Multi-omic association study identifies DNA methylation-mediated genotype and smoking exposure effects on lung function in children living in urban settings.

Impaired lung function in early life is associated with the subsequent development of chronic respiratory disease. Most genetic associations with lung function have been identified in adults of European descent and therefore may not represent those most relevant to pediatric populations and populations of different ancestries. In this study, we performed genome-wide association analyses of lung function in a multiethnic cohort of children (n = 1,035) living in low-income urban neighborhoods. We identified one novel locus at the TDRD9 gene in chromosome 14q32.33 associated with percent predicted forced expiratory volume in one second (FEV1) (p = 2.4x10-9; ßz = -0.31, 95% CI = -0.41- -0.21). Mendelian randomization and mediation analyses revealed that this genetic effect on FEV1 was partially mediated by DNA methylation levels at this locus in airway epithelial cells, which were also associated with environmental tobacco smoke exposure (p = 0.015). Promoter-enhancer interactions in airway epithelial cells revealed chromatin interaction loops between FEV1-associated variants in TDRD9 and the promoter region of the PPP1R13B gene, a stimulator of p53-mediated apoptosis. Expression of PPP1R13B in airway epithelial cells was significantly associated the FEV1 risk alleles (p = 1.3x10-5; ß = 0.12, 95% CI = 0.06-0.17). These combined results highlight a potential novel mechanism for reduced lung function in urban youth resulting from both genetics and smoking exposure.

A pediatric randomized, controlled trial of German cockroach subcutaneous immunotherapy.

BACKGROUND: Cockroach allergy contributes to morbidity among urban children with asthma. Few trials address the effect of subcutaneous immunotherapy (SCIT) with cockroach allergen among these at-risk children. OBJECTIVES: We sought to determine whether nasal allergen challenge (NAC) responses to cockroach allergen would improve following 1 year of SCIT. METHODS: Urban children with asthma, who were cockroach-sensitized and reactive on NAC, participated in a year-long randomized double-blind placebo-controlled SCIT trial using German cockroach extract. The primary endpoint was the change in mean Total Nasal Symptom Score (TNSS) during NAC after 12 months of SCIT. Changes in nasal transcriptomic responses during NAC, skin prick test wheal size, serum allergen-specific antibody production, and T-cell responses to cockroach allergen were assessed. RESULTS: Changes in mean NAC TNSS did not differ between SCIT-assigned (n = 28) versus placebo-assigned (n = 29) participants (P = .63). Nasal transcriptomic responses correlated with TNSS, but a treatment effect was not observed. Cockroach serum-specific IgE decreased to a similar extent in both groups, while decreased cockroach skin prick test wheal size was greater among SCIT participants (P = .04). A 200-fold increase in cockroach serum-specific IgG4 was observed among subjects receiving SCIT (P < .001) but was unchanged in the placebo group. T-cell IL-4 responses following cockroach allergen stimulation decreased to a greater extent among SCIT versus placebo (P = .002), while no effect was observed for IL-10 or IFN-γ. CONCLUSIONS: A year of SCIT failed to alter NAC TNSS and nasal transcriptome responses to cockroach allergen challenge despite systemic effects on allergen-specific skin tests, induction of serum-specific IgG4 serum production and down-modulation of allergen-stimulated T-cell responses.

Mepolizumab for urban children with exacerbation-prone eosinophilic asthma in the USA (MUPPITS-2): a randomised, double-blind, placebo-controlled, parallel-group trial.

