the relationship between atopic status and the clinical features of the disease has not been fully described. OBJECTIVES: The aim of the study was to determine the proportion of atopy in AU patients and to see whether atopy is related to the clinical characteristics of AU and whether it has an impact on the outcome of the disease. MATERIALS AND METHOD: A retrospective analysis of patients with AU was performed. Demographic data, clinical features, and laboratory results were compared and analyzed between the atopic and non-atopic AU (napAU). RESULTS: In total, 139 participants were included. 54 (38.8%) patients were atopic AU (apAU) and 85 (61.2%) were napAU. Compared with napAU patients, apAU patients were more likely to have anaphylaxis, higher levels of C4, and lower levels of antistreptolysin. There were no significant differences between the two groups in terms of other clinical features, laboratory tests, the natural course of the disease, or disease outcomes. CONCLUSION: Atopy does exist in some patients with AU, and AU patients with an atopic background are at higher risk for anaphylaxis. Atopy does not influence the clinical outcome of AU and is not correlated with other clinical features and laboratory results of AU.

Changes in Prevalence of IgE Sensitization and Allergenic Exposition over a 10-Year Period in a Tropical Region.

INTRODUCTION: Multiple antigen environmental sources have been identified as possible causes of allergies, but few studies have evaluated changes in the sensitization profiles over time. The aim of this study was to evaluate the changes in IgE sensitization and exposure to dust mites, cats, dogs, and cockroaches over a 10-year period. METHODS: During a period of 10 years among patients with asthma, rhinitis and/or atopic dermatitis, we evaluated the annual frequency of atopy to Dermatophagoides farinae, Dermatophagoides pteronyssinus, Blomia tropicalis, Canis familiaris, Felis domesticus and cockroaches (Periplaneta americana and Blatella germanica). Exposure to sources was also assessed using questionnaires (Pets) or direct counts (House dust mites and cockroaches). The association between some risk factors and the prevalence of atopy was explored. RESULTS: A total of 6,000 records were included. Among the patients, 82% had IgE sensitization to at least one of the six allergenic sources. Sensitization to Dermatophagoides spp. was the most frequent (>78%). Exposure and sensitization in the first decade of life to Dermatophagoides spp. seem to determine the molecular spreading to other allergenic sources. Exposure to Blomia tropical increases significantly over time (year 2015; 38% vs. year 2022; 51%, p 0.03). Exposure to dogs was higher than with cats but association between atopy and exposure was stronger with cats (OR 27.4, 95% CI: 22.3-33.6, p < 0.01). CONCLUSION: Exposure and sensitization in the first decade of life to Dermatophagoides spp. determine the molecular spreading of IgE antibodies to other allergenic sources. Household exposure to dogs and cats seems to be important for the subsequent development of atopy. Sensitization to B. tropicalis and cockroach appears to be mostly from cross-reactivity rather than direct exposure.

Characteristics and Clinical Significance of Atopy in Chronic Spontaneous Urticaria: A Cross-Sectional Observational Study.

INTRODUCTION: Atopy is an important and non-negligible clinical phenomenon in chronic spontaneous urticaria (CSU). However, the characteristics and clinical significance of atopy in patients with CSU have not been fully described. This study aimed to analyze the characteristics and clinical significance of atopy in patients with CSU. METHODS: A descriptive cross-sectional design was used. The study enrolled 176 patients with CSU. All enrolled patients underwent total IgE, specific IgE, and autologous serum skin tests (ASSTs). The relationships between atopy, the demographic and clinical data of patients with CSU, and the response to ASST were analyzed in detail; the distribution of allergens in atopic CSU was also analyzed. RESULTS: Atopy was confirmed in 48.9% of patients with CSU. Patients with atopic CSU were more likely than patients with non-atopic CSU to have dermatographism (57.0% vs. 41.1%, p < 0.05), history of urticaria (37.2% and 18.9%, respectively; p < 0.01), angioedema (39.5% and 24.4%, respectively; p < 0.05), and anaphylaxis (7/86 and 1/90, respectively; p < 0.05). Atopy was not associated with ASST response, disease duration, or response to antihistamine treatment in patients with CSU, nor was it associated with the urticaria activity score (UAS7), chronic urticaria quality of life questionnaire (CU-Q2oL), or pruritus visual analog scale (VAS) scores (all p < 0.05). The most common allergen in patients with atopic CSU was dust mites, followed by animal food allergens, tree/grass pollen, and cockroaches. CONCLUSIONS: Although larger prospective studies are needed to confirm these results, our study found atopy occurred in nearly half of patients with CSU, and preliminarily links atopy to CSU, suggesting it as a potential risk factor for angioedema, anaphylaxis, and recurrent urticaria, mirroring allergen patterns in other allergic disease.

