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BACKGROUND: Thymic stromal lymphopoietin (TSLP) is an epithelial-derived cytokine important in initiation of allergic inflammation. Single nucleotide polymorphisms (SNPs) in TSLP are associated with asthma, yet studies have shown inconsistent associations between circulating TSLP and asthma. Studies that integrate the combined effects of TSLP genotype, TSLP mRNA, circulating TSLP levels, and asthma outcome are lacking. OBJECTIVE: To recruit a novel cohort based on asthma-relevant TSLP SNPs and determine their impact on TSLP mRNA expression and TSLP circulating protein levels, and their individual and combined effects on asthma. METHODS: We developed an algorithm to prioritize TSLP SNPs and recruited 51 carriers and non-carriers based on TSLP genotypes. We quantified TSLP mRNA in nasal epithelial cells and circulating TSLP levels in plasma. We determined associations of defined TSLP risk genotypes and/or TSLP mRNA and protein levels with asthma. RESULTS: TSLP mRNA expression, but not circulating TSLP, was significantly increased in asthmatics compared to non-asthmatics (P=0.007; OR=1.44). Notably, 90% of children with the defined TSLP risk genotypes and high nasal TSLP mRNA expression (top tertile) had asthma compared to 40% of subjects without risk genotypes and with low TSLP expression (bottom tertile) (P=0.024). No association between circulating TSLP and asthma was observed. CONCLUSION: Collectively, these data suggest childhood asthma is modified by the combined effects of TSLP genotype and TSLP expression in the nasal epithelium. The increased asthma risk likely manifests when genetic variation enables eQTL in the TSLP locus to elevate TSLP. It is important to consider both biomarkers when factoring asthma risk. CLINICAL IMPLICATIONS: TSLP genotype and nasal mRNA expression may be useful biomarkers to aid asthma prediction and/or identify individuals who would benefit from therapy targeting this pathway.

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), SPT(PEP,) 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 SPT(Other). SPT(NEG) included children with no sensitization(s). SPT(PEP) children had higher median non-lesional TEWL (16.9 g/m(2)/h) and IgE (90 kU/L) compared with SPT(OTHER) (8.8 g/m(2)/h and 24 kU/L; p = .01 and p < .001) and SPT(NEG) (9 g/m(2)/h and 26 kU/L; p = .003 and p < .001). SPT(PEP) children had lower median lesional (0.70) and non-lesional (1.09) FLG expression compared with SPT(OTHER) (lesional: 0.9; p = .047, non-lesional: 1.78; p = .01) and SPT(NEG) (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.

Background Atopic dermatitis (AD) patients are often colonized with Staphylococcus aureus, and staphylococcal biofilms have been reported on adult AD skin lesions. The commensal S epidermidis can antagonize S aureus, although its role in AD is unclear. We sought to characterize S aureus and S epidermidis colonization and biofilm propensity and determine their associations with AD severity, barrier function, and epidermal gene expression in the first US early-life cohort of children with AD, the Mechanisms of Progression of Atopic Dermatitis to Asthma in Children (MPAACH). Methods The biofilm propensity of staphylococcal isolates was assessed by crystal violet assays. Gene expression of filaggrin and antimicrobial alarmins S100A8 and S100A9 was measured in keratinocyte RNA extracted from skin tape strips. Staphylococcal biofilms sampled from MPAACH skin were visualized using scanning electron microscopy. Results Sixty-two percent of staphylococcal isolates (sampled from 400 subjects) formed moderate/strong biofilms. Sixty-eight percent of subjects co-colonized with both staphylococcal species exhibited strains that formed cooperative mixed-species biofilms. Scanning electron microscopy verified the presence of staphylococcal biofilms on the skin of MPAACH children. Staphylococcus aureus strains showing higher relative biofilm propensity compared with S epidermidis were associated with increased AD severity (P = .03) and increased lesional and nonlesional transepidermal water loss (P = .01, P = .03). Conclusions Our data suggest a pathogenic role for S aureus biofilms in AD. We found that strain-level variation in staphylococcal isolates governs the interactions between S epidermidis and S aureus and that the balance between these two species, and their biofilm propensity, has important implications for AD.

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.