BACKGROUND: Black and Hispanic children living in urban environments in the USA have an excess burden of morbidity and mortality from asthma. Therapies directed at the eosinophilic phenotype reduce asthma exacerbations in adults, but few data are available in children and diverse populations. Furthermore, the molecular mechanisms that underlie exacerbations either being prevented by, or persisting despite, immune-based therapies are not well understood. We aimed to determine whether mepolizumab, added to guidelines-based care, reduced the number of asthma exacerbations during a 52-week period compared with guidelines-based care alone. METHODS: This is a randomised, double-blind, placebo-controlled, parallel-group trial done at nine urban medical centres in the USA. Children and adolescents aged 6-17 years, who lived in socioeconomically disadvantaged neighbourhoods and had exacerbation-prone asthma (defined as ≥two exacerbations in the previous year) and blood eosinophils of at least 150 cells per µL were randomly assigned 1:1 to mepolizumab (6-11 years: 40 mg; 12-17 years: 100 mg) or placebo injections once every 4 weeks, plus guideline-based care, for 52 weeks. Randomisation was done using a validated automated system. Participants, investigators, and the research staff who collected outcome measures remained masked to group assignments. The primary outcome was the number of asthma exacerbations that were treated with systemic corticosteroids during 52 weeks in the intention-to-treat population. The mechanisms of treatment response were assessed by study investigators using nasal transcriptomic modular analysis. Safety was assessed in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, NCT03292588. FINDINGS: Between Nov 1, 2017, and Mar 12, 2020, we recruited 585 children and adolescents. We screened 390 individuals, of whom 335 met the inclusion criteria and were enrolled. 290 met the randomisation criteria, were randomly assigned to mepolizumab (n=146) or placebo (n=144), and were included in the intention-to-treat analysis. 248 completed the study. The mean number of asthma exacerbations within the 52-week study period was 0·96 (95% CI 0·78-1·17) with mepolizumab and 1·30 (1·08-1·57) with placebo (rate ratio 0·73; 0·56-0·96; p=0·027). Treatment-emergent adverse events occurred in 42 (29%) of 146 participants in the mepolizumab group versus 16 (11%) of 144 participants in the placebo group. No deaths were attributed to mepolizumab. INTERPRETATION: Phenotype-directed therapy with mepolizumab in urban children with exacerbation-prone eosinophilic asthma reduced the number of exacerbations. FUNDING: US National Institute of Allergy and Infectious Diseases and GlaxoSmithKline.

Longitudinal atopic dermatitis endotypes: An atopic march paradigm that includes Black children.

BACKGROUND: The atopic march has been studied mostly in White populations, biasing our current paradigms. OBJECTIVE: We sought to define the atopic march in Black and White children and explore mechanisms for racial differences. METHODS: Utilizing the Mechanisms of Progression of Atopic Dermatitis to Asthma in Children (MPAACH) cohort (n = 601), we assessed longitudinal sensitization, food allergy (FA), allergic rhinitis, risk of asthma development (through the Pediatric Asthma Risk Score), Scoring for Atopic Dermatitis (SCORAD), transepidermal water loss, skin filaggrin (FLG) expression, exposures, and genetic heritability to define AD progression endotypes in Black and White children. RESULTS: White MPAACH children were more likely to be sensitized to aero and food allergens (P = .0001) and over 3 times more likely to develop FA and/or allergic rhinitis (AR) without asthma risk (P < .0001). In contrast, Black children were over 6 times more likely to proceed to high asthma risk without FA, sensitization, or AR (P < .0001). White children had higher lesional and nonlesional transepidermal water loss (both P < .001) as well as decreased nonlesional keratinocyte FLG expression (P = .02). Black children had increased genetic heritability for asthma risk and higher rates of exposures to secondhand smoke and traffic-related air pollution. CONCLUSIONS: Black and White children with AD have distinct allergic trajectories defined by different longitudinal endotypes. Black children exhibit higher asthma risk despite a more intact skin barrier and less sensitization, FA, and AR. White children have less asthma risk, despite a more dysfunctional skin barrier, and more FA, AR, and sensitization. The observed racial differences are likely due in part to increased genetic heritability for asthma risk and harmful environmental exposures in Black children. Collectively, our findings provide a new paradigm for an atopic march that is inclusive of Black children.

