Search

Asthma is a disorder of the lower airways, characterized by bronchial hyperresponsiveness and airflow limitation, the pathogenesis of which is yet to be fully understood. Regardless of its triggers, asthma's hallmark is a state of inflammation that, when uncontrolled, results in persistence of symptoms. Inhaled corticosteroids are established as the mainstay of asthma therapy. This paper examines what is currently available among this class of drugs, features of the ideal inhaled corticosteroid, the delivery systems, dose-response relationships, adverse effects, combination with long-acting beta agonists, equipotent doses among the different types, and several special scenarios that involve the apparent incomplete or lack of response to treatment with inhaled corticosteroids among certain subgroups of patients, such as smokers and obese individuals, and we will discuss the scientific basis of such resistance and suggest alternative approaches to therapy. [ABSTRACT FROM AUTHOR]

Background: Most genetic studies of asthma and allergy have focused on common variation in individuals primarily of European ancestry. Studying the role of rare variation in quantitative phenotypes and in asthma phenotypes in populations of diverse ancestries can provide additional, important insights into the development of these traits., Objective: We sought to examine the contribution of rare variants to different asthma- or allergy-associated quantitative traits in children with diverse ancestries and explore their role in asthma phenotypes., Methods: We examined whole-genome sequencing data from children participants in longitudinal studies of asthma (n = 1035; parent-identified as 67% Black and 25% Hispanic) to identify rare variants (minor allele frequency < 0.01). We assigned variants to genes and tested for associations using an omnibus variant-set test between each of 24,902 genes and 8 asthma-associated quantitative traits. On combining our results with external data on predicted gene expression in humans and mouse knockout studies, we identified 3 candidate genes. A burden of rare variants in each gene and in a combined 3-gene score was tested for its associations with clinical phenotypes of asthma. Finally, published single-cell gene expression data in lower airway mucosal cells after allergen challenge were used to assess transcriptional responses to allergen., Results: Rare variants in USF1 were significantly associated with blood neutrophil count (P = 2.18 × 10 -7 ); rare variants in TNFRSF21 with total IgE (P = 6.47 × 10 -6 ) and PIK3R6 with eosinophil count (P = 4.10 × 10 -5 ) reached suggestive significance. These 3 findings were supported by independent data from human and mouse studies. A burden of rare variants in TNFRSF21 and in a 3-gene score was associated with allergy-related phenotypes in cohorts of children with mild and severe asthma. Furthermore, TNFRSF21 was significantly upregulated in bronchial basal epithelial cells from adults with allergic asthma but not in adults with allergies (but not asthma) after allergen challenge., Conclusions: We report novel associations between rare variants in genes and allergic and inflammatory phenotypes in children with diverse ancestries, highlighting TNFRSF21 as contributing to the development of allergic asthma., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Sleep disordered breathing (SDB) may exacerbate asthma and is a treatable comorbidity., Objective: To design and implement a screening process for SDB in patients hospitalized for asthma exacerbation using quality improvement (QI) methods. We sought to improve screening for SDB from zero to 60% from July 2019 to December 2020., Design/methods: A multidisciplinary team used QI methods to screen for SDB using the Michigan pediatric sleep questionnaire (PSQ) in patients 2-18 years hospitalized for asthma exacerbation. Key interventions included: pairing the PSQ screen with another element of routine care (the asthma risk factor screen), educating staff and physicians, engaging respiratory therapists to complete the PSQ and document scores, and modifying the electronic medical record (asthma order set and flowsheet for PSQ score documentation). A run chart tracked progress and descriptive statistics were generated., Results: There were 2067 patients admitted for asthma exacerbation during this project. The PSQ was completed for 1531 patients (74%) overall. Of screened patients, 360 (24%) had a positive PSQ; the mean age was 8.6 years. Approximately 14 months after the project began, ~90% of children admitted for asthma were being screened; subsequently, >80% of patients were being screened until May 2022. Screening with the PSQ occurred approximately 90% of the time when routine asthma risk screens were completed., Conclusion: A screening process for SDB was successfully implemented and appeared feasible and sustainable. The high proportion of positive screens reinforces the importance of evaluating for SDB in the high-risk population of children requiring hospitalization for asthma exacerbation., (© 2023 Wiley Periodicals LLC.)

Background: Asthma prevalence and severity have markedly increased with urbanisation, and children in low-income urban centres have among the greatest asthma morbidity. Outdoor air pollution has been associated with adverse respiratory effects in children with asthma. However, the mechanisms by which air pollution exposure exacerbates asthma, and how these mechanisms compare with exacerbations induced by respiratory viruses, are poorly understood. We aimed to investigate the associations between regional air pollutant concentrations, respiratory illnesses, lung function, and upper airway transcriptional signatures in children with asthma, with particular focus on asthma exacerbations occurring in the absence of respiratory virus., Methods: We performed a retrospective analysis of data from the MUPPITS1 cohort and validated our findings in the ICATA cohort. The MUPPITS1 cohort recruited 208 children aged 6-17 years living in urban areas across nine US cities with exacerbation-prone asthma between Oct 7, 2015, and Oct 18, 2016, and monitored them during reported respiratory illnesses. The last MUPPITS1 study visit occurred on Jan 6, 2017. The ICATA cohort recruited 419 participants aged 6-20 years with persistent allergic asthma living in urban sites across eight US cities between Oct 23, 2006, and March 25, 2008, and the last study visit occurred on Dec 30, 2009. We included participants from the MUPPITS1 cohort who reported a respiratory illness at some point during the follow-up and participants from the ICATA cohort who had nasal samples collected during respiratory illness or at a scheduled visit. We used air quality index values and air pollutant concentrations for PM 2·5 , PM 10 , O 3 , NO 2 , SO 2 , CO, and Pb from the US Environmental Protection Agency spanning the years of both cohorts, and matched values and concentrations to each illness for each participant. We investigated the associations between regional air pollutant concentrations and respiratory illnesses and asthma exacerbations, pulmonary function, and upper airway transcriptional signatures by use of a combination of generalised additive models, case crossover analyses, and generalised linear mixed-effects models., Findings: Of the 208 participants from the MUPPITS1 cohort and 419 participants from the ICATA cohort, 168 participants in the MUPPITS1 cohort (98 male participants and 70 female participants) and 189 participants in the ICATA cohort (115 male participants and 74 female participants) were included in our analysis. We identified that increased air quality index values, driven predominantly by increased PM 2·5 and O 3 concentrations, were significantly associated with asthma exacerbations and decreases in pulmonary function that occurred in the absence of a provoking viral infection. Moreover, individual pollutants were significantly associated with altered gene expression in coordinated inflammatory pathways, including PM 2·5 with increased epithelial induction of tissue kallikreins, mucus hypersecretion, and barrier functions and O 3 with increased type-2 inflammation., Interpretation: Our findings suggest that air pollution is an important independent risk factor for asthma exacerbations in children living in urban areas and is potentially linked to exacerbations through specific inflammatory pathways in the airway. Further investigation of these potential mechanistic pathways could inform asthma prevention and management approaches., Funding: National Institutes of Health, National Institute of Allergy and Infectious Diseases., Competing Interests: Declaration of interests MCA, MK, GTO, RCM, EW, PL, AC, MAG, RSG, AHL, SL-D, JAP, CMK, GKKH, EMZ, SJT, LBB, WWB, JEG, and DJJ report grants from the US National Institutes of Health (NIH), National Institute of Allergy and Infectious Diseases, and Division of Allergy, Immunology, and Transplantation during the conduct of study. MCA reports personal fees for consulting from Regeneron, outside the submitted work. AHL reports personal fees from Phadia ThermoFisher as consulting honoraria; grants and non-financial support from ResMed–Propeller Health; non-financial support from Revenio; grants and personal fees from Avillion; and personal fees from Labcorp, all outside the submitted work. SL-D reports funding from the National Heart, Lung, and Blood Institute (NHLBI) and the Robert Wood Johnson Foundation. JAP reports provisions of study drug for other asthma studies from GlaxoSmithKline, Boehringer Ingelheim, and Genentech–Novartis. CMK reports royalties from UpToDate. SJT reports grant meetings to support the CAUSE network from NIH–NIAID, payment for episode on biologics in asthma care from Medscape, and personal fees from UpToDate, all outside the submitted work. LBB reports personal fees from GlaxoSmithKline, Genentech–Novartis, Teva, AstraZeneca, WebMD–Medscape, DBV Technologies, Sanofi–Regeneron, OM Pharma, Kinaset, Vertex, and the American Board of Allergy and Immunology; non-financial support from the American Academy of Allergy Asthma and Immunology; and royalties from Elsevier, all outside the submitted work. WWB reports personal fees from Novartis, GlaxoSmithKline, Genentech, Sanofi, AstraZeneca, Regeneron, and Elsevier, outside the submitted work. JEG reports personal fees and stock options from Meissa Vaccines, personal fees from AstraZeneca and Ena Therapeutics, and a patent on methods for production of rhinoviruses. DJJ reports personal fees from Novartis, Avillion, Pfizer, AstraZeneca, and Sanofi; grants and personal fees from GlaxoSmithKline and Regeneron; and grants from NIH–NHLBI, all outside the submitted work. LMW, SMS, PJG, and AT declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Background: Asthma is the most common chronic disease in children, occurring at higher frequencies and with more severe disease in children with African ancestry., Methods: We tested for association with haplotypes at the most replicated and significant childhood-onset asthma locus at 17q12-q21 and asthma in European American and African American children. Following this, we used whole-genome sequencing data from 1060 African American and 100 European American individuals to identify novel variants on a high-risk African American-specific haplotype. We characterized these variants in silico using gene expression and ATAC-seq data from airway epithelial cells, functional annotations from ENCODE, and promoter capture (pc)Hi-C maps in airway epithelial cells. Candidate causal variants were then assessed for correlation with asthma-associated phenotypes in African American children and adults., Results: Our studies revealed nine novel African-specific common variants, enriched on a high-risk asthma haplotype, which regulated the expression of GSDMA in airway epithelial cells and were associated with features of severe asthma. Using ENCODE annotations, ATAC-seq, and pcHi-C, we narrowed the associations to two candidate causal variants that are associated with features of T2 low severe asthma., Conclusions: Previously unknown genetic variation at the 17q12-21 childhood-onset asthma locus contributes to asthma severity in individuals with African ancestries. We suggest that many other population-specific variants that have not been discovered in GWAS contribute to the genetic risk for asthma and other common diseases., (© 2022. The Author(s).)