BACKGROUND: Mold sensitization and exposure are associated with asthma severity, but the specific species that contribute to difficult-to-control (DTC) asthma are unknown. OBJECTIVE: To determine the association between overall and specific mold levels in the homes of urban children and DTC asthma. METHODS: The Asthma Phenotypes in the Inner-City (APIC) study recruited participants, 6 to 17 years of age, from eight US cities and classified each participant as having either DTC asthma or easy-to-control (ETC) asthma based on treatment step level. Dust samples had been collected in each participant’s home (n=485) and any dust remaining (n=265 samples), after other analyses, were frozen at −20°C. The dust samples (n=265) were analyzed using qPCR to determine the concentrations of the 36 molds in the Environmental Relative Moldiness Index (ERMI). Logistic regression was performed to discriminate specific mold content of dust from homes of children with DTC versus ETC asthma. RESULTS: Frozen-dust samples were available from 54% of homes of children with DTC (139/253) and ETC asthma (126/232). Only the average concentration of the mold Mucor was significantly (p

Early sensitization is ~50% higher in children with atopic dermatitis compared to children from a high-risk allergy cohort with comparable rates of parental atopy. AD may increase sensitization risk over heredity alone.

Background Low epidermal filaggrin (FLG) is a risk factor for atopic dermatitis (AD) and allergic comorbidity. FLG mutations do not fully explain the variation in epidermal FLG levels, highlighting that other genetic loci may also regulate FLG expression. Objective We sought to identify genetic loci that regulate FLG expression and elucidate their functional and mechanistic consequences. Methods A genome-wide association study of quantified skin FLG expression in lesional and baseline non(never)-lesional skin of children with AD in the Mechanisms of Progression of Atopic Dermatitis to Asthma in Children cohort was conducted. Clustered regularly interspaced short palindromic repeat approaches were used to create isogenic human keratinocytes differing only at the identified variant rs11652075, and caspase recruitment domain family member 14 (CARD14)-deficient keratinocytes for subsequent mechanistic studies. Results The genome-wide association study identified the CARD14 rs11652075 variant to be associated with FLG expression in non(never)-lesional skin of children with AD. Rs11652075 is a CARD14 expression quantitative trait locus in human skin and primary human keratinocytes. The T variant destroys a functional cytosine-phosphate-guanine site, resulting in reduced cytosine-phosphate-guanine methylation at this site (but not neighboring sites) in TT and CT compared with CC primary human keratinocytes and Mechanisms of Progression of Atopic Dermatitis to Asthma in Children children's skin samples, and rs11652075 increases CARD14 expression in an allele-specific fashion. Furthermore, studies in clustered regularly interspaced short palindromic repeat-generated CC and TT isogenic keratinocytes, as well as CARD14-haplosufficient and deficient keratinocytes, reveal that IL-17A regulates FLG expression via CARD14, and that the underlying mechanisms are dependent on the rs11652075 genotype. Conclusions Our study identifies CARD14 as a novel regulator of FLG expression in the skin of children with AD. Furthermore, CARD14 regulates skin FLG homeostasis in an rs11652075-dependent fashion.

BACKGROUND Second-hand smoke (SHS) exposure is associated with paediatric asthma, and oxidative stress is believed to play a role in mediating this association. The nuclear factor (erythroid-derived 2)-like 2 (NFE2L2) is important for the defence against oxidative stress. OBJECTIVE To explore interactions between NFE2L2 genotype and SHS exposure in paediatric asthma risk. METHODS We used a genotyped subset of patients of European ancestry (N = 669, median age at enrolment = 6.8 years) enrolled in the clinical cohort Greater Cincinnati Pediatric Clinic Repository as the study population, and a population-based paediatric cohort (N = 791) to replicate our findings. History of asthma diagnosis was obtained from medical records, and SHS exposure was obtained from questionnaires. Four NFE2L2 tagging SNPs were included in the analysis, and interactions between SHS and NFE2L2 genotype were evaluated using logistic regression. RESULTS Three of the analysed SNPs, rs10183914, rs1806649 and rs2886161, interacted significantly with SHS exposure to increase asthma risk (p ≤ .02). The interaction was replicated in an independent cohort for rs10183914 (p = .04). Interactions between SHS exposure and NFE2L2 genotype were also associated with an increased risk of hospitalization (p = .016). In stratified analyses, NFE2L2 genotype was associated with daily asthma symptoms in children with SHS exposure (OR = 3.1; p = .048). No association was found in children without SHS exposure. Examination of publicly available chromatin immunoprecipitation followed by sequencing (ChIP-seq) data sets confirmed the presence of active histone marks and binding sites for particular transcription factors overlapping the coordinates for the significantly associated SNPs. CONCLUSIONS AND CLINICAL RELEVANCE Our study provides evidence that NFE2L2 genotype interacts with SHS exposure to affect both asthma risk and severity in children and identifies a population of children at increased risk of asthma development.

