Aeroallergen Sensitization, Serum IgE, and Eosinophilia as Predictors of Response to Omalizumab Therapy During the Fall Season Among Children with Persistent Asthma.

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.

The Safety Explorer Suite: Interactive Safety Monitoring for Clinical Trials.

BACKGROUND: Frequent and thorough monitoring of patient safety is a requirement of clinical trials research. Safety data are traditionally reported in a tabular or listing format, which often translates into many pages of static displays. This poses the risk that clinically relevant signals will be obscured by the sheer volume of data reported. Interactive graphics enable the delivery of the vast scope of information found in traditional reports, but allow the user to interact with the charts in real time, focusing on signals of interest. METHODS: Clinical research staff, including biostatisticians, project managers, and a medical monitor, were consulted to guide the development of a set of interactive data visualizations that enable key safety assessments for participants. The resulting "Safety Explorer" is a set of 6 interactive, web-based, open source tools designed to address the shortcomings of traditional, static reports for safety monitoring. RESULTS: The Safety Explorer is freely available on GitHub as individual JavaScript libraries: Adverse Event Explorer, Adverse Event Timelines, Safety Histogram, Safety Outlier Explorer, Safety Results Over Time, and Safety Shift Plot; or in a single combined framework: Safety Explorer Suite. The suite can also be utilized through its R interface, the safetyexploreR package. CONCLUSIONS: The Safety Explorer provides interactive charts that contain the same information available in standard displays, but the interactive interface allows for improved exploration of patterns and comparisons. Medical Monitors, Safety Review Boards, and Project Teams can use these tools to effectively track and analyze key safety variables and study endpoints.

Enhanced plasmacytoid dendritic cell antiviral responses after omalizumab.

BACKGROUND: Atopy and viral respiratory tract infections synergistically promote asthma exacerbations. IgE cross-linking inhibits critical virus-induced IFN-α responses of plasmacytoid dendritic cells (pDCs), which can be deficient in patients with allergic asthma. OBJECTIVE: We sought to determine whether reducing IgE levels in vivo with omalizumab treatment increases pDC antiviral IFN-α responses in inner-city children with asthma. METHODS: PBMCs and pDCs isolated from children with exacerbation-prone asthma before and during omalizumab treatment were stimulated ex vivo with rhinovirus and influenza in the presence or absence of IgE cross-linking. IFN-α levels were measured in supernatants, and mRNA expression of IFN-α pathway genes was determined by using quantitative RT-PCR (qRT-PCR) in cell pellets. FcεRIα protein levels and mRNA expression were measured in unstimulated cells by using flow cytometry and qRT-PCR, respectively. Changes in these outcomes and associations with clinical outcomes were analyzed, and statistical modeling was used to identify risk factors for asthma exacerbations. RESULTS: Omalizumab treatment increased rhinovirus- and influenza-induced PBMC and rhinovirus-induced pDC IFN-α responses in the presence of IgE cross-linking and reduced pDC surface FcεRIα expression. Omalizumab-induced reductions in pDC FcεRIα levels were significantly associated with a lower asthma exacerbation rate during the outcome period and correlated with increases in PBMC IFN-α responses. PBMC FcεRIα mRNA expression measured on study entry significantly improved an existing model of exacerbation prediction. CONCLUSIONS: These findings indicate that omalizumab treatment augments pDC IFN-α responses and attenuates pDC FcεRIα protein expression and provide evidence that these effects are related. These results support a potential mechanism underlying clinical observations that allergic sensitization is associated with increased susceptibility to virus-induced asthma exacerbations.

The nasal methylome and childhood atopic asthma.

