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Reassessment of omalizumab-dosing strategies and pharmacodynamics in inner-city children and adolescents.

ABSTRACT: Treatment regimens for omalizumab are guided by a dosing table that is based on total serum IgE and body weight. Limited data exist about onset and offset of omalizumab efficacy in children and adolescents or subgroups that most benefit from treatment.Post hoc analyses were conducted to (1) examine patient characteristics of those eligible and ineligible for omalizumab, (2) describe onset of effect after initiation of omalizumab and offset of treatment effect after stopping therapy, and (3) determine whether the efficacy differs by age, asthma severity, dosing regimen, and prespecified biomarkers.Inner-city children and adolescents with persistent allergic asthma were enrolled in the Inner-City Anti-IgE Therapy for Asthma trial that compared omalizumab with placebo added to guidelines-based therapy for 60 weeks.Two hundred ninety-three of 889 participants (33%) clinically suitable for omalizumab were ineligible for dosing according to a modified dosing table specifying IgE level and body weight criteria. Baseline symptoms were comparable among those eligible and ineligible to receive omalizumab, but other characteristics (rate of health care utilization and skin test results) differed. The time of onset of omalizumab effect was <30 days and time of offset was between 30 and 120 days. No difference in efficacy was noted by age or asthma severity, but high exhaled nitric oxide, blood eosinophils, and body mass index predicted efficacy.A significant portion of children and adolescents particularly suited for omalizumab because of asthma severity status may be ineligible due to IgE >1300 IU/mL. Omalizumab reduced asthma symptoms and exacerbations rapidly; features associated with efficacy can be identified to guide patient selection.

SUBMITTER: Sorkness CA

PROVIDER: S-EPMC4254887 | biostudies-literature | 2013 Mar

REPOSITORIES: biostudies-literature

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Reassessment of omalizumab-dosing strategies and pharmacodynamics in inner-city children and adolescents.

Sorkness Christine A CA Wildfire Jeremy J JJ Calatroni Agustin A Mitchell Herman E HE Busse William W WW O'Connor George T GT Pongracic Jacqueline A JA Ross Kristie K Gill Michelle A MA Kattan Meyer M Morgan Wayne J WJ Teach Stephen J SJ Gergen Peter J PJ Liu Andrew H AH Szefler Stanley J SJ

The journal of allergy and clinical immunology. In practice 20130226 2

<h4>Background</h4>Treatment regimens for omalizumab are guided by a dosing table that is based on total serum IgE and body weight. Limited data exist about onset and offset of omalizumab efficacy in children and adolescents or subgroups that most benefit from treatment.<h4>Objectives</h4>Post hoc analyses were conducted to (1) examine patient characteristics of those eligible and ineligible for omalizumab, (2) describe onset of effect after initiation of omalizumab and offset of treatment effec ...[more]

PMID: 24565455

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Project description:BackgroundTreatment 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.ObjectiveWe sought to identify the clinical characteristics that distinguish difficult-to-control asthma from easy-to-control asthma.MethodsAsthmatic 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.ResultsAmong 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.ConclusionsDespite 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.

Project description: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.

Project description:For adolescents growing up in poor urban South African settings, violence is often a part of daily life and has lasting effects on physical and mental health outcomes in adulthood. We conducted a qualitative study to document and understand the forms of interpersonal violence experienced by adolescents living in Hillbrow, Johannesburg. In this article, we explore how violence is experienced differently by adolescent boys and girls, how they conceptualise 'dangerous' and 'safe' spaces in their neighbourhood and what gaps exist in available services for youth in Hillbrow.The article draws on data collected in the formative phase of the 'Wellbeing of Adolescents in Vulnerable Environments' (WAVE) Study of challenges faced by adolescents (15-19 years) growing up in impoverished parts of five cities. This article reports on analysis using only data from the Johannesburg site. Using both purposive and snowball sampling to select participants, we conducted in-depth interviews (n = 20) and community mapping exercises with female (n = 19) and male (n = 20) adolescents living in Hillbrow, as well as key informant interviews with representatives of residential shelters, CBOs, and NGOs working with youth (n = 17). Transcripts were coded manually and analysed using an inductive thematic analysis approach.Both girls and boys reported high exposure to witnessing violence and crime. For girls, the threat of sexual harassment and violence was pervasive, while boys feared local gangs, the threat of physical violence, and being drawn into substance-abuse. Home was largely a safe haven for boys, whereas for girls it was often a space of sexual violence, abuse and neglect. Some adolescents developed coping mechanisms, such as actively seeking out community theatres, churches and other places of sanctuary from violence. Community-based services and shelters that support adolescents reported a lack of resources, overall instability and difficulties networking effectively.Adolescents in Hillbrow commonly witnessed and had direct experience of many forms of violence in their environment, and these experiences differed markedly by gender. Interventions that build young peoples' social capital and resilience are essential for reducing violence-related trauma and long-term health and social consequences for adolescents in this community.

Project description:BACKGROUND:Along with the rise in obesity, cardiovascular disease (CVD) has become the major cause of death in developed countries. Although overt coronary heart disease rarely manifests during childhood, atherosclerosis can begin by the second decade of life. Therefore, identifying reliable risk markers of early vascular disease in childhood could be important. Alteration in endothelial function (EF) is an early preclinical marker of the atherosclerotic process and can be assessed non-invasively using reactive hyperemia peripheral arterial tonometry (RH-PAT). The purpose of this study was to investigate if obesity in children is associated with lower EF as measured with RH-PAT, and if obese children with impaired glucose regulation have further impairment in RH-PAT measured EF compared to obese children with normal glucose tolerance. METHODS:Cardiovascular risk factors, adipocytokines and EF using RH-PAT were evaluated in lean (n?=?14) and obese (n?=?37) adolescents (age 12-18 years). Based on an oral glucose tolerance test, the obese group was subdivided into: obese with normal (NGT, n?=?22) and obese with impaired glucose regulation (IGR, n?=?15). RESULTS:RH-PAT score was lower in obese subjects compared to lean controls (1.70?±?0.02 vs. 1.98?±?0.09, P?=?0.02), indicating worse EF. This difference remained significant when adjusted for age, sex and ethnicity (P?=?0.02). We observed a pattern of worsening EF with increasing metabolic burden, with RH-PAT scores of 1.98?±?0.09,1.73?±?0.08 and 1.65?±?0.12 in the lean, obese-NGT and obese-IGR groups, respectively, ptrend?=?0.03. Obese subjects were more insulin resistant [higher HOMA] (p?=?0.03), and had higher levels of leptin (p?=?0.004), hsCRP (p?=?0.0004), and TNF-? (p?=?0.03) compared to lean subjects. Adjusting for insulin resistance and adipocytokines substantially attenuated the obesity association with RH-PAT, suggesting that insulin resistance and inflammation may mediate the association of EF with obesity. CONCLUSIONS:Risk factors for adult cardiovascular disease, including impaired EF, insulin resistance and inflammation, are evident in obese adolescents. Whether early detection of these cardiovascular risk factors will be useful for informing interventions to prevent disease progression needs further study. TRIAL REGISTRATION:Clinical Trials Identifier: NCT01879033.

Dataset Information

Reassessment of omalizumab-dosing strategies and pharmacodynamics in inner-city children and adolescents.

Publications

Reassessment of omalizumab-dosing strategies and pharmacodynamics in inner-city children and adolescents.

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