Atopy and Response to Omalizumab Treatment in Chronic Spontaneous Urticaria.

INTRODUCTION: The possible influence of sensitization to aeroallergens on omalizumab response in chronic spontaneous urticaria (CSU) has been insufficiently investigated. This study's aim was to investigate atopy's influence on omalizumab response in CSU patients. METHOD: Retrospective study of CSU patients followed at a Portuguese Urticaria Center of Reference and Excellence (UCARE), treated with omalizumab for at least 6 months, between 2015 and 2022. At T0, all patients underwent quantification of specific immunoglobulin E (IgE) for total extract of most prevalent aeroallergens (ImmunoCAP Thermo Fisher Scientific®) and were divided in 2 groups, according to their response to omalizumab during the first 16 weeks of treatment: responders (R) (UAS7 <7) versus partial (PR) (UAS7 = 7-15) and nonresponders (UAS7 >15). R were further classified as fast (FR) (4-6 weeks) and slow responders (SR) (12-16 weeks). Total serum IgE, circulating eosinophil, and basophil counts were compared between groups at T0. p < 0.05 was considered statistically significant (SPSS® v25.0). RESULTS: Ninety-six patients (80% female) were studied, mean age 49 ± 14 years. Median CSU duration pre-omalizumab was 3 (0.6-20) years and mean omalizumab treatment duration was 3.7 ± 2.3 years. 38 (40%) had concomitant chronic inducible urticaria and 72 (75%) angioedema. Based on positive results of the specific IgE assay, 35 patients (36%) were considered atopic. Most patients (n = 30; 86%) were sensitized to house dust mites (HDM) (Dermatophagoides farinae = 28, Dermatophagoides pteronyssinus = 27, Blomia tropicalis = 19, Lepidoglyphus destructor = 17), followed by pollens (n = 12; 34%) (mixture of grasses = 10, Olea europaea = 7, Parietaria officinalis = 6), epithelia (n = 9; 26%) (dog = 8, cat = 7), and fungi (Alternaria alternata = 4; 11%). Eight patients (23%) were monosensitized to HDM and 4 (11%) to pollens. No significant association was found between aeroallergen sensitization and CSU duration, concomitant chronic inducible urticaria, or angioedema. Atopic patients featured significantly higher levels of baseline total serum IgE than nonatopic (469 vs. 94 U/mL, respectively; p = 0.0009). Mean baseline counts of eosinophils and basophils were not significantly different between atopic and non-atopic, respectively: eosinophils (128 vs. 121/mm3) and basophils (26 vs. 28/mm3). Regarding response to omalizumab, most patients (58; 60%) were responders: FR - 46 (79%); SR - 12 (21%). There was no significant association between aeroallergen sensitization and omalizumab response or speed of response. CONCLUSIONS: As far as we know, this is the first study exploring the influence of atopy sensitization pattern on omalizumab response in CSU. According to our results, presence of atopy/sensitization pattern does not influence omalizumab response in CSU patients.

Vaccines and allergy: Back to the right places.

Hypersensitivity reactions represent one of the most common causes of hesitancy for adherence to national vaccination programs. The majority of hypersensitivity reactions after vaccination are mild, and anaphylaxis is reported to be rare, although it remains challenging to estimate the frequency attributed to each single vaccine, either because of the lower number of administered doses of less common vaccines, or the administration of simultaneous vaccine in most of the vaccination programs. Although literature remains scattered, international consensus guides clinicians in identifying patients who might need the administration of vaccines in protected environments due to demonstrated hypersensitivity to vaccine components or adjuvants. Here we provide the current guidance on hypersensitivity reactions to vaccines and on vaccination of children with allergy disorders.

Effect of dupilumab on asthma and aeroallergen sensitization in pediatric atopic dermatitis patients: Results of the BioDay registry.

BACKGROUND: Atopic dermatitis (AD) is frequently associated with asthma and allergic rhinitis (AR). Dupilumab is an effective treatment for pediatric AD, although the effect on atopic comorbidities in pediatric AD patients is limited. OBJECTIVE: To investigate the prevalence of asthma and AR in pediatric AD patients starting dupilumab treatment and to evaluate the effect of dupilumab on these comorbidities. METHODS: This study included pediatric AD patients (aged 3-17 years) treated with dupilumab between 2019 and 2023. Patients were screened at baseline by a pulmonologist for the presence of asthma and AR. Screening included evaluation of medical history and current symptoms, spirometry (including Forced Expiratory Volume in 1 s (FEV1)), Fractional exhaled Nitric Oxide (FeNO), and measurement of aeroallergen-specific IgE levels. In patients diagnosed with comorbid asthma and/or AR, measurements were repeated at weeks 16 and 52. Spirometry measurements, FeNO, and aeroallergen-specific IgE levels during treatment were analyzed using a covariance pattern model. RESULTS: Eighty-four patients were included. Asthma was diagnosed in 50 patients (59.5%) and AR in 72 patients (85.7%). Baseline FeNO levels were elevated in both patients with (29.0 ppb (95% CI 22.0-54.0)) and without asthma (26.0 ppb (95% CI 22.0-30.0)). During treatment, FeNO levels decreased (p < .001) and FEV1 scores increased (p < .001) in patients with asthma. In patients with asthma and/or AR, all aeroallergen-specific IgE levels decreased between 61.3% and 89.1% at 52 weeks of treatment. CONCLUSION: One year of dupilumab treatment, primarily indicated for AD, resulted in a significant improvement in comorbid asthma and a profound decrease in aeroallergen-specific IgE levels in patients with asthma and/or AR.