BACKGROUND: Given the strong environmental influence on both epigenetic marks and allergic asthma in children, the epigenetic alterations in respiratory epithelia might provide insight into allergic asthma. OBJECTIVE: We sought to identify DNA methylation and gene expression changes associated with childhood allergic persistent asthma. METHODS: We compared genomic DNA methylation patterns and gene expression in African American children with persistent atopic asthma (n = 36) versus healthy control subjects (n = 36). Results were validated in an independent population of asthmatic children (n = 30) by using a shared healthy control population (n = 36) and in an independent population of white adult atopic asthmatic patients (n = 12) and control subjects (n = 12). RESULTS: We identified 186 genes with significant methylation changes, differentially methylated regions or differentially methylated probes, after adjustment for age, sex, race/ethnicity, batch effects, inflation, and multiple comparisons. Genes differentially methylated included those with established roles in asthma and atopy and genes related to extracellular matrix, immunity, cell adhesion, epigenetic regulation, and airflow obstruction. The methylation changes were substantial (median, 9.5%; range, 2.6% to 29.5%). Hypomethylated and hypermethylated genes were associated with increased and decreased gene expression, respectively (P < 2.8 × 10-6 for differentially methylated regions and P < 7.8 × 10-10 for differentially methylated probes). Quantitative analysis in 53 differentially expressed genes demonstrated that 32 (60%) have significant methylation-expression relationships within 5 kb of the gene. Ten loci selected based on the relevance to asthma, magnitude of methylation change, and methylation-expression relationships were validated in an independent cohort of children with atopic asthma. Sixty-seven of 186 genes also have significant asthma-associated methylation changes in nasal epithelia of adult white asthmatic patients. CONCLUSIONS: Epigenetic marks in respiratory epithelia are associated with allergic asthma and gene expression changes in inner-city children.

Asthma phenotypes in inner-city children.

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/mm3), 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.

Distinguishing characteristics of difficult-to-control asthma in inner-city children and adolescents.

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 ß-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, FEV1 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.

Pathways through which asthma risk factors contribute to asthma severity in inner-city children.

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.

From Design to Dissemination: Implementing Community-Based Participatory Research in Postdisaster Communities.

OBJECTIVES: To review how disasters introduce unique challenges to conducting population-based research and community-based participatory research (CBPR). METHODS: From 2007-2009, we conducted the Head-off Environmental Asthma in Louisiana (HEAL) Study in the aftermath of Hurricane Katrina in a Gulf Coast community facing an unprecedented triple burden: Katrina's and other disasters' impact on the environment and health, historic health disparities, and persistent environmental health threats. RESULTS: The unique triple burden influenced every research component; still, most existing CBPR principles were applicable, even though full adherence was not always feasible and additional tailored principles govern postdisaster settings. CONCLUSIONS: Even in the most challenging postdisaster conditions, CBPR can be successfully designed, implemented, and disseminated while adhering to scientific rigor.

Adapting and implementing an evidence-based asthma counseling intervention for resource-poor populations.

OBJECTIVE: To report implementation strategies and outcomes of an evidence-based asthma counseling intervention. The Head-off Environmental Asthma in Louisiana (HEAL) intervention integrated asthma counseling (AC) capacity and addressed challenges facing children with asthma in post-disaster New Orleans. METHODS: The HEAL intervention enrolled 182 children (4-12 years) with moderate-to-severe persistent asthma. Recruitment occurred from schools in the Greater New Orleans area for one year. Participants received home environmental assessments and tailored asthma counseling sessions during the study period based on the National Cooperative Inner City Asthma Study and the Inner City Asthma Study. Primary (i.e., asthma symptoms) and secondary outcomes (i.e., healthcare utilization) were captured. During the study, changes were made to meet the demands of a post-hurricane and resource-poor environment which included changes to staffing, training, AC tools, and AC sessions. RESULTS: After study changes were made, the AC visit rate increased by 92.3%. Significant improvements were observed across several adherence measures (e.g., running out of medications (p = 0.009), financial/insurance problems for appointments (p = 0.006), worried about medication side-effects (p = 0.01), felt medications did not work (p < 0.001)). Additionally, an increasing number of AC visits was modestly associated with a greater reduction in symptoms (test-for-trend p = 0.059). CONCLUSION: By adapting to the needs of the study population and setting, investigators successfully implemented a counseling intervention that improved participant behaviors and clinical outcomes. The strategies for implementing the AC intervention may serve as a guide for managing asthma and other chronic conditions in resource-poor settings.