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IL-6 high phenotype in childhood asthma

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PROJECT SUMMARY Asthma, now the most common chronic disease in childhood, disproportionately burdens minority children and children from low-income families. Obesity, also a prevalent disorder in children, increases the risk of asthma in adults. Systemic inflammation related to obesity, via production of mediators such as interleukin-6 (IL-6) by adipocytes and macrophages, may worsen airway inflammation. Recent studies in adult patients with asthma suggest the existence of a new ?IL-6 high phenotype? characterized by high concentrations of plasma IL-6. Adults in this phenotype have a higher body mass index (BMI), a higher prevalence of diabetes and hyperten- sion, worse lung function, and a greater number of asthma exacerbations. We recently performed a study in adults that corroborated the existence of the IL-6 high phenotype in both black and white patients with asthma; our study shows that this phenotype occurs almost exclusively in the ?T2-low phenotype? and correlates with BMI. This study and other recent work clearly suggests the clinical importance of this phenotype and sets the stage for anti-IL-6 therapeutic trials in adults with asthma. However, whether a similar IL-6 high phenotype ex- ists in children with asthma, and particularly whether this is related to obesity, is not known. Our major objec- tive is to determine whether an IL-6 high phenotype exists in children with asthma, and if so, whether this is associated with obesity. Prior to embarking on major multi-center clinical trials, a clear demonstration of this phenotype is required. We propose a single-center, observational study that focuses on children ages 6 to 17 with asthma in an urban, academic medical center and surrounding community. We will use a registry of such children, carefully characterized for asthma severity, atopy status, BMI, co-morbidities, and key clinical param- eters such as spirometry, serum IgE, and blood eosinophils, combined with community engagement in the south side of Chicago to recruit 100 normal-weighted and obese children, and will recruit 50 normal-weighted and obese children without known disease to serve as contrtols. Clinical data, BMI, spirometry, and biomarkers such as serum IgE, blood eosinophil count and exhaled nitric oxide will be compared to plasma IL-6 concentra- tions. Race-adjusted threshold values for plasma IL-6 will be established in the non-asthmatic children. We will determine whether this phenotype exists in pediatric asthma and, if so, whether the children with high IL-6 are separated from T2-high children, and whether obesity, defined as a BMI > 85th percentile for age and height, is associated with higher IL-6 concentrations. Demonstration of a IL-6 high phenotype in children with asthma in a single-center, observational trial will lead to larger studies that determine associations between IL-6, obesity, and asthma control, particularly in urban and minority children. Such studies will lay the ground-work for thera- peutic interventions that target IL-6 to attenuate airway inflammation and gain better control of poorly-controlled asthma in a vulnerable population, thereby providing a substantial benefit to health care.
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