Sensitization to peanut, egg or pets is associated with skin barrier dysfunction in children with atopic dermatitis.

BACKGROUND: Children with atopic dermatitis (AD) are often sensitized to food and aeroallergens, but sensitization patterns have not been analysed with biologic measures of disease pathogenicity. OBJECTIVE: We sought to define allergen sensitization grouping(s) using unbiased machine learning and determine their associations with skin filaggrin (FLG) and transepidermal water loss (TEWL) (assesses skin barrier integrity), S100A8 and S100A9 expression (assesses skin inflammation) and AD severity. METHODS: We studied 400 children with AD in the Mechanisms of Progression from Atopic Dermatitis to Asthma in Children (MPAACH) cohort to identify groupings of food and aeroallergen sensitizations. MPAACH is a paediatric AD cohort, aged 1-2, recruited through hospital/community settings between 2016 and 2018. We analysed these groupings' associations with AD biomarkers: skin FLG, S100A8 and S100A9 expression, total IgE, TEWL and AD severity. RESULTS: An unbiased machine learning approach revealed five allergen clusters. The most common cluster (N = 131), SPTPEP, had sensitization to peanut, egg and/or pets. Three low prevalence clusters, which included children with allergen sensitization other than peanut, egg or pets, were combined into SPTOther . SPTNEG included children with no sensitization(s). SPTPEP children had higher median non-lesional TEWL (16.9 g/m2 /h) and IgE (90 kU/L) compared with SPTOTHER (8.8 g/m2 /h and 24 kU/L; p = .01 and p < .001) and SPTNEG (9 g/m2 /h and 26 kU/L; p = .003 and p < .001). SPTPEP children had lower median lesional (0.70) and non-lesional (1.09) FLG expression compared with SPTOTHER (lesional: 0.9; p = .047, non-lesional: 1.78; p = .01) and SPTNEG (lesional: 1.47; p < .001, non-lesional: 2.21; p < .001). There were no differences among groupings in S100A8 or S100A9 expression. CONCLUSIONS AND CLINICAL RELEVANCE: In this largely clinic-based cohort of young children with AD, allergic sensitization to peanut, egg, cat or dog was associated with more severe disease and skin barrier function but not markers of cutaneous inflammation. These data need replicating in a population-based cohort but may have important implications for understanding the interaction between AD and allergic sensitization.

On the surface: Skin microbial exposure contributes to allergic disease.

OBJECTIVE: To discuss the skin microbiome modulates immunity by interactions between skin immunology with keratinocytes to combat pathogens. Allergic disorders are classified by immunoglobulin E sensitivity and aberrant TH2 cell responses, and an increasing number of studies have described the associations with skin microbiome fluctuations. In this review, we discuss commensal-epidermal homeostasis and its influence on allergic disease. DATA SOURCES: All included references were obtained from the PubMed database. STUDY SELECTIONS: Studies addressing relevant aspects of commensal-epidermal homeostasis, skin microbiome dysbiosis, microbiome-targeted therapeutics, and prevention in allergy were included. RESULTS: Homeostasis between the commensal microbiome and the epidermis is important in protecting against allergic disease. Commensals promote antiallergic TH1 and TH17 immunophenotypes within the skin and induce keratinocytes to secrete antimicrobial peptides and alarmins that enhance barrier function and antagonize proallergic organisms. Perturbations in this homeostasis, however, is associated with allergic disease development. Atopic dermatitis is associated with decreases in skin commensals and increases in the pathogen, Staphylococcus aureus. Fluctuations in the skin microbiome contributes to decreased barrier dysfunction, allergic sensitization, and TH2 cytokine secretion. Little is known about how the skin microbiome affects food allergy, allergic rhinitis, and asthma, and it is poorly understood how cutaneous inflammation influences systemic allergic responses. Therapies are targeted toward maintenance of the skin barrier, replacement of healthy commensals, and anti-TH2 biologic therapy. CONCLUSION: Although the effects of commensal-epidermal homeostasis on allergy within the skin are becoming increasingly clear, future studies are necessary to assess its effects on extracutaneous allergic disorders and explore potential therapeutics targeting the skin microbiome.