BACKGROUND: Non-lesional skin in atopic dermatitis (AD) is abnormal, but the pathobiology of lesional and non-lesional skin and the definition of endotypes are poorly understood. OBJECTIVE: To define lesional and non-lesional 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 (MPAACH) cohort. METHODS: We assessed lesional and non-lesional skin TEWL, filaggrin (FLG) and alarmin (S100A8, S100A9) expression, staphylococcal colonization, and patterns of aeroallergen and food sensitization to define non-lesional and lesional phenotypes and endotypes. RESULTS: Pathophysiologic changes were present in lesional and non-lesional skin and were associated with SCORAD. Non-lesional skin had features characteristic of diseased skin including low FLG and high alarmin expression, and increased colonization with S. aureus. In a multivariate model, non-lesional, but not lesional, FLG expression was associated with the development of co-sensitization and moderate-severe AD. Lesional skin was characterized by further deficits in FLG expression (p

Adequate nutrition is essential for growth in children with cystic fibrosis (CF). The new CF Foundation Clinical Practice Guidelines bring attention to monitoring macronutrient intake as well as total energy.Dietary intake of 75 preschool children with CF and pancreatic insufficiency was examined and compared to the Clinical Practice Guidelines. Regression analyses examined relationships between macronutrient intake and growth.Approximately 45% of children met the 110% minimum recommended dietary allowance (RDA) recommendation. Children consumed 35.3% (6.1) of total daily energy intake from fat, 12.7% (1.7) from protein, and 52.0% (6.1) from carbohydrates. Percent energy from protein was associated with height growth.Many preschoolers with CF are not meeting nutrition benchmarks for total energy and fat. To optimize nutrition early, dietary monitoring with frequent individualized feedback is needed. Optimizing intake of macronutrients that promote growth, especially fat and protein, should be a primary clinical target.

We compared headache frequency trajectories between clinical trial participants who received cognitive-behavioral therapy (CBT) and amitriptyline (CBT+A) or headache education (HE) and amitriptyline (HE+A) to determine if there was a differential time course of treatment response between the groups. One hundred thirty-five patients (age 10–17 years) diagnosed with chronic migraine participated, attending 8 one-hour one-on-one CBT or HE sessions with a trained psychologist for 8 weekly sessions, 2 sessions at weeks 12 and 16, and a post-treatment visit at week 20. Participants kept daily headache diaries and completed take-home assignments between visits. Data from daily headache diaries are presented for each day and according to 28-day periods. Trajectories of improvement indicate initial decrease in headache days began during the first month of treatment, for both groups, and continued to decrease throughout treatment. The CBT+A group had greater daily improvement than the HE+A group. A significantly greater proportion of the CBT+A group had a ≥50% reduction in headache days each month, and a significantly greater proportion of the CBT+A group had ≤4 headache days per month in months 3 through 5. Results indicate the trajectory of decrease in headache days is significantly better for patients receiving CBT+A versus HE+A. Perspective This article presents daily information about headache frequency over a 20-week clinical trial. Youth with chronic migraine who received CBT+A improved faster than those in the control group. Findings provide clinicians with evidence-based expectations for treatment response over time and ways of monitoring treatment success. Trial registration clinicaltrials.gov identifier NCT00389038 .

Objective: Little is known about weight status and its effects on clinical course during hospitalization for asthma exacerbation. We sought to evaluate associations between weight status, specifica...