Background: Seasonal variation in respiratory illnesses and exacerbations in pediatric populations with asthma is well described, though whether upper airway microbes play season-specific roles in these events is unknown., Objective: We hypothesized that nasal microbiota composition is seasonally dynamic and that discrete microbe-host interactions modify risk of asthma exacerbation in a season-specific manner., Methods: Repeated nasal samples from children with exacerbation-prone asthma collected during periods of respiratory health (baseline; n = 181 samples) or first captured respiratory illness (n = 97) across all seasons, underwent bacterial (16S ribosomal RNA gene) and fungal (internal transcribed spacer region 2) biomarker sequencing. Virus detection was performed by multiplex PCR. Paired nasal transcriptome data were examined for seasonal dynamics and integrative analyses., Results: Upper airway bacterial and fungal microbiota and rhinovirus detection exhibited significant seasonal dynamics. In seasonally adjusted analysis, variation in both baseline and respiratory illness microbiota related to subsequent exacerbation. Specifically, in the fall, when respiratory illness and exacerbation events were most frequent, several Moraxella and Haemophilus members were enriched both in virus-positive respiratory illnesses and those that progressed to exacerbations. The abundance of 2 discrete bacterial networks, characteristically comprising either Streptococcus or Staphylococcus, exhibited opposing interactions with an exacerbation-associated SMAD3 nasal epithelial transcriptional module to significantly increase the odds of subsequent exacerbation (odds ratio = 14.7, 95% confidence interval = 1.50-144, P = .02; odds ratio = 39.17, 95% confidence interval = 2.44-626, P = .008, respectively)., Conclusions: Upper airway microbiomes covary with season and with seasonal trends in respiratory illnesses and asthma exacerbations. Seasonally adjusted analyses reveal specific bacteria-host interactions that significantly increase risk of asthma exacerbation in these children., (Copyright © 2022. Published by Elsevier Inc.)

Background: Asthma is heterogeneous, contributing to difficulty in disease management., Objective: To develop a biomarker-informed treatment model for difficult-to-treat (DTT) asthma and conduct a pilot feasibility study., Methods: School-aged children (n = 21) with DTT asthma were enrolled and completed 3 medical visits (V1-V3). V2 and V3 were completed approximately 3.5 months and 12 months after V1, respectively. At V1, guideline care and adherence interventions were initiated, and blood samples were collected for asthma biomarker assessment. A personalized treatment algorithm was developed based on biomarkers (treatment by endotype) and was implemented at V2. Asthma outcomes were compared from V1 to V2 (guideline-based care) to V2 to V3 (guideline + biomarker-informed care)., Results: Overall retention was 86%. There was an even distribution of participants with allergy, without allergy, and with mixed allergies. The participants received an average of 5.9 interventions (range, 3-9). The allergic phenotype was characterized by increased CDHR3 risk genotype and high transepidermal water loss. High serum interleukin-6 level was most notable in the mixed allergic subgroup. The nonallergic phenotype was characterized by vitamin D deficiency and poor steroid treatment responsiveness. The personalized treatment plans were associated with decreased emergency department visits (median, 1 vs 0; P = .04) and increased asthma control test scores (median, 22.5 vs 23.0; P = .01)., Conclusion: The biomarker-based treatment algorithm triggered interventions on top of guideline care in all children with DTT asthma studied, supporting the need for this type of multipronged approach. Our findings identify the minimal biomarker set that is informative, reveal that this treatment-by-endotype intervention is feasible and may be superior to guideline care alone, and provide a strong foundation for a definitive trial., Trial Registration: ClinicalTrials.gov identifier: NCT04179461., (Copyright © 2022 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

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: We sought 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 study recruited participants, aged 6 to 17 years, from 8 US cities and classified each participant as having either DTC asthma or easy-to-control (ETC) asthma on the basis of 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, was frozen at -20 o C. The dust samples (n = 265) were analyzed using quantitative PCR to determine the concentrations of the 36 molds in the Environmental Relative Moldiness Index. 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 of 253) and ETC asthma (126 of 232). Only the average concentration of the mold Mucor was significantly (P < .001) greater in homes of children with DTC asthma. In homes with window air-conditioning units, the Mucor concentration contributed about a 22% increase (1.6 odds ratio; 95% CI, 1.2-2.2) in the ability to discriminate between cases of DTC and ETC asthma., Conclusions: Mucor levels in the homes of urban youth were a predictor of DTC asthma, and these higher Mucor levels were more likely in homes with a window air-conditioner., (Copyright © 2021 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Objectives: Dexamethasone is increasingly used for the management of children hospitalized with asthma in place of prednisone, yet data regarding the effectiveness of dexamethasone in children with asthma exacerbation severe enough to require hospitalization are limited. Our objective is to compare the effectiveness of dexamethasone versus prednisone in children hospitalized with an asthma exacerbation on 30-day reutilization., Methods: We conducted a retrospective cohort study at an urban, quaternary children's hospital of children aged 4 to 17 years, hospitalized from January 1, 2014 to December 31, 2017, with a primary discharge diagnosis of asthma. A covariate-balanced propensity score was derived to account for physician discretion in steroid selection. A generalized linear model, including inverse probability treatment weighting, was used to detect differences in 30-day return utilization (unplanned readmission or emergency department visit) between children whose first dose of corticosteroid was dexamethasone versus prednisone., Results: Inclusion criteria were met by 1161 patients, of which 510 (44%) first received dexamethasone versus 651 (56%) who first received prednisone. The total cohort had a mean age of 8.5 years (SD 3.4). The covariate-balanced cohort had no significant differences in demographic characteristics or illness severity between groups. The dexamethasone group had a return utilization of 3.9% (20 of 510) versus 2.2% (14 of 651) for children treated with prednisone. The propensity score-adjusted analysis revealed the steroid treatment was not found to significantly affect the 30-day reutilization (adjusted odds ratio [aOR] 1.61; 95%CI 0.80-3.31)., Conclusions: The initial steroid choice (dexamethasone versus prednisone) was not associated with 30-day reutilization after hospitalization for an asthma exacerbation., (Copyright © 2022 by the American Academy of Pediatrics.)

