Research Article: Endotypes of difficult-to-control asthma in inner-city African American children

Date Published: July 7, 2017

Publisher: Public Library of Science

Author(s): K. R. Brown, R. Z. Krouse, A. Calatroni, C. M. Visness, U. Sivaprasad, C. M. Kercsmar, E. C. Matsui, J. B. West, M. M. Makhija, M. A. Gill, H. Kim, M. Kattan, D. Pillai, J. E. Gern, W. W. Busse, A. Togias, A. H. Liu, G. K. Khurana Hershey, Heinz Fehrenbach.


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.

Partial Text

Asthma is a heterogeneous disease comprised of varying clinical, cellular, and molecular phenotypes[1]. Cluster analyses of well-characterized asthma cohorts have identified several distinct clinical phenotypes in adults and children, but they have limited ability to improve management or guide treatment choices because the phenotypes often overlap and do not necessarily relate to specific underlying pathophysiologic mechanisms[2–4]. Further, although cluster studies have identified distinct molecular phenotypes of severe asthma, these phenotypes have not proven to vary by race despite the differing clinical phenotypes. Recently, it has been suggested that the asthma burden seen in urban US populations may be largely explained by demographic factors such as race rather than by environmental factors secondary to living in an urban location[5, 6]. Accordingly, a comparable prevalence of asthma was found in urban and rural populations of African Americans teenagers[7]. African Americans have higher rates of asthma prevalence, morbidity, and mortality in comparison with other racial groups in America[8–10]. It has been suggested that this racial disparity cannot be explained solely by socioeconomic or environmental factors with black race being reported as an independent risk factor for asthma[11, 12]. Collectively, these findings suggest that immunologic profiles that characterize asthma in African Americans may predispose to more severe or difficult to control phenotypes. Interestingly, higher TH17 activation was reported in Asians versus European Americans with atopic dermatitis, suggesting a racial difference in immunologic mechanisms of disease[13].

Despite the strong racial disparities observed in asthma morbidity, previous studies have not characterized immunophenotypes of Difficult-to-Control asthma in African American children[23, 24]. We found that although blood eosinophils and neutrophils were useful biomarkers of Difficult-to-Control asthma, serum cytokines significantly enhanced the definition of Difficult-to-Control asthma. Mixed responses characterized by IL-5 and IL-17 upregulation were associated with Difficult-to-Control disease while IL-4 and IL-13 were associated with Easy-to-Control asthma. This data may contribute to the ability to risk stratify this population of Difficult-to-Control asthmatics. These findings may have important treatment implications as they suggest consideration of the use of biologics to target multiple inflammatory pathways in African American children with Difficult-to-Control asthma.




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