BACKGROUND: Asthma phenotypes are currently not amenable to primary prevention or early intervention because their natural history cannot be reliably predicted. Clinicians remain reliant on poorly predictive asthma outcome tools because of a lack of better alternatives.OBJECTIVE: We sought to develop a quantitative personalized tool to predict asthma development in young children.METHODS: Data from the Cincinnati Childhood Allergy and Air Pollution Study (n = 762) birth cohort were used to identify factors that predicted asthma development. The Pediatric Asthma Risk Score (PARS) was constructed by integrating demographic and clinical data. The sensitivity and specificity of PARS were compared with those of the Asthma Predictive Index (API) and replicated in the Isle of Wight birth cohort.RESULTS: PARS reliably predicted asthma development in the Cincinnati Childhood Allergy and Air Pollution Study (sensitivity = 0.68, specificity = 0.77). Although both the PARS and API predicted asthma in high-risk children, the PARS had improved ability to predict asthma in children with mild-to-moderate asthma risk. In addition to parental asthma, eczema, and wheezing apart from colds, variables that predicted asthma in the PARS included early wheezing (odds ratio [OR], 2.88; 95% CI, 1.52-5.37), sensitization to 2 or more food allergens and/or aeroallergens (OR, 2.44; 95% CI, 1.49-4.05), and African American race (OR, 2.04; 95% CI, 1.19-3.47). The PARS was replicated in the Isle of Wight birth cohort (sensitivity = 0.67, specificity = 0.79), demonstrating that it is a robust, valid, and generalizable asthma predictive tool.CONCLUSIONS: The PARS performed better than the API in children with mild-to-moderate asthma. This is significant because these children are the most common and most difficult to predict and might be the most amenable to prevention strategies.

Objective The purpose of this investigation was to examine treatment adherence to medication and lifestyle recommendations among pediatric migraine patients using electronic monitoring systems. Background Nonadherence to medical treatment is a significant public health concern, and can result in poorer treatment outcomes, decreased cost-effectiveness of medical care, and increased morbidity. No studies have systematically examined adherence to medication and lifestyle recommendations in adolescents with migraine outside of a clinical trial. Methods Participants included 56 adolescents ages 11-17 who were presenting for clinical care. All were diagnosed with migraine with or without aura or chronic migraine and had at least 4 headache days per month. Medication adherence was objectively measured using electronic monitoring systems (Medication Event Monitoring Systems technology) and daily, prospective self-report via personal electronic devices. Adherence to lifestyle recommendations of regular exercise, eating, and fluid intake were also assessed using daily self-report on personal electronic devices. Results Electronic monitoring indicates that adolescents adhere to their medication 75% of the time, which was significantly higher than self-reported rates of medication adherence (64%). Use of electronic monitoring of medication detected rates of adherence that were significantly higher for participants taking once daily medication (85%) versus participants taking twice daily medication (59%). Average reported adherence to lifestyle recommendations of consistent noncaffeinated fluid intake (M = 5 cups per day) was below recommended levels of a minimum of 8 cups per day. Participants on average also reported skipping 1 meal per week despite recommendations of consistently eating three meals per day. Conclusions Results suggest that intervention focused on adherence to preventive treatments (such as medication) and lifestyle recommendations may provide more optimal outcomes for children and adolescents with migraine and their families. Once daily dosing of medication may be preferred to twice daily medication for increased medication adherence among children and adolescents.

Atopic dermatitis (AD) is a common chronic inflammatory disease associated with skin barrier dysfunction. AD often precedes the development of atopic co-morbidities, including food allergy, asthma and allergic rhinitis. The contributions of natural killer (NK) cells to pathogenesis of AD and progression to allergic disease are unclear. Peripheral blood mononuclear cells (PBMCs) were isolated from blood samples collected from n=82 children participating in the Mechanisms of Progression of Atopic Dermatitis to Asthma (MPAACH) study, a cohort of toddlers with AD. The children underwent skin prick testing to 11 aeroallergens and 6 foods, and wheezing was defined as one or more episodes of wheezing in the past 12 months. We used flow cytometry to evaluate the phenotype of NK cells in patient PBMC from MPAACH subjects. Our analyses revealed that CD56brightNK cells derived from sensitized children expressed significantly less NKG2D (73.8 ± 3.0 % versus 82.3 ± 2.7 %, respectively, p=0.020) and more TIM-3 (440 ± 462 versus 353 ± 391 median fluorescence intensity, respectively, p=0.085) compared to non-sensitized children. Increased expression of TIM-3 on CD56neg NK cells was also associated with wheezing (47.5 ± 0.51 % versus 19.2 ± 0.40 %, p=0.020). Collectively, these observations suggest that changes within the NK-cell repertoire may promote progressive development of AD and atopic co-morbidities in early life.