Background: Characterization of allergic responses to cockroach (CR), a common aeroallergen associated with asthma, has focused mainly on IgE reactivity, but little is known about T cell responses, particularly in children. We conducted a functional evaluation of CR allergen-specific T cell reactivity in a cohort of CR allergic children with asthma., Methods: Peripheral blood mononuclear cells (PBMCs) were obtained from 71 children, with mild-to-moderate asthma who were enrolled in a CR immunotherapy (IT) clinical trial, prior to treatment initiation. PBMC were stimulated with peptide pools derived from 11 CR allergens, and CD4+ T cell responses assessed by intracellular cytokine staining., Results: Highly heterogeneous responses in T cell reactivity were observed among participants, both in terms of the magnitude of cytokine response and allergen immunodominance. Reactivity against Bla g 9 and Bla g 5 was most frequent. The phenotype of the T cell response was dominated by IL-4 production and a Th2 polarized profile in 54.9% of participants, but IFNγ production and Th1 polarization was observed in 25.3% of the participants. The numbers of regulatory CD4+ T cells were also highly variable and the magnitude of effector responses and Th2 polarization were positively correlated with serum IgE levels specific to a clinical CR extract., Conclusions: Our results demonstrate that in children with mild-to-moderate asthma, CR-specific T cell responses display a wide range of magnitude, allergen dominance, and polarization. These results will enable examination of whether any of the variables measured are affected by IT and/or are predictive of clinical outcomes., Competing Interests: All authors declare no conflict of interest., (© 2021 The Authors. Clinical and Translational Allergy published by John Wiley & Sons Ltd on behalf of European Academy of Allergy and Clinical Immunology.)

Background: Nasal allergen challenge (NAC) could be a means to assess indication and/or an outcome of allergen-specific therapies, particularly for perennial allergens. NACs are not commonly conducted in children with asthma, and cockroach NACs are not well established. This study's objective was to identify a range of German cockroach extract doses that induce nasal symptoms and to assess the safety of cockroach NAC in children with asthma., Methods: Ten adults (18-37 years) followed by 25 children (8-14 years) with well-controlled, persistent asthma and cockroach sensitization underwent NAC with diluent followed by up to 8 escalating doses of cockroach extract (0.00381-11.9 µg/mL Bla g 1). NAC outcome was determined by Total Nasal Symptom Score (TNSS) and/or sneeze score. Cockroach allergen-induced T-cell activation and IL-5 production were measured in peripheral blood mononuclear cells., Results: 67% (6/9) of adults and 68% (17/25) of children had a positive NAC at a median response dose of 0.120 µg/mL [IQR 0.0380-0.379 µg/mL] of Bla g 1. Additionally, three children responded to diluent alone and did not receive any cockroach extract. Overall, 32% (11/34) were positive with sneezes alone, 15% (5/34) with TNSS alone, and 21% (7/34) with both criteria. At baseline, NAC responders had higher cockroach-specific IgE (P = .03), lower cockroach-specific IgG/IgE ratios (children, P = .002), and increased cockroach-specific IL-5-producing T lymphocytes (P = .045). The NAC was well tolerated., Conclusion: We report the methodology of NAC development for children with persistent asthma and cockroach sensitization. This NAC could be considered a tool to confirm clinically relevant sensitization and to assess responses in therapeutic studies., (© 2021 European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd. This article has been contributed to by US Government employees and their work is in the public domain in the USA.)

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, specifically body mass index (BMI), with inpatient clinical course and clinical history. Methods: We retrospectively analyzed data from 2012 to 2013 on children hospitalized for asthma exacerbation in a state-wide longitudinal cohort, the Ohio Pediatric Asthma Repository. We examined BMI continuously ( z scores) and categorically, comparing overweight and obese (Ov/Ob) to non-overweight and non-obese (nOv/nOb) children. We used linear mixed models controlling for site effects to determine if BMI was related to length of stay, as determined by physiologic readiness for discharge (PRD), defined as time to albuterol spaced every 4 h, need for nonstandard care or clinical history. Results: Across six hospitals, 874 children were included in analyses. BMI was positively associated with PRD ( p =.008) but this increase was unlikely to be clinically significant. Ov/Ob children were more likely than nOv/nOb to require nonstandard care with repeat magnesium dosing in intensive care after dosing in the emergency department (OR = 3.23, 95%CI 1.39-7.78). Hospitalization in the year prior to enrollment was positively associated with BMI percentile (73.3 vs. 66.0, p =.028). Sleep disordered breathing was also associated with higher BMI percentile (78.2 vs. 65.9; p =.0013). Conclusions: Ov/Ob children had similar PRD to nOv/nOb children and were prone to repeat magnesium dosing. Previous hospitalization for exacerbation was positively associated with increasing BMI percentile. Additional research should investigate differential magnesium use by weight status, quantifying risks and benefits.

Background: Perennial aeroallergen sensitization is associated with greater asthma morbidity and is required for treatment with omalizumab., Objective: To investigate the predictive relationship between the number of aeroallergen sensitizations, total serum IgE, and serum eosinophil count, and response to omalizumab in children and adolescents with asthma treated during the fall season., Methods: This analysis includes inner-city patients with persistent asthma and recent exacerbations aged 6-20 years comprising the placebo- and omalizumab-treated groups in 2 completed randomized clinical trials, the Inner-City Anti-IgE Therapy for Asthma study and the Preventative Omalizumab or Step-Up Therapy for Fall Exacerbations study. Logistic regression modeled the relationship between greater degrees of markers of allergic inflammation and the primary outcome of fall season asthma exacerbations., Results: The analysis included 761 participants who were 62% male and 59% African American with a median age of 10 years. Fall asthma exacerbations were significantly higher in children with greater numbers of aeroallergen-specific sensitizations in the placebo group (odds ratio [OR], 1.33; 95% confidence interval [CI], 1.11-1.60; P < .01), but not in the omalizumab-treated children (OR, 1.08; 95% CI, 0.91-1.28; P = .37), indicating a significant differential effect (P < .01). Likewise, there was a differential effect of omalizumab treatment in children with greater baseline total serum IgE levels (P < .01) or greater baseline serum eosinophil counts (P < .01). Multiple aeroallergen sensitization was the best predictor of response to omalizumab; treated participants sensitized to ≥4 different groups of aeroallergens had a 51% reduction in the odds of a fall exacerbation (OR, 0.49; 95% CI, 0.30-0.81; P < .01)., Conclusions: In preventing fall season asthma exacerbations, treatment with omalizumab was most beneficial in children with a greater degree of allergic inflammation., (Copyright © 2020 American Academy of Allergy, Asthma & Immunology. All rights reserved.)

Background: In infants, distinct nasopharyngeal bacterial microbiotas differentially associate with the incidence and severity of acute respiratory tract infection and childhood asthma development., Objective: We hypothesized that distinct nasal airway microbiota structures also exist in children with asthma and relate to clinical outcomes., Methods: Nasal secretion samples (n = 3122) collected after randomization during the fall season from children with asthma (6-17 years, n = 413) enrolled in a trial of omalizumab (anti-IgE) underwent 16S rRNA profiling. Statistical analyses with exacerbation as the primary outcome and rhinovirus infection and respiratory illnesses as secondary outcomes were performed. Using A549 epithelial cells, we assessed nasal isolates of Moraxella, Staphylococcus, and Corynebacterium species for their capacity to induce epithelial damage and inflammatory responses., Results: Six nasal airway microbiota assemblages, each dominated by Moraxella, Staphylococcus, Corynebacterium, Streptococcus, Alloiococcus, or Haemophilus species, were observed. Moraxella and Staphylococcus species-dominated microbiotas were most frequently detected and exhibited temporal stability. Nasal microbiotas dominated by Moraxella species were associated with increased exacerbation risk and eosinophil activation. Staphylococcus or Corynebacterium species-dominated microbiotas were associated with reduced respiratory illness and exacerbation events, whereas Streptococcus species-dominated assemblages increased the risk of rhinovirus infection. Nasal microbiota composition remained relatively stable despite viral infection or exacerbation; only a few taxa belonging to the dominant genera exhibited relative abundance fluctuations during these events. In vitro, Moraxella catarrhalis induced significantly greater epithelial damage and inflammatory cytokine expression (IL-33 and IL-8) compared with other dominant nasal bacterial isolates tested., Conclusion: Distinct nasal airway microbiotas of children with asthma relate to the likelihood of exacerbation, rhinovirus infection, and respiratory illnesses during the fall season., (Copyright © 2019. Published by Elsevier Inc.)

Asthma is a complex heterogeneous disease characterized by reversible airflow obstruction. After appropriate diagnosis, the management in school-aged children centers on 3 broad domains: pharmacologic treatment, treatment of underlying comorbidities, and education of the patient and caregivers. It is important to understand that the phenotypic differences that exist in the school-aged child with asthma may impact underlying comorbid conditions as well as pharmacologic treatment choices. Following initiation of therapy, asthma control must be continually evaluated in order to optimize management., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Respiratory infections are common precursors to asthma exacerbations in children, but molecular immune responses that determine whether and how an infection causes an exacerbation are poorly understood. By using systems-scale network analysis, we identify repertoires of cellular transcriptional pathways that lead to and underlie distinct patterns of asthma exacerbation. Specifically, in both virus-associated and nonviral exacerbations, we demonstrate a set of core exacerbation modules, among which epithelial-associated SMAD3 signaling is upregulated and lymphocyte response pathways are downregulated early in exacerbation, followed by later upregulation of effector pathways including epidermal growth factor receptor signaling, extracellular matrix production, mucus hypersecretion, and eosinophil activation. We show an additional set of multiple inflammatory cell pathways involved in virus-associated exacerbations, in contrast to squamous cell pathways associated with nonviral exacerbations. Our work introduces an in vivo molecular platform to investigate, in a clinical setting, both the mechanisms of disease pathogenesis and therapeutic targets to modify exacerbations.