Association of food allergy and decreased lung function in children and young adults with asthma.

BACKGROUND: Food allergy (FA) appears early in the atopic march, a progression that may lead to the development of asthma. The association between FA and pulmonary function in children with and without asthma remains unknown. OBJECTIVE: To investigate the association between FA and lung function in children with and without asthma. METHODS: We enrolled 1,068 children as a part of a family-based FA cohort. We then categorized children as having FA by physician diagnosis, evidence of specific IgE, and typical symptoms within 2 hours of food ingestion. We categorized asthma by physician diagnosis. We used American Thoracic Society criteria for spirometry measurements. We assessed the effects of asthma classification and FA number on lung function using mixed-effect models. RESULTS: We enrolled 1,068 children: 417 (39%) had asthma, 402 (38%) had at least 1 FA, and 162 (15%) had 2 or more FAs. Unstratified analyses found no significant association between FA number and lung function. In children with asthma, we detected statistically significant differences in predicted forced expiratory flow at 25% to 75% between children with 2 or more FAs compared with those with none (mean [SE] ß = -7.5 [3.6]; P = .04). This effect lost significance after adjusting for aeroallergen sensitization. We detected no significant associations between FA number and predicted forced expiratory volume in 1 second, forced vital capacity, and ratio of forced expiratory volume in 1 second to forced vital capacity. CONCLUSION: Having 2 or more FAs is a potential risk factor for greater small airway airflow obstruction among children with asthma, highlighting the need for close clinical follow-up and improved intervention strategies for these patients.

Events in Normal Skin Promote Early-Life Atopic Dermatitis-The MPAACH Cohort.

BACKGROUND: Nonlesional skin in atopic dermatitis (AD) is abnormal, but the pathobiology of lesional and nonlesional skin and the definition of endotypes are poorly understood. OBJECTIVE: To define lesional and nonlesional endotypes of AD by building the first US-based early-life prospective cohort of children with AD, the Mechanisms of Progression from AD to Asthma in Children cohort. METHODS: We assessed lesional and nonlesional skin transepidermal water loss, filaggrin (FLG) and alarmin (S100A8, S100A9) expression, staphylococcal colonization, and patterns of aeroallergen and food sensitization to define nonlesional and lesional phenotypes and endotypes. RESULTS: Pathophysiologic changes were present in lesional and nonlesional skin and were associated with SCORing for Atopic Dermatitis. Nonlesional skin had features characteristic of diseased skin including low FLG and high alarmin expression, and increased colonization with Staphylococcus aureus. In a multivariate model, nonlesional, but not lesional, FLG expression was associated with the development of cosensitization and moderate to severe AD. Lesional skin was characterized by further deficits in FLG expression (P < .001), but alarmin expression was the same as observed in nonlesional skin. CONCLUSIONS: This study reveals that events in the nonlesional, not the lesional, skin promote the subsequent development of AD severity and cosensitization, which is a key risk factor for allergic comorbidities. Collectively, these data suggest the presence of a subclinical eczema endotype that may predispose to the development of allergic disease in the absence of overt eczema. This may represent a new definition of the atopic march that starts with skin barrier dysfunction rather than eczema.

Fetal cord blood and tissue immune responses to chronic placental inflammation and chorioamnionitis.