Background Asthma is an allergic airway inflammation-driven disease that affects more than 300 million people world-wide. Targeted therapies for asthma are largely lacking. Although asthma symptoms can be prevented from worsening, asthma development cannot be prevented. Cdc42 GTPase has been shown to regulate actin cytoskeleton, cell proliferation and survival. Objectives To investigate the role and targeting of Cdc42 in Th2 cell differentiation and Th2-mediated allergic airway inflammation. Methods Post-thymic Cdc42-deficient mice were generated by crossing Cdc42flox/flox mice with dLckicre transgenic mice in which Cre expression is driven by distal Lck promoter. Effects of post-thymic Cdc42 deletion and pharmacological targeting Cdc42 on Th2 cell differentiation were evaluated in vitro under Th2-polarized culture conditions. Effects of post-thymic Cdc42 deletion and pharmacological targeting Cdc42 on allergic airway inflammation were evaluated in ovalbumin- and/or house dust mite-induced mouse models of asthma. Results Post-thymic deletion of Cdc42 led to reduced peripheral CD8+ T cells and attenuated Th2 cell differentiation, with no effect on closely related Th1, Th17 and induced regulatory T (iTreg) cells. Post-thymic Cdc42 deficiency ameliorated allergic airway inflammation. The selective inhibition of Th2 cell differentiation by post-thymic deletion of Cdc42 was recapitulated by pharmacological targeting of Cdc42 with CASIN, a Cdc42 activity-specific chemical inhibitor. CASIN also alleviated allergic airway inflammation. CASIN-treated Cdc42-deficient mice showed comparable allergic airway inflammation to vehicle-treated Cdc42-deficient mice, indicative of negligible off-target effect of CASIN. CASIN had no effect on established allergic airway inflammation. Conclusion and clinical relevance Cdc42 is required for Th2 cell differentiation and allergic airway inflammation, and rational targeting Cdc42 may serve as a preventive but not therapeutic approach for asthma control.

BACKGROUND: Large-scale, multisite studies in which researchers evaluate patient- and systems-level factors associated with pediatric asthma exacerbation outcomes are lacking. We sought to investigate patient-level risks and system-level practices related to physiologic readiness for discharge (PRD) in the prospective Ohio Pediatric Asthma Repository. METHODS: Participants were children ages 2 to 17 years admitted to an Ohio Pediatric Asthma Repository hospital for asthma exacerbation. Demographics, disease characteristics, and individual hospital practices were collected. The primary outcome was PRD timing (hours from admission or emergency department [ED] presentation until the first 4-hour albuterol spacing). RESULTS: Data for 1005 participants were available (865 ED presentations). Several nonstandard care practices were associated with time to PRD (P < .001). Continuous pulse oximetry was associated with increased time to PRD (P = .004). ED dexamethasone administration was associated with decreased time to PRD (P < .001) and less ICU admittance and intravenous steroid use (P < .0001). Earlier receipt of chest radiograph, antibiotics, and intravenous steroids was associated with shorter time to PRD (P < .05). Care practices associated with shorter time to PRD varied markedly by hospital. CONCLUSIONS: Substantial variation in care practices for inpatient asthma treatment exists among children’s hospital systems in Ohio. We found several modifiable, system-level factors and therapies that contribute to PRD that warrant further investigation to identify the best and safest care practices. We also found that there was no standardized measure of exacerbation severity used across the hospitals. The development of such a tool is a critical gap in current practice and is needed to enable definitive comparative effectiveness studies of the management of acute asthma exacerbation.

Objectives To examine treatment adherence among children and adolescents with chronic migraine who volunteered to be in a clinical trial using 3 measures: treatment session attendance, therapy homework completion, and preventive medication use by daily diary. Materials and methods Analyses are secondary from a trial of 135 youth aged 10 to 17 years diagnosed with chronic migraine and with a Pediatric Migraine Disability Score over 20. Participants were randomly assigned to cognitive-behavioral therapy plus amitriptyline (CBT+A, N=64) or headache education plus amitriptyline (HE+A, N=71). Therapists recorded session attendance. Completion of homework/practice between sessions was reported to therapists by patients. Patients reported preventive medication adherence using a daily headache diary. Results Mean session attendance adherence out of 10 treatment sessions was 95% for CBT+A and 99% for HE+A. CBT+A participants reported completing a mean of 90% of home practice of CBT skills between the 10 sessions. Participants reported taking amitriptyline daily at a mean level of 90% when missing diaries were excluded and 79% when missing diaries were considered as missed doses of medication. Discussion Our findings demonstrate that youth with chronic migraine who agree to be a part of a clinical trial do quite well at attending therapy sessions, and report that they are adherent to completing home/practice between sessions and taking medication. These results lend further support to consideration of CBT+A as a first-line treatment for youth with chronic migraine and suggest that measurement of adherence when this treatment is provided in practice will be important.