Background: Multicenter randomized controlled trials (RCTs) for asthma management that incorporate usual-care regimens could benefit from standardized application of evidence-based guidelines., Objective: We sought to evaluate performance of a computerized decision support tool, the Asthma Control Evaluation and Treatment (ACET) Program, to standardize usual-care regimens for asthma management in RCTs., Methods: Children and adolescents with persistent uncontrolled asthma living in urban census tracts were recruited into 3 multicenter RCTs (each with a usual-care arm) between 2004 and 2014. A computerized decision support tool scored asthma control and assigned an appropriate treatment step based on published guidelines. Control-level determinants (symptoms, rescue medication use, pulmonary function measure, and adherence estimates) were collected at visits and entered into the ACET Program. Changes in control levels and treatment steps were examined during the trials., Results: At screening, more than half of the participants were rated as having symptoms that were not controlled or poorly controlled. The proportion of participants who gained good control between screening and randomization increased significantly in all 3 trials. Between 51% and 70% had symptoms that were well controlled by randomization. The proportion of well-controlled participants remained constant or improved slightly from randomization until the last posttreatment visit. Nighttime symptoms were the most common control-level determinant; there were few (<1%) instances of complete overlap of factors. FEV 1 was the driver of control-level assignment in 30% of determinations., Conclusion: The ACET Program decision support tool facilitated standardized asthma assessment and treatment in multicenter RCTs and was associated with attaining and maintaining good asthma control in most participants., (Copyright © 2018 American Academy of Allergy, Asthma & Immunology. All rights reserved.)

Background: Rhinitis and asthma are linked, but substantial knowledge gaps in this relationship exist., Objective: We sought to determine the prevalence of rhinitis and its phenotypes in children and adolescents with asthma, assess symptom severity and medication requirements for rhinitis control, and investigate associations between rhinitis and asthma., Methods: Seven hundred forty-nine children with asthma participating in the Asthma Phenotypes in the Inner-City study received baseline evaluations and were managed for 1 year with algorithm-based treatments for rhinitis and asthma. Rhinitis was diagnosed by using a questionnaire focusing on individual symptoms, and predefined phenotypes were determined by combining symptom patterns with skin tests and measurement of serum specific IgE levels., Results: Analyses were done on 619 children with asthma who completed at least 4 of 6 visits. Rhinitis was present in 93.5%, and phenotypes identified at baseline were confirmed during the observation/management year. Perennial allergic rhinitis with seasonal exacerbations was most common (34.2%) and severe. Nonallergic rhinitis was least common (11.3%) and least severe. The majority of children remained symptomatic despite use of nasal corticosteroids with or without oral antihistamines. Rhinitis was worse in patients with difficult-to-control versus easy-to-control asthma, and its seasonal patterns partially corresponded to those of difficult-to-control asthma., Conclusion: Rhinitis is almost ubiquitous in urban children with asthma, and its activity tracks that of lower airway disease. Perennial allergic rhinitis with seasonal exacerbations is the most severe phenotype and most likely to be associated with difficult-to-control asthma. This study offers strong support to the concept that rhinitis and asthma represent the manifestations of 1 disease in 2 parts of the airways., (Copyright © 2018 American Academy of Allergy, Asthma & Immunology. All rights reserved.)

Background: Small-airways instability resulting in premature airway closure has been recognized as a risk for asthma severity and poor control. Although spirometry has limited sensitivity for detecting small-airways dysfunction, a focus on the air-trapping component of obstruction might identify a risk factor for asthma instability., Objective: We sought to use spirometric measurements to identify patterns of airway obstruction in children and define obstruction phenotypes that relate to asthma instability., Methods: Prebronchodilation and postbronchodilation spirometric data were obtained from 560 children in the Asthma Phenotypes in the Inner City study. An air-trapping obstruction phenotype (A Trpg) was defined as a forced vital capacity (FVC) z score of less than -1.64 or an increase in FVC of 10% of predicted value or greater with bronchodilation. The airflow limitation phenotype (A Limit) had an FEV 1 /FVC z score of less than -1.64 but not A Trpg. The no airflow limitation or air-trapping criteria (None) phenotype had neither A Trpg nor A Limit. The 3 obstruction phenotypes were assessed as predictors of number of exacerbations, asthma severity, and airway lability., Results: Patients with the A Trpg phenotype (14% of the cohort) had more exacerbations during the 12-month study compared with those with the A Limit (P < .03) and None (P < .001) phenotypes. Patients with the A Trpg phenotype also had the highest Composite Asthma Severity Index score, the highest asthma treatment step, the greatest variability in FEV 1 over time, and the greatest sensitivity to methacholine challenge., Conclusions: A Trpg and A Limit patterns of obstruction, as defined by using routine spirometric measurements, can identify obstruction phenotypes that are indicators of risk for asthma severity and instability., (Copyright © 2017 American Academy of Allergy, Asthma & Immunology. All rights reserved.)

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., Competing Interests: POTENTIAL CONFLICT OF INTEREST: Dr Kercsmar reports personal fees from GlaxoSmithKline outside the submitted work; the other authors have indicated they have no potential conflicts of interest to disclose., (Copyright © 2018 by the American Academy of Pediatrics.)

Objectives: To identify associations between use of ipratropium and/or intravenous magnesium and outcomes of children hospitalized with acute asthma exacerbations and treated with continuous albuterol., Methods: Secondary analysis of data from children prospectively enrolled in the multicenter Ohio Pediatric Asthma Repository restricted to only children who were treated with continuous albuterol in their initial inpatient location. Children were treated with adjunctive therapies per the clinical team., Results: Among 242 children who received continuous albuterol, 94 (39%) received ipratropium only, 13 (5%) received magnesium alone, 42 (17%) received both, and 93 (38%) received neither. The median duration of continuous albuterol was 7.0 (interquartile range [IQR]: 2.8-12.0) hours. Ipratropium use was associated with a shorter duration of continuous albuterol (4.9 [IQR: 2.0-10.0] hours) compared with dual therapy (11.0 [IQR: 5.6-28.6] hours; P = .001), but magnesium use was not (7.5 [IQR: 2.5-16.0] hours; P = .542). In Cox proportional models (adjusted for hospital, demographics, treatment location, and respiratory failure), magnesium was associated with longer durations of continuous albuterol (hazard ratio, 0.54 [95% confidence interval: 0.37-0.77]; P < .001) and hospitalization (hazard ratio, 0.41 [95% confidence interval: 0.28-0.60]; P < .001), but ipratropium was not., Conclusions: Ipratropium and magnesium were both often used in children with severe asthma hospitalizations that required continuous albuterol therapy. Magnesium use was associated with unfavorable outcomes, possibly reflecting preferential treatment to patients with more severe cases and differing practices between centers. Given the high prevalence of asthma, wide variations in practice, and the potential to improve outcomes and costs, prospective trials of these adjunctive therapies are needed., Competing Interests: POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose., (Copyright © 2018 by the American Academy of Pediatrics.)

