Th1 Signatures Are Present in the Lower Airways of Children with Severe Asthma, Regardless of Allergic Status.

The pathogenesis of severe asthma in childhood remains poorly understood.To construct the immunological landscape in the airways of children with severe asthma.Comprehensive analysis of multiple cell types and mediators was performed by flow cytometry and multiplex assay using bronchoalveolar lavage (BAL) specimens (n=68) from 52 highly characterized allergic and non-allergic children (0.5-17 years) with severe treatment-refractory asthma. Multiple relationships were tested by linear mixed-effects modeling.Memory CCR5(+) Th1 cells were enriched in BAL fluid versus blood, and pathogenic respiratory viruses and bacteria were readily detected. IFN-γ(+)IL-17(+) and IFN-γ(-)IL-17(+) subsets constituted secondary Th types, and BAL CD8(+) T cells were almost exclusively IFN-γ(+). The Th17-associated mediators, IL-23 and MIP-3α/CCL20 were highly expressed. Despite low Th2 numbers, Th2 cytokines were detected and Th2-skewing correlated with total IgE levels. ILC2s and basophils were scarce in BAL fluid. Levels of IL-5, IL-33 and IL-28A/IFN-λ2, were increased in multi-sensitized children and correlated with IgE to dust mite, ryegrass and fungi, but not cat, ragweed or food sources. Additionally, levels of IL-5, but no other cytokine, increased with age and correlated with eosinophil numbers in BAL fluid and blood. Both plasmacytoid and IgE(+)FcεRI(+) myeloid dendritic cells were present in BAL fluid.The lower airways of children with severe asthma display a dominant Th1 signature, and atypical cytokine profiles that link to allergic status. Our findings deviate from established paradigms, and warrant further assessment of the pathogenicity of Th1 cells in severe asthma.