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RATIONALE Children with preschool wheezing or school-age asthma are reported to have airway microbial imbalances. OBJECTIVE To identify clusters in children with asthma or wheezing using oropharyngeal microbiota profiles. METHODS Oropharyngeal swabs, from the Unbiased BIOmarkers for the Prediction of REspiratory Disease outcomes pediatric asthma/wheezing cohort, were characterized by 16S rRNA gene sequencing and unsupervised hierarchical clustering was performed on the Bray-Curtis β-diversity. Enrichment scores (ESs) of the MSigDB Hallmark gene sets were computed from the blood transcriptome using gene set variation analysis. Children with severe asthma or severe wheezing were followed up for 12-18 months, with assessing the frequency of exacerbations. MEASUREMENTS AND MAIN RESULTS Oropharyngeal samples of 241 children (age range: 1-17 years, 40% female) revealed 4 taxa-driven clusters dominated by Streptococcus, Veillonella, Rothia and Haemophilus, respectively. The clusters showed significant differences in atopic dermatitis, grass pollen sensitization, FEV1 % predicted post-salbutamol, and the annual asthma exacerbation frequency during follow-up. The Veillonella-cluster was the most allergic and included highest percentage of children with ≥2 exacerbations/year during follow-up. The oropharyngeal clusters were different in the ESs of transforming growth factor β (highest in Veillonella-cluster) and Wnt/β-Catenin signaling (highest in Haemophilus-cluster) transcriptomic pathways in blood (all q-values < 0.05). CONCLUSION The analysis of the oropharyngeal microbiota of children with asthma/wheezing identified four clusters with distinct clinical characteristics (phenotypes) that associate with exacerbations' risk and transcriptomic pathways involved in airway remodeling. This suggests that further exploration of the oropharyngeal microbiota may lead to novel pathophysiological insights and potentially new treatment approaches.

Rationale: A link among sphingolipids, 17q21 genetic variants, and childhood asthma has been suggested, but the underlying mechanisms and characteristics of such an asthma endotype remain to be elu...

Bacterial colonization of neonatal airways with the pathogenic bacterial species, Moraxella catarrhalis, Streptococcus pneumoniae, and Haemophilus influenzae, is associated with later development of childhood asthma.To study a possible association between colonization with pathogenic bacterial strains and the immune signature of the upper airways in healthy neonates.A total of 20 cytokines and chemokines were quantified in vivo in the airway mucosal lining fluid of 662 neonates from the Copenhagen Prospective Study of Asthma in Childhood 2010 birth cohort. Colonization of the hypopharynx with M. catarrhalis, S. pneumoniae, H. influenzae, and Staphylococcus aureus was assessed simultaneously. The association between immune signatures and bacterial colonization or noncolonized controls was analyzed using conventional statistical methods supplemented by a multivariate approach for pattern identification.Colonization with M. catarrhalis and H. influenzae induced a mixed T helper cell (Th) type 1/Th2/Th17 response with high levels of IL-1β (M. catarrhalis, P = 2.2 × 10(-12); H. influenzae, P = 7.1 × 10(-10)), TNF-α (M. catarrhalis, P = 1.5 × 10(-9); H. influenzae, P = 5.9 × 10(-7)), and macrophage inflammatory protein-1β (M. catarrhalis, P = 1.6 × 10(-11); H. influenzae, P = 2.7 × 10(-7)). S. aureus colonization demonstrated a Th17-promoting profile with elevated IL-17 levels (P = 1.6 × 10(-24)). S. pneumoniae colonization was not significantly associated with any of the mediators.M. catarrhalis and H. influenzae colonization of the airways of asymptomatic neonates is associated with an inflammatory immune response of the airway mucosa, which may result in chronic inflammation.