Importance: Asthma is the most common chronic condition of childhood. Hospitalizations and emergency department (ED) visits for asthma are more frequently experienced by minority children and adolescents and those with low socioeconomic status., Objective: To reduce asthma-related hospitalizations and ED visits for Medicaid-insured pediatric patients residing in Hamilton County, Ohio., Design, Setting, and Participants: From January 1, 2010, through December 31, 2015, a multidisciplinary team used quality-improvement methods and the chronic care model to conduct interventions in inpatient, outpatient, and community settings in a large, urban academic pediatric hospital in Hamilton County, Ohio. Children and adolescents aged 2 to 17 years who resided in Hamilton County, had a diagnosis of asthma, and were Medicaid insured were studied., Interventions: Interventions were implemented in 3 phases: hospital-based inpatient care redesign, outpatient-based care enhancements, and community-based supports. Plan-do-study-act cycles allowed for small-scale implementation of change concepts and rapid evaluation of how such tests affected processes and outcomes of interest., Main Outcomes and Measures: The study measured asthma-related hospitalizations and ED visits per 10 000 Medicaid-insured pediatric patients. Data were measured monthly on a rolling 12-month mean basis. Data from multiple previous years were used to establish a baseline. Data were tracked with annotated control charts and with interrupted time-series analysis., Results: Of the estimated 36 000 children and adolescents with asthma in Hamilton County (approximately 13 000 of whom are Medicaid insured and 6000 of whom are cared for in Cincinnati Children's Hospital primary care practices), asthma-related hospitalizations decreased from 8.1 (95% CI, 7.7-8.5) to 4.7 (95% CI, 4.3-5.1) per 10 000 Medicaid patients per month by June 30, 2014, a 41.8% (95% CI, 41.7%-42.0%) relative reduction. Emergency department visits decreased from 21.5 (95% CI, 20.6-22.3) to 12.4 (95% CI, 11.5-13.2) per 10 000 Medicaid patients per month by June 30, 2014, a 42.4% (95% CI, 42.2%-42.6%) relative reduction. Improvements were sustained for the subsequent 12 months. The proportion of patients who were rehospitalized or had a return ED visit for asthma within 30 days of an index hospitalization was reduced from 12% to 7%. The proportion of patients with documented well-controlled asthma in this study's primary care population increased from 48% to 54%., Conclusions and Relevance: An integrated, multilevel approach focused on enhancing availability and accessibility of treatments, removing barriers to adherence, mitigating multidomain risks, augmenting self-management, and creating a collaborative relationship between the family and the health care system was associated with improved asthma outcomes for a population of Medicaid-insured pediatric patients. Similar models used in accountable care organizations or across patient panels and with other chronic conditions could be feasible and warrant evaluation.

Rationale: Allergic inflammation has been linked to increased susceptibility to viral illnesses, but it is unclear whether this association is causal., Objectives: To test whether omalizumab treatment to reduce IgE would shorten the frequency and duration of rhinovirus (RV) illnesses in children with allergic asthma., Methods: In the PROSE (Preventative Omalizumab or Step-up Therapy for Severe Fall Exacerbations) study, we examined children with allergic asthma (aged 6-17 yr; n = 478) from low-income census tracts in eight U.S. cities, and we analyzed virology for the groups randomized to treatment with guidelines-based asthma care (n = 89) or add-on omalizumab (n = 259). Weekly nasal mucus samples were analyzed for RVs, and respiratory symptoms and asthma exacerbations were recorded over a 90-day period during the fall seasons of 2012 or 2013. Adjusted illness rates (illnesses per sample) by treatment arm were calculated using Poisson regression., Measurements and Main Results: RVs were detected in 97 (57%) of 171 exacerbation samples and 2,150 (36%) of 5,959 nonexacerbation samples (OR, 2.32; P < 0.001). Exacerbations were significantly associated with detection of rhinovirus C (OR, 2.85; P < 0.001) and rhinovirus A (OR, 2.92; P < 0.001), as well as, to a lesser extent, rhinovirus B (OR, 1.98; P = 0.019). Omalizumab decreased the duration of RV infection (11.2 d vs. 12.4 d; P = 0.03) and reduced peak RV shedding by 0.4 log units (95% confidence interval, -0.77 to -0.02; P = 0.04). Finally, omalizumab decreased the frequency of RV illnesses (risk ratio, 0.64; 95% confidence interval, 0.49-0.84)., Conclusions: In children with allergic asthma, treatment with omalizumab decreased the duration of RV infections, viral shedding, and the risk of RV illnesses. These findings provide direct evidence that blocking IgE decreases susceptibility to RV infections and illness. Clinical trial registered with www.clinicaltrials.gov (NCT01430403).

Background: A Seasonal Asthma Exacerbation Predictive Index (saEPI) was previously reported based on 2 prior National Institute of Allergy and Infectious Diseases Inner City Asthma Consortium trials., Objective: This study sought to validate the saEPI in a separate trial designed to prevent fall exacerbations with omalizumab therapy., Methods: The saEPI and its components were analyzed to characterize those who had an asthma exacerbation during the Preventative Omalizumab or Step-Up Therapy for Fall Exacerbations (PROSE) study. We characterized those inner-city children with and without asthma exacerbations in the fall period treated with guidelines-based therapy (GBT) in the absence and presence of omalizumab., Results: A higher saEPI was associated with an exacerbation in both the GBT alone (P < .001; area under the curve, 0.76) and the GBT + omalizumab group (P < .01; area under the curve, 0.65). In the GBT group, younger age at recruitment, higher total IgE, higher blood eosinophil percentage and number, and higher treatment step were associated with those who had an exacerbation compared with those who did not. In the GBT + omalizumab group, younger age at recruitment, increased eosinophil number, recent exacerbation, and higher treatment step were also associated with those who had an exacerbation. The saEPI was associated with a high negative predictive value in both groups., Conclusions: An exacerbation in children treated with GBT with or without omalizumab was associated with a higher saEPI along with higher markers of allergic inflammation, treatment step, and a recent exacerbation. Those that exacerbated on omalizumab had similar features with the exception of some markers of allergic sensitization, indicating a need to develop better markers to predict poor response to omalizumab therapy and alternative treatment strategies for children with these risk factors. The saEPI was able to reliably predict those children unlikely to have an asthma exacerbation in both groups., (Copyright © 2017 American Academy of Allergy, Asthma & Immunology. All rights reserved.)

African Americans have higher rates of asthma prevalence, morbidity, and mortality in comparison with other racial groups. We sought to characterize endotypes of childhood asthma severity in African American patients in an inner-city pediatric asthma population. Baseline blood neutrophils, blood eosinophils, and 38 serum cytokine levels were measured in a sample of 235 asthmatic children (6-17 years) enrolled in the NIAID (National Institute of Allergy and Infectious Diseases)-sponsored Asthma Phenotypes in the Inner City (APIC) study (ICAC (Inner City Asthma Consortium)-19). Cytokines were quantified using a MILLIPLEX panel and analyzed on a Luminex analyzer. Patients were classified as Easy-to-Control or Difficult-to-Control based on the required dose of controller medications over one year of prospective management. A multivariate variable selection procedure was used to select cytokines associated with Difficult-to-Control versus Easy-to-Control asthma, adjusting for age, sex, blood eosinophils, and blood neutrophils. In inner-city African American children, 12 cytokines were significant predictors of Difficult-to-Control asthma (n = 235). CXCL-1, IL-5, IL-8, and IL-17A were positively associated with Difficult-to-Control asthma, while IL-4 and IL-13 were positively associated with Easy-to-Control asthma. Using likelihood ratio testing, it was observed that in addition to blood eosinophils and neutrophils, serum cytokines improved the fit of the model. In an inner-city pediatric population, serum cytokines significantly contributed to the definition of Difficult-to-Control asthma endotypes in African American children. Mixed responses characterized by TH2 (IL-5) and TH17-associated cytokines were associated with Difficult-to-Control asthma. Collectively, these data may contribute to risk stratification of Difficult-to-Control asthma in the African American population.

Objective: The prevalence of obstructive sleep apnea (OSA) is higher in children with poorly controlled asthma. We aimed to determine the validity of the Pediatric Sleep Questionnaire (PSQ) to screen for OSA in children with asthma., Methods: This retrospective review encompassed sleep studies and medical records of asthmatic children evaluated in the sleep center at CCHMC over 13 years. Measures of validity were calculated using various cut-off values for obstructive apnea-hypopnea index (OI; >1, >2, >5) and PSQ scores (>0.33, >0.5). Correlation between PSQ and OI, PSQ and spirometry, and OI and spirometry was assessed using Spearman's correlation coefficient., Results: One-hundred and sixty children were included (mean age 11 ± 4 years; 64% males). The mean OI was 4.2 ± 14.3 and the mean PSQ score was 0.57 ± 0.19. Thirty-eight percent of patients had a diagnosis of allergic rhinitis. A total of 70 children (43%) were obese (BMI ≥95th percentile). The correlation between OI and PSQ was statistically significant (r = 0.19, P = 0.015). Using a PSQ cutoff of 0.33, and OI cutoffs of 1, 2, and 5, the sensitivities were 81.6%, 81.6%, and 76.2%, and the specificities were 13.1%, 14.4%, and 14.4%, respectively. When the cutoff for PSQ was raised to 0.5 and using an OI of 1, the sensitivity decreased to 71.1%, but the specificity increased to 36.9%., Conclusions: The sensitivity of PSQ in asthmatic children is high and comparable to previous studies, but the specificity is low. The PSQ may be considered a reasonable first-line screening tool for OSA in asthmatic children. Pediatr Pulmonol. 2017;52:382-389. © 2016 Wiley Periodicals, Inc., (© 2016 Wiley Periodicals, Inc.)