Urinary eosinophil-derived neurotoxin is associated with reduced lung function in pediatric asthma.

INTRODUCTION: Eosinophil-derived neurotoxin (EDN) is a biomarker for eosinophilic activation. Urinary (u) EDN may allow non-invasive monitoring of asthma, but clinical recommendations are lacking. We assessed the potential of uEDN as a marker of disease activity in pediatric asthma. METHODS: We assessed urine samples of 371 children from the German ALLIANCE study cohort, from which we had: 169 preschool wheezers (<6 years), 80 asthmatics (≥6 years), and 122 healthy controls using the ImmunoCAP™ EDN Assay. Creatinine (Cr)-adjusted uEDN values were analyzed using correlations, association tests, (non) parametric statistics, multiple linear, and multivariable regression. RESULTS: uEDN/uCr values were higher in atopic versus non-atopic preschool-aged subjects (p = .035) and associated with the sum of allergen-specific IgE in younger (r = 0.24, p = .003), and older subjects (r = 0.23, p = .043). uEDN/uCr was marginally a good determinant for atopy (p = .078, for subjects aged <6 years, and p = .058 for subjects ≥6 years). Children with the T2-high phenotype had higher uEDN/uCr (p < .001) versus T2-low-irrespective of using uEDN/uCr or blood eosinophils in combination to allergen sIgE for disease phenotyping. uEDN/uCr significantly correlated with reduced lung function among asthmatics (FEV1 z-scores: r = -0.30, p = .007, and FEV1/FVC z-scores: r = -0.24, p = .038). Using multivariable modeling, uEDN/uCr was an independent determinant of FEV1 (p = .038), and to a lesser extent, FEV1/FVC (p = .080). CONCLUSIONS: uEDN/uCr may serve as a non-invasive biomarker for clinical features such as lung function in pediatric asthma. We highlight the utility of uEDN/uCr as a biomarker that can be easily assessed using widely available robust diagnostic immunoassays.

Helicobacter pylori Infection Does Not Protect Against Allergic Diseases: Evidence From a Pediatric Cohort From Northern Sardinia, Italy.

BACKGROUND: The "hygiene hypothesis" states that reduced exposure to microbial antigens due to an excessively hygienic environment can increase the risk of developing autoimmune diseases, including atopic disorders and asthma. In recent decades, there has been a progressive decline in the prevalence of numerous microorganisms following improved hygienic-sanitary conditions. More specifically, several studies reported an inverse association between the reduction in Helicobacter pylori infection and the rise of asthma and allergic disorders. AIM: To evaluate the prevalence of atopic disorders in a pediatric population in relation to seropositivity against H. pylori. METHODS: Children from Northern Sardinia, Italy, referred to the local Children's Hospital for any reason, were investigated to identify risk factors, especially H. pylori infection, associated with atopic disorders. A validated questionnaire, including demographics, house size, history of breastfeeding, residence, school or daycare center attendance, exposure to animals, and a defined diagnosis of atopy-including asthma-was filled out by a trained pediatrician according to parents' answers and child records. A blood sample was collected from each participant and immunoglobulin G against H. pylori was assessed by a locally validated ELISA test. RESULTS: The seroprevalence of H. pylori infection was 11.7% among 492 children (240 females). Thirty-two children had a confirmed diagnosis of asthma and 12 of allergy. No one child showed both conditions. Statistically significant differences in H. pylori seropositivity were not detected between children with or without atopy (8.4% vs. 12.6; p = 0.233). Although atopic disorders were more frequent in children exposed to traditional atopic risk factors, none of them showed to be significant after adjusting for all covariates. CONCLUSIONS: Serologically assessed H. pylori infection was not significantly associated with a reduced risk of atopic diseases in children.

Environmental Interventions for Preventing Atopic Diseases.