BACKGROUND: Chorioamnionitis is a risk factor for future asthma development. Animal models of chorioamnionitis demonstrate increased TH17-to-Treg ratios associated with proinflammatory cytokine elevations. The association of chorioamnionitis on human neonatal immune cells systemically and within tissues is not known. METHODS: We enrolled two cohorts to evaluate TH17 and regulatory T cell (Treg) phenotypic markers in chorioamnionitis. From a cohort of 19 live birth infants, we collected cord blood and placenta samples to evaluate for signs of acute and chronic histologic inflammation and cell phenotype characterization. We analyzed a second cohort of stillborn infants with and without chorioamnionitis to classify and enumerate cell infiltrate phenotypes in the spleen, thymus, and lung. We used linear regression analysis determine the association of retinoic acid-related orphan receptor gamma t positive (RORγt+) and Treg cell frequency with different types of inflammation seen in the live cohort subjects. Using linear mixed models, we evaluated for any associations between chorioamnionitis and T- and B-cell with a logarithmic scale for level of expression of cellular markers. We then performed Wilcoxon rank sum tests to assess the associations between cell count and chorioamnionitis. RESULTS: In the live birth subjects with chronic placental inflammation we observed an increased proportion of RORγt+ cells in Foxp3+ cells, regardless of the presence of acute inflammation, compared to subjects with neither acute nor chronic inflammation. We also found an increased proportion of RORγt+ cells within Foxp3+ cells in subjects with acute high stage fetal and maternal inflammation compared to those without acute or chronic inflammation. In the stillborn subjects with chorioamnionitis, we observed a decrease in splenic Foxp3+ cells and an increase in lung CD3+ cells compared with subjects that did not have chorioamnionitis. CONCLUSION: Exposure to chorioamnionitis in utero may affect immune activation in neonates with an increased frequency of RORγt+ cells systemically as well as lymphocytic infiltrate in the lung. Our findings suggest an increase in RORγt+ cells during chorioamnionitis and thus may support the known associations between chorioamnionitis with asthma.

Decreasing Duration of Antibiotic Prescribing for Uncomplicated Skin and Soft Tissue Infections.

BACKGROUND AND OBJECTIVE: Short courses of antibiotics are often indicated for uncomplicated skin and soft tissue infections (uSSTIs). Our objective was to decrease duration of antibiotics prescribed in children hospitalized for uSSTIs by using quality improvement (QI) methods. METHODS: QI methods were used to decrease duration of antibiotics prescribed upon hospital discharge for uSSTIs. We sought to accomplish this goal by increasing outpatient prescriptions for short courses of therapy (≤7 days). Key drivers included awareness of evidence among physicians, changing the culture of prescribing, buy-in from prescribers, and monitoring of prescribing. Physician education, modification of antibiotic order sets for discharge prescriptions, and continual identification and mitigation of therapy plans, were key interventions implemented by using plan-do-study-act cycles. A run chart assessed the impact of the interventions over time. RESULTS: We identified 641 index admissions for uSSTIs over a 23-month period for patients aged >90 days to 18 years. The proportion of children discharged with short courses of antibiotics increased from a baseline median of 23% to 74%, which was sustained for 6 months. Differences in the proportion of children admitted for treatment failure or recurrence before and after project initiation were not significant. CONCLUSIONS: Using QI methodology, we decreased duration of antibiotics prescribed in children hospitalized for uSSTIs by increasing prescriptions for short courses of antibiotics. Modification of electronic order sets for discharge prescriptions allowed for sustained improvement in prescribing practices. Our findings support the use of shorter outpatient antibiotic courses in most children with uSSTIs, and suggest criteria for complicated SSTIs.

Caustic ingestions mimicking anaphylaxis: case studies and literature review.

Anaphylaxis presents in children with rapid involvement of typically 2 or more organ systems including cutaneous, gastrointestinal, and respiratory. Caustic ingestions (CI) may also present with acute involvement of cutaneous, gastrointestinal, and respiratory systems. We present 2 cases of "missed diagnosis" that illustrate how CI presenting with respiratory symptoms can be mistaken for anaphylaxis owing to these similarities. Both of these patients had delay in appropriate care for CI as a result. These cases demonstrate the importance of considering CI in children who have gastrointestinal symptoms, respiratory distress, and oropharyngeal edema.