Background: Pathway analyses can be used to determine how host and environmental factors contribute to asthma severity., Objective: To investigate pathways explaining asthma severity in inner-city children., Methods: On the basis of medical evidence in the published literature, we developed a conceptual model to describe how 8 risk-factor domains (allergen sensitization, allergic inflammation, pulmonary physiology, stress, obesity, vitamin D, environmental tobacco smoke [ETS] exposure, and rhinitis severity) are linked to asthma severity. To estimate the relative magnitude and significance of hypothesized relationships among these domains and asthma severity, we applied a causal network analysis to test our model in an Inner-City Asthma Consortium study. Participants comprised 6- to 17-year-old children (n = 561) with asthma and rhinitis from 9 US inner cities who were evaluated every 2 months for 1 year. Asthma severity was measured by a longitudinal composite assessment of day and night symptoms, exacerbations, and controller usage., Results: Our conceptual model explained 53.4% of the variance in asthma severity. An allergy pathway (linking allergen sensitization, allergic inflammation, pulmonary physiology, and rhinitis severity domains to asthma severity) and the ETS exposure pathway (linking ETS exposure and pulmonary physiology domains to asthma severity) exerted significant effects on asthma severity. Among the domains, pulmonary physiology and rhinitis severity had the largest significant standardized total effects on asthma severity (-0.51 and 0.48, respectively), followed by ETS exposure (0.30) and allergic inflammation (0.22). Although vitamin D had modest but significant indirect effects on asthma severity, its total effect was insignificant (0.01)., Conclusions: The standardized effect sizes generated by a causal network analysis quantify the relative contributions of different domains and can be used to prioritize interventions to address asthma severity., (Copyright © 2016 American Academy of Allergy, Asthma & Immunology. All rights reserved.)

Background: Treatment levels required to control asthma vary greatly across a population with asthma. The factors that contribute to variability in treatment requirements of inner-city children have not been fully elucidated., Objective: We sought to identify the clinical characteristics that distinguish difficult-to-control asthma from easy-to-control asthma., Methods: Asthmatic children aged 6 to 17 years underwent baseline assessment and bimonthly guideline-based management visits over 1 year. Difficult-to-control and easy-to-control asthma were defined as daily therapy with 500 μg of fluticasone or greater with or without a long-acting β-agonist versus 100 μg or less assigned on at least 4 visits. Forty-four baseline variables were used to compare the 2 groups by using univariate analyses and to identify the most relevant features of difficult-to-control asthma by using a variable selection algorithm. Nonlinear seasonal variation in longitudinal measures (symptoms, pulmonary physiology, and exacerbations) was examined by using generalized additive mixed-effects models., Results: Among 619 recruited participants, 40.9% had difficult-to-control asthma, 37.5% had easy-to-control asthma, and 21.6% fell into neither group. At baseline, FEV 1 bronchodilator responsiveness was the most important characteristic distinguishing difficult-to-control asthma from easy-to-control asthma. Markers of rhinitis severity and atopy were among the other major discriminating features. Over time, difficult-to-control asthma was characterized by high exacerbation rates, particularly in spring and fall; greater daytime and nighttime symptoms, especially in fall and winter; and compromised pulmonary physiology despite ongoing high-dose controller therapy., Conclusions: Despite good adherence, difficult-to-control asthma showed little improvement in symptoms, exacerbations, or pulmonary physiology over the year. In addition to pulmonary physiology measures, rhinitis severity and atopy were associated with high-dose asthma controller therapy requirement., (Copyright © 2016 American Academy of Allergy, Asthma & Immunology. All rights reserved.)

Background: Children with asthma in low-income urban areas have high morbidity. Phenotypic analysis in these children is lacking, but may identify characteristics to inform successful tailored management approaches., Objective: We sought to identify distinct asthma phenotypes among inner-city children receiving guidelines-based management., Methods: Nine inner-city asthma consortium centers enrolled 717 children aged 6 to 17 years. Data were collected at baseline and prospectively every 2 months for 1 year. Participants' asthma and rhinitis were optimally managed by study physicians on the basis of guidelines. Cluster analysis using 50 baseline and 12 longitudinal variables was performed in 616 participants completing 4 or more follow-up visits., Results: Five clusters (designated A through E) were distinguished by indicators of asthma and rhinitis severity, pulmonary physiology, allergy (sensitization and total serum IgE), and allergic inflammation. In comparison to other clusters, cluster A was distinguished by lower allergy/inflammation, minimally symptomatic asthma and rhinitis, and normal pulmonary physiology. Cluster B had highly symptomatic asthma despite high step-level treatment, lower allergy and inflammation, and mildly altered pulmonary physiology. Cluster C had minimally symptomatic asthma and rhinitis, intermediate allergy and inflammation, and mildly impaired pulmonary physiology. Clusters D and E exhibited progressively higher asthma and rhinitis symptoms and allergy/inflammation. Cluster E had the most symptomatic asthma while receiving high step-level treatment and had the highest total serum IgE level (median, 733 kU/L), blood eosinophil count (median, 400 cells/mm 3 ), and allergen sensitizations (15 of 22 tested)., Conclusions: Allergy distinguishes asthma phenotypes in urban children. Severe asthma often coclusters with highly allergic children. However, a symptomatic phenotype with little allergy or allergic inflammation was identified., (Copyright © 2016 American Academy of Allergy, Asthma & Immunology. All rights reserved.)

Rationale: Risk factors for severe asthma exacerbations in children requiring admission to the intensive care unit (ICU) may occur in variety of medical, environmental, economic, and socioeconomic domains., Objectives: We sought to characterize medical and sociodemographic risk factors among children who required admission to the intensive care unit for asthma., Methods: Data were obtained from the Greater Cincinnati Asthma Risk Study, a population-based, prospective, observational cohort of children admitted for treatment of acute asthma or bronchodilator-responsive wheezing. Data collected on 774 children included race, socioeconomic status, allergen sensitization, environmental exposures, psychosocial strain, and financial hardship. Analyses compared children admitted to the ICU to those admitted to a medical inpatient unit., Measurements and Main Results: One hundred sixty-one (20.9%) children required admission to intensive care. There was no difference in sex, race, insurance status, caregiver educational level, income, financial strain, psychological distress, or marital status between the ICU and non-ICU cohorts. Risk for medication nonadherence assessed by parent report was not different between groups. Although previous hospital admission or emergency department visit history did not differ between the groups, prior ICU admission was more common among those admitted to the ICU at the index admission (27 vs. 16%, P = 0.002). Children requiring intensive care admission were more likely to be sensitized to multiple aeroallergens. Exposure to cigarette smoke (measured as salivary cotinine), although a risk factor for hospital admission, was negatively associated with risk of ICU admission., Conclusions: Social and economic risk factors typically predictive of increased asthma morbidity, including exposure to tobacco smoke, were not associated with ICU admission among a population of children admitted to the hospital for treatment of acute asthma. Intrinsic disease factors, including allergic sensitization, may be more important predictors of ICU admission.

Background: Short-term targeted treatment can potentially prevent fall asthma exacerbations while limiting therapy exposure., Objective: We sought to compare (1) omalizumab with placebo and (2) omalizumab with an inhaled corticosteroid (ICS) boost with regard to fall exacerbation rates when initiated 4 to 6 weeks before return to school., Methods: A 3-arm, randomized, double-blind, double placebo-controlled, multicenter clinical trial was conducted among inner-city asthmatic children aged 6 to 17 years with 1 or more recent exacerbations (clincaltrials.gov #NCT01430403). Guidelines-based therapy was continued over a 4- to 9-month run-in phase and a 4-month intervention phase. In a subset the effects of omalizumab on IFN-α responses to rhinovirus in PBMCs were examined., Results: Before the falls of 2012 and 2013, 727 children were enrolled, 513 were randomized, and 478 were analyzed. The fall exacerbation rate was significantly lower in the omalizumab versus placebo arms (11.3% vs 21.0%; odds ratio [OR], 0.48; 95% CI, 0.25-0.92), but there was no significant difference between omalizumab and ICS boost (8.4% vs 11.1%; OR, 0.73; 95% CI, 0.33-1.64). In a prespecified subgroup analysis, among participants with an exacerbation during the run-in phase, omalizumab was significantly more efficacious than both placebo (6.4% vs 36.3%; OR, 0.12; 95% CI, 0.02-0.64) and ICS boost (2.0% vs 27.8%; OR, 0.05; 95% CI, 0.002-0.98). Omalizumab improved IFN-α responses to rhinovirus, and within the omalizumab group, greater IFN-α increases were associated with fewer exacerbations (OR, 0.14; 95% CI, 0.01-0.88). Adverse events were rare and similar among arms., Conclusions: Adding omalizumab before return to school to ongoing guidelines-based care among inner-city youth reduces fall asthma exacerbations, particularly among those with a recent exacerbation., (Copyright © 2015 American Academy of Allergy, Asthma & Immunology. All rights reserved.)