PURPOSE OF REVIEW: In this review, we detail the exposome (consisting of environmental factors such as diet, microbial colonization, allergens, pollutants, and stressors), mechanistic and clinical research supporting its influence on atopic disease, and potentiation from climate change. We highlight contemporary environmental interventions and available evidence substantiating their roles in atopic disease prevention, from observational cohorts to randomized controlled trials, when available. RECENT FINDINGS: Early introduction to allergenic foods is an effective primary prevention strategy to reduce food allergy. Diverse dietary intake also appears to be a promising strategy for allergic disease prevention, but additional study is necessary. Air pollution and tobacco smoke are highly associated with allergic disease, among other medical comorbidities, paving the way for campaigns and legislation to reduce these exposures. There is no clear evidence that oral vitamin D supplementation, prebiotic or probiotic supplementation, daily emollient application, and antiviral prophylaxis are effective in preventing atopic disease, but these interventions require further study. While some environmental interventions have a well-defined role in the prevention of atopic disease, additional study of many remaining interventions is necessary to enhance our understanding of their role in disease prevention. Alignment of research findings from randomized controlled trials with public policy is essential to develop meaningful public health outcomes and prevent allergic disease on the population level.

Screening asthmatics for atopic status using the ALergy EXplorer (ALEX2) macroarray.

BACKGROUND: Screening asthma patients for atopy facilitates management. Since 2010, the core biomarker for screening asthma subjects for atopic status has been the qualitative Phadiatop. multi-aeroallergen screen. A more quantitative macroarray, the Allergy Explorer (ALEX2), shows promise as an alternative. OBJECTIVE: The study's goal was to examine the pros and cons of the use of ALEX2 in the screening of asthma patients for atopic status. METHODS: We evaluated the atopic (IgE-sensitization) status in asthmatic Amish and Hutterite farm children using the ImmunoCAP and ALEX2 assays in Phadiatop equivocal and positive subjects. RESULTS: All 42 asthmatic children were analyzed by Phadiatop and total serum IgE. Of these, 22 had a negative Phadiatop (<0.1 kUa/L) and total IgE <100 kU/L which defined them as non-atopic and they were excluded from ALEX2 testing. Of six children with equivocal Phadiatops (0.1-0.2 kUa/L-Group 1) and three children with a negative Phadiatop but total IgE >100 kUa/L (group 3), 44% (n = 4) had detectable IgE antibody by ALEX2 to mite, tree pollen, and other allergens not detected by Phadiatop, but confirmed by allergen-specific ImmunoCAP testing. In 11 Phadiatop positive subjects (>0.2 kUa/L-group 2), all but one were positive by ALEX2. IgE antibody specific for mold and rabbit aeroallergens matched their agricultural and pet exposure history. Three children were positive for IgE antibody to allergens in the profilin, nsLTP, or PR-10 cross-reactive protein families. CONCLUSION: Judicious use of ALEX2's enhanced specificity data not provided by the Phadiatop can aid in the interpretation of sensitization patterns and planning management of atopic asthmatics, but sensitization relevance must be confirmed by the patient's clinical history.

Atopic dermatitis in early life and pain at 10 years of age: An exploratory study.

Pain is a distinctive burden in atopic dermatitis and recognized as an important and highly prevalent symptom. It is unknown if the presence of atopic disease may sensitize children to adverse pain profiles in the long term. We aimed to assess the impact of early-life atopic dermatitis-like symptoms on pain at 10 years of age. We used data from 1302 and 874 participants of the Generation XXI birth cohort evaluated at 6 and 15 months, respectively, and 10 years. Atopy-like symptoms since birth, including atopic dermatitis, were collected at ages 6 and 15 months by interviewing parents. Pain history in the last 3 months at age 10 was collected from parents and children using structured questionnaires. We computed relative risks (RR) and respective 95% confidence intervals of pain features at age 10 according to each atopic-like symptom at 6 and 15 months. Children whose parents reported atopic dermatitis-like symptoms at 6 months and at 15 months had higher risk of reporting any pain (RR 1.75 [1.15-2.66]) and multisite pain, respectively (RR 1.67 [1.18-2.37]) at 10 years of age.  Conclusion: Atopic dermatitis symptoms in early life were associated with a higher risk of pain at age 10, suggesting that potential for sensitization during the first decade of life and highlighting the importance of improving the health care of children with atopic dermatitis is worth investigating. What is Known: • Atopic disorders have been associated with many non-atopic comorbidities, including chronic pain. • Pain and atopic dermatitis share common inflammatory pathways. Inflammation, injury to the skin from scratching, fissures, and intolerance to irritants related to atopic dermatitis can cause pain. What is New: • Atopic dermatitis in early life is linked to an increased likelihood of experiencing pain at the age of 10, which suggests that exploring the potential for sensitization is a worthwhile area of investigation. • Our proof-of-concept study highlights the potential benefit of studying management targets and improving itching and relieving skin pain as quickly as possible, avoiding potential long-term consequences of the sensitization process.