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.
Asthma phenotypes in inner-city children Zoratti, Edward M., MD; Krouse, Rebecca Z., MS; Babineau, Denise C., PhD, MS ...
Journal of allergy and clinical immunology,
10/2016, Letnik:
138, Številka:
4
Journal Article
Recenzirano
Odprti dostop
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.
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, 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.
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.
CASI scores in each of the 5 domains were aligned with the National Asthma Education and Prevention Program Expert Panel Report asthma guidelines.8 As a result, a 1-point change in CASI score ...corresponds to either a 1-point increase in the participant's asthma control level (for day symptoms/albuterol use, night symptoms/albuterol use, and lung function measure) or a change in medication (inhaled corticosteroids for the controller treatment domain and prednisone for the exacerbation domain). ...a 1-point difference in any domain constitutes a change that could be considered clinically significant, serving as a lower bound for the MID. ...APIC's observational design presents a limitation to the analysis; validation of the results using a true case-control population would be valuable.
Background Cockroach allergy is a key contributor to asthma morbidity in children living in urban environments. Objective We sought to document immune responses to cockroach allergen and provide ...direction for the development of immunotherapy for cockroach allergy. Methods Four pilot studies were conducted: (1) an open-label study to assess the safety of cockroach sublingual immunotherapy (SLIT) in adults and children; (2) a randomized, double-blind biomarker study of cockroach SLIT versus placebo in adults; (3) a randomized, double-blind biomarker study of 2 doses of cockroach SLIT versus placebo in children; and (4) an open-label safety and biomarker study of cockroach subcutaneous immunotherapy (SCIT) in adults. Results The adult SLIT trial (n = 54; age, 18-54 years) found a significantly greater increase in cockroach-specific IgE levels between the active and placebo groups (geometric mean ratio, 1.92; P < .0001) and a trend toward increased cockroach-specific IgG4 levels in actively treated subjects ( P = .09) but no evidence of functional blocking antibody response. The pediatric SLIT trial (n = 99; age, 5-17 years) found significant differences in IgE, IgG, and IgG4 responses between both active groups and the placebo group but no consistent differences between the high- and low-dose groups. In the SCIT study the treatment resulted in significant changes from baseline in cockroach IgE, IgG4 , and blocking antibody levels. The safety profile of cockroach immunotherapy was reassuring in all studies. Conclusions The administration of cockroach allergen by means of SCIT is immunologically more active than SLIT, especially with regard to IgG4 levels and blocking antibody responses. No safety concerns were raised in any age group. These pilot studies suggest that immunotherapy with cockroach allergen is more likely to be effective with SCIT.
Background Atopic sensitization (ie, atopy) is the most commonly reported risk factor for asthma. Recent studies have begun to suggest that atopy, as conventionally defined, might be an umbrella term ...that obfuscates more specific allergic disease types. Objective We sought to determine whether distinct and meaningful atopic phenotypes exist within a racially diverse birth cohort using 10 allergen-specific serum IgE (sIgE) measurements from children aged 2 years. Methods Using the Wayne County Health, Environment, Allergy and Asthma Longitudinal Study (WHEALS) birth cohort (62% black), we analyzed sIgE data on 10 allergens ( Dermatophagoides farinae , dog, cat, timothy grass, ragweed, Alternaria alternata , egg, peanut, milk, and German cockroach) obtained from 594 children at age 2 years. Conventional atopy was defined as at least 1 sIgE level of 0.35 IU/mL or greater. Results A 4-class solution (latent class model) was the best fit. Class types were labeled “low to no sensitization” (76.9% of sample), “highly sensitized” (2.7%), “milk and egg dominated” (15.3%), and “peanut and inhalant(s)” (5.1%). Almost one third (32.2%) of the low to no sensitization group met the criteria for conventional atopy. The highly sensitized group was significantly associated with a doctor's diagnosis of asthma after age 4 years (odds ratio OR, 5.3; 95% CI, 1.6-17.4), whereas the milk and egg dominated and peanut and inhalant(s) groups were not (ORs of 1.6 95% CI, 0.8-3.0 and 1.8 95% CI, 0.6-4.9, respectively). Children of black race were more likely to be in the 3 multisensitized groups ( P = .04). Conclusion Classification by sIgE patterns defined groups whose membership is more strongly associated with atopic dermatitis, wheeze, and asthma compared with conventional atopy.