Introduction: We report an unusual finding of pneumatocele in an infant., Case Report: A previously well four month old presented with worsening respiratory distress over 6 weeks. He had no antecedent signs or symptoms of respiratory infection. Chest radiograph demonstrated a lucent hemithorax concerning for tension pneumothorax. Urgent needle decompression was performed. Chest CT showed a persistent dominant macrocyst on the left. Thoracotomy revealed a large cystic lesion necessitating a left lower lobectomy. Histopathology was consistent with a pneumatocele. He remains clinically stable at 16 months postoperatively., Discussion: Pneumatocele is a rare cause of cystic lung disease presenting in infancy. The young age at onset, prolonged symptoms without preceding infection, and tension physiology in our patient are unique., (© 2015 Wiley Periodicals, Inc.)

Background: There is considerable heterogeneity in asthma treatment response., Objective: We sought to identify biomarkers of corticosteroid treatment response in children with asthma and evaluate the utility and mechanistic basis of these biomarkers., Methods: Children (5-18 years) presenting to the emergency department with an acute asthma exacerbation were recruited and followed during hospitalization. Nasal epithelial cells were collected on presentation to the emergency department (T0) and 18 to 24 hours later (T1), and T1/T0 gene expression ratios were analyzed to identify genes associated with good and poor corticosteroid treatment response phenotypes. The utility of these genes in discriminating between systemic corticosteroid treatment response groups was then tested prospectively in a new cohort of patients. A gene candidate (vanin-1 [VNN1]) that consistently distinguished good versus poor response phenotypes was further studied in an experimental asthma model, and VNN1 promoter methylation was measured by means of bisulfite pyrosequencing in patients., Results: VNN1 mRNA expression changes were associated with systemic corticosteroid treatment response in children with acute asthma, and VNN1 was required for optimal response to corticosteroid treatment in an experimental asthma model. A CpG site within the VNN1 promoter was differentially methylated between good versus poor treatment response groups, and methylation at this site correlated with VNN1 mRNA expression., Conclusions: We have identified a biological basis for poor corticosteroid treatment response that can be used to distinguish a subgroup of asthmatic children who respond poorly to systemic corticosteroid treatment. VNN1 contributes to corticosteroid responsiveness, and changes in VNN1 nasal epithelial mRNA expression and VNN1 promoter methylation might be clinically useful biomarkers of treatment response in asthmatic children., (Copyright © 2015 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Background: Asthma exacerbations remain common, even in children and adolescents, despite optimal medical management. Identification of host risk factors for exacerbations is incomplete, particularly for seasonal episodes., Objective: We sought to define host risk factors for asthma exacerbations unique to their season of occurrence., Methods: This is a retrospective analysis of patients aged 6 to 20 years who comprised the control groups of the Asthma Control Evaluation study and the Inner City Anti-IgE Therapy for Asthma study. Univariate and multivariate models were constructed to determine whether patients' demographic and historical factors, allergic sensitization, fraction of exhaled nitric oxide values, spirometric measurements, asthma control, and treatment requirements were associated with seasonal exacerbations., Results: The analysis included 400 patients (54.5% male; 59.0% African American; median age, 13 years). Exacerbations occurred in 37.5% of participants over the periods of observation and were most common in the fall (28.8% of participants). In univariate analysis impaired pulmonary function was significantly associated with greater odds of exacerbations for all seasons, as was an exacerbation in the previous season for all seasons except spring. In multivariate analysis exacerbation in the previous season was the strongest predictor in fall and winter, whereas a higher requirement for inhaled corticosteroids was the strongest predictor in spring and summer. The multivariate models had the best predictive power for fall exacerbations (30.5% variance attributed)., Conclusions: Among a large cohort of inner-city children with asthma, patients' risk factors for exacerbation vary by season. Thus information on individual patients might be beneficial in strategies to prevent these seasonal events., (Copyright © 2015 American Academy of Allergy, Asthma & Immunology. All rights reserved.)

Rationale: Allergen sensitization is associated with asthma morbidity. A better understanding of allergen sensitization patterns among children hospitalized for asthma could help clinicians tailor care more effectively. To our knowledge, however, sensitization profiles among children hospitalized for asthma are unknown., Objectives: We sought to describe allergen sensitization profiles and the distribution of self-reported in-home exposures among children hospitalized for asthma. We also sought to assess how sensitization profiles varied by sociodemographic and clinical factors., Methods: This population-based cohort study includes data for 478 children, aged 4-16 years, hospitalized for an asthma exacerbation. Predictors included child age, race, sex, insurance status, reported income, salivary cotinine, exposure to traffic-related air pollution, asthma and atopic history, and season of admission. Outcomes included serum IgE specific to Alternaria alternata/A. tenuis, Aspergillus fumigatus, American cockroach, mouse epithelium, dust mite (Dermatophagoides pteronyssinus and farinae), cat dander, and dog dander (deemed sensitive if IgE ≥ 0.35). Self-reported adverse exposures included mold/mildew, water leaks, cockroaches, rodents, and cracks or holes in the walls or ceiling. Presence of carpeting and furry pets was also assessed., Measurements and Main Results: More than 50% of included patients were sensitized to each of Alternaria, Aspergillus, dust mite, cat dander, and dog dander; 28% were sensitized to cockroach and 18% to mouse. Roughly 68% were sensitized to three or more allergens with evidence of clustering. African American children, compared with white children, were more likely to be sensitized to Alternaria, Aspergillus, cockroach, and dust mite (all P<0.01). White children were more likely to be sensitized to mouse, cat, and dog (all P<0.01). Lower income was associated with cockroach sensitization whereas higher income was associated with dog and cat sensitization (all P<0.01). Atopic history was associated with sensitization to three or more allergens (P<0.01). Although 42% reported exposure to at least one adverse in-home exposure (and 72% to carpet, 51% to furry pets), only weak relationships were seen between reported exposures and sensitizations., Conclusions: Most children admitted to the hospital for asthma exacerbations are sensitized to multiple indoor allergens. Atopy on the inpatient unit serves as a potential target for improvement in chronic asthma management.

Background and Objective: Asthma heterogeneity causes difficulty in studying and treating the disease. We built a comprehensive statewide repository linking questionnaire and medical record data with health outcomes to characterize the variability of clinical practices at Ohio children's hospitals for the treatment of hospitalized asthma., Methods: Children hospitalized at 6 participating Ohio children's hospitals for asthma exacerbation or reactive airway disease aged 2 to 17 were eligible. Medical, social, and environmental histories and past asthma admissions were collected from questionnaires and the medical record., Results: From December 2012 to September 2013, 1012 children were enrolled. There were significant differences in the population served, emergency department and inpatient practices, intensive care unit usage, discharge criteria, and length of stay across the sites (all P < .0001, total n = 1012). Public insurance was highest in Cleveland and Cincinnati (72 and 65%). In the emergency department, Cincinnati and Akron had the highest intravenous magnesium sulfate use (37% and 33%); Columbus administered the most intramuscular epinephrine (15%). Cleveland and Columbus had the highest intensive care unit admittance (44% and 41%) and proportion of long-stay patients (95% and 85%). Moderate/severe asthma severity classification was associated with discharge prescription for inhaled corticosteroids (odds ratio = 2.7; 95% confidence interval: 1.6-4.5; P = .004) but not stay length., Conclusions: These data highlight the need for standardization of treatment practices for inpatient asthma care. There is considerable opportunity for personalized care plans that incorporate a patient's asthma impairment, risk, and treatment response history into hospital practices for asthma exacerbation treatment. The Ohio Pediatric Asthma Repository is a unique statewide resource in which to conduct observational, comparative effectiveness, and ultimately intervention studies for pediatric asthma., (Copyright © 2015 by the American Academy of Pediatrics.)

Asthma is the most common chronic disorder of childhood and continues to be a leading cause of pediatric hospital admission. The National Asthma Education and Prevention Program (NAEPP) recommends that spirometry be obtained for asthma patients upon hospital admission, after bronchodilation during the acute phase of asthma symptoms, and at least one additional time before discharge from the hospital. The objectives of this study were to describe the use of spirometry in children hospitalized with asthma and to determine association of pulmonary function with future exacerbations. A retrospective cohort study design was utilized involving review of medical records of children ≥5 years old admitted with asthma to Cincinnati Children's Hospital Medical Center from September 1, 2009 to March 31, 2011. Hospitalization or emergency department (ED) visits were identified by the ICD-9-CM codes of having either a primary diagnosis of asthma (493) or a respiratory illness (460-496) plus a secondary diagnosis of asthma. Asthma re-exacerbation was defined as either having an ED visit or hospitalization for asthma that occurred within 3 months after the index hospitalization. All spirometries were performed in a pediatric pulmonary function laboratory. Among 1,037 admissions included in this study, 89 (8.6%) had spirometry that was recommended by a consulting asthma specialist and usually performed on the day of discharge. Spirometries for forty-five of these patients (54.9%) met all acceptability and repeatability criteria of the American Thoracic Society. Patients who performed acceptable spirometry were significantly older (12.4 ± 3.8 vs. 10.7 ± 3.0 years; P = 0.041). The average forced expiratory volume in the first second (FEV1 ) was 84.4 ± 19.7% predicted; forced vital capacity (FVC) was 98.1 ± 16.0% predicted; FEV1 /FVC was 74.6 ± 9.6%; forced expiratory flow at 25-75% (FEF25-75 ) was 61.2 ± 30.1% predicted. Ten patients (22%) who performed spirometry developed a re-exacerbation. Patients with versus without re-exacerbation had significantly lower FEV1 /FVC (P = 0.027) and FEF25-75 (P = 0.031). Nevertheless, separate logistic regression models found that FEV1 /FVC and FEF25-75 were not associated with re-exacerbation when adjusted for age and length-of-stay. We found that few children admitted with asthma had spirometry as recommended in the NAEPP guidelines unless recommended by specialists and both lower lung function (FEV1 /FVC and FEF25-75 ) and history of more frequent and more recent prior health-care utilization for asthma were associated with repeat asthma exacerbation. However, the value of performing spirometry on asthmatic children prior to hospital discharge remains unclear and will require prospective study., (© 2013 Wiley Periodicals, Inc.)

Objective: To examine the relationships among obesity, sleep-disordered breathing (SDB, defined as intermittent nocturnal hypoxia and habitual snoring), and asthma severity in children. We hypothesized that obesity and SDB are associated with severe asthma at a 1- year follow-up., Study Design: Children aged 4-18 years were recruited sequentially from a specialty asthma clinic and underwent physiological, anthropometric, and biochemical assessment at enrollment. Asthma severity was determined after 1 year of follow-up and guideline-based treatment, using a composite measure of level of controller medication, symptom burden, and health care utilization. Multivariate logistic regression was used to examine adjusted associations of SDB and obesity with asthma severity at 12-month follow-up., Results: Among 108 subjects (mean age, 9.1±3.4 years; 45.4% African-American; 67.6% male), obesity and SDB were common, affecting 42.6% and 29.6% of subjects, respectively. After adjusting for obesity, race, and sex, children with SDB had a 3.62-fold increased odds of having severe asthma at follow-up (95% CI, 1.26-10.40). Obesity was not associated with asthma severity., Conclusion: SDB is a modifiable risk factor for severe asthma after 1 year of specialty asthma care. Further studies are needed to determine whether treating SDB improves asthma morbidity., (Copyright © 2012 Mosby, Inc. All rights reserved.)

Objective: Low-income and minority adolescents are at high risk for poor asthma outcomes, due in part to adherence. We tested acceptability, feasibility, and effect sizes of an adherence intervention for low socioeconomic status (SES) minority youth with moderate- and severe-persistent asthma. Design and Methods Single-site randomized pilot trial: intervention (n = 12; asthma education, motivational interviewing, problem-solving skills training, 1 month cell-phone with tailored text messaging) versus control (n = 14; asthma education; cell-phone without tailored messaging). Calculated effect-sizes of relative change from baseline (1 and 3 months)., Results: Intervention was judged acceptable and feasible by participants. Participants (12-18 years, mean = 15.1, SD = 1.67) were 76.9% African-American, 80.7% public/no insurance. At 1 and 3 months, asthma symptoms (Cohen's d's = 0.40, 0.96) and HRQOL (PedsQL™; Cohen's d's = 0.23, 1.25) had clinically meaningful medium to large effect sizes., Conclusions: This intervention appears promising for at-risk youth with moderate- and severe-persistent asthma.

Background: Outcomes of pulmonary physiology have a central place in asthma clinical research., Objective: At the request of National Institutes of Health (NIH) institutes and other federal agencies, an expert group was convened to provide recommendations on the use of pulmonary function measures as asthma outcomes that should be assessed in a standardized fashion in future asthma clinical trials and studies to allow for cross-study comparisons., Methods: Our subcommittee conducted a comprehensive search of PubMed to identify studies that focused on the validation of various airway response tests used in asthma clinical research. The subcommittee classified the instruments as core (to be required in future studies), supplemental (to be used according to study aims and in a standardized fashion), or emerging (requiring validation and standardization). This work was discussed at an NIH-organized workshop in March 2010 and finalized in September 2011., Results: A list of pulmonary physiology outcomes that applies to both adults and children older than 6 years was created. These outcomes were then categorized into core, supplemental, and emerging. Spirometric outcomes (FEV(1), forced vital capacity, and FEV(1)/forced vital capacity ratio) are proposed as core outcomes for study population characterization, for observational studies, and for prospective clinical trials. Bronchodilator reversibility and prebronchodilator and postbronchodilator FEV(1) also are core outcomes for study population characterization and observational studies., Conclusions: The subcommittee considers pulmonary physiology outcomes of central importance in asthma and proposes spirometric outcomes as core outcomes for all future NIH-initiated asthma clinical research., (Published by Mosby, Inc.)

Background: There is an association between adiposity and asthma prevalence, but the relationship to asthma control is unclear., Objectives: We sought to understand the relationships among adiposity, sex, and asthma control in inner-city adolescents with asthma., Methods: We prospectively followed 368 adolescents with moderate-to-severe asthma (ages 12-20 years) living in 10 urban areas for 1 year. Asthma symptoms and exacerbations were recorded, and pulmonary function and exhaled nitric oxide levels were measured every 6 weeks. Adiposity measures (body mass index [BMI] and dual-energy X-ray absorptiometric scans) were made, and blood was collected for measurement of allergy markers, adiponectin, leptin, TNF-alpha, IL-6, and C-reactive protein levels., Results: More than 60% of female subjects and 50% of male subjects were above the 85th percentile of BMI for age. Higher BMI was associated with more symptom days (R = 0.18, P = .02) and exacerbations (R = 0.18, P = .06) among female subjects only. Adiponectin was inversely related to asthma symptoms (R = -0.18, P < .05) and exacerbations (R = -0.20, P < .05) and positively with FEV(1)/forced vital capacity ratio (R = 0.15, P < .05) in male subjects only independent of body size. There was no relationship between adiposity or adipokines and total IgE levels, blood eosinophil counts, and exhaled nitric oxide levels. Dual-energy X-ray absorptiometry provided little additional value in relating adiposity to asthma outcome in this population of adolescents., Conclusion: Adiposity is associated with poorer asthma control in female subjects. Adiponectin is associated with improved asthma control in male subjects.

Objective: Although there is mounting evidence that childhood obesity is a risk factor for incident asthma, it remains unclear if there is a distinct "asthma-obesity" phenotype. This study characterized body composition, obesity related co-morbidities, and traditional risk factors for asthma in a cohort of children referred for asthma management in a pulmonary clinic. We hypothesized that children with asthma and obesity would have distinct risk factors and co-morbidities, particularly with respect to metabolic and sleep abnormalities., Participants and Methods: One hundred sixteen asthmatic children ages 4-18 years underwent comprehensive measurements of common asthma risk factors as well as measurements of obesity-related morbidities, including lung function tests, atopy, and assessments of sleep (overnight oximetry and actigraphy), physical activity (accelerometry), and metabolism. Characteristics of children who were obese (BMI > or =95th percentile) were compared to those who were not obese (BMI <95th percentile)., Results: Obesity was present in 44% of participants. Obese participants had similar rates of atopy and family history of atopy, lung function, and asthma control at enrolment as their non-obese peers. A significantly higher proportion of obese participants had metabolic syndrome (23% vs. 0%) and habitual snoring (60% vs. 33%) compared to non-obese participants; insufficient sleep and nocturnal desaturations tended to be more prevalent among obese subjects., Conclusions: Obesity and obesity related co-morbidities were common in a referral population of children with asthma. The specific influence of metabolic abnormalities on asthma morbidity and management is still uncertain and likely will need to be addressed in prospective studies., (Copyright 2009 Wiley-Liss, Inc.)