Background Allergy-related studies that include biological measurements of vitamin D preceding well-measured outcomes are needed. Objective We sought to examine the associations between early-life ...vitamin D levels and the development of allergy-related outcomes in the racially diverse Wayne County Health, Environment, Allergy, and Asthma Longitudinal Study birth cohort. Methods 25-Hydroxyvitamin D (25OHD) levels were measured in stored blood samples from pregnancy, cord blood, and age 2 years. Logistic regression models were used to calculate odds ratios (ORs) with 95% CIs for a 5 ng/mL increase in 25(OH)D levels for the following outcomes at age 2 years: eczema, skin prick tests (SPTs), increased allergen-specific IgE level (≥0.35 IU/mL), and doctor's diagnosis of asthma (3-6 years). Results Prenatal 25(OH)D levels were inversely associated with eczema (OR, 0.85; 95% CI, 0.75-0.96). The association was stronger in white children (white children: OR, 0.79; 95% CI, 0.57-1.09; black children: OR, 0.96; 95% CI, 0.82-1.12), although this was not statistically significant. Cord blood 25(OH)D levels were inversely associated with having 1 or more positive SPT responses and aeroallergen sensitization. Both associations were statistically significant in white children (positive SPT response: OR, 0.50; 95% CI, 0.32-0.80; ≥1 aeroallergen sensitization: OR, 0.50; 95% CI, 0.28-0.92) in contrast with black children (positive SPT response: OR, 0.88; 95% CI, 0.68-1.14; ≥1 aeroallergen sensitization: OR, 0.85; 95% CI, 0.65-1.11). 25(OH)D levels measured concurrently with outcome assessment were inversely associated with aeroallergen sensitization (OR, 0.79; 95% CI, 0.66-0.96) only among black children (white children: OR, 1.21; 95% CI, 0.87-1.69). Conclusions Prenatal and cord blood 25(OH)D levels were associated with some allergy-related outcomes, with a general pattern indicating that children with higher 25(OH)D levels tend to have fewer allergy-related outcomes.
Recruitment for research studies is a challenging endeavor that was further complicated by the coronavirus disease 2019 pandemic. We launched a new multicenter birth cohort, Childhood Allergy and the ...NeOnatal Environment (CANOE), supported by the National Institutes of Health in January 2020 across 4 sites. Although the pandemic temporarily halted clinical research, we restructured the study and instituted novel recruitment methods that we hypothesized would enable brisk enrollment when research activities resumed.
We sought to develop protocol modifications and recruitment methods that promote successful recruitment of diverse populations in clinical research despite a global pandemic.
Even though study activities were suspended, we modified recruitment strategies to limit in-person contact, shifting toward alternative HIPAA-compliant methods such as clinician referrals, institutional social media, and telemedicine screening and consent procedures. Protocol changes included reducing the frequency of in-person visits, leveraging clinical care visits to collect biospecimens, expanded self-collection of samples at home, and making study materials available online.
Remote methods, including targeted social media posts, mailed letters, and email, combined with in-clinic recruitment with modifications for social distancing led to successful recruitment at all sites. Rates of consent have been similar across recruitment sites, with the highest rates of enrollment of mother-infant dyads realized by sites that implemented multiple recruitment strategies.
Study procedures that prioritize health and safety measures such as social distancing, study participant convenience, and use diverse recruitment strategies enable successful enrollment of pregnant women and their newborns into clinical research while adhering to public health restrictions during a global pandemic.
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