Unique Airway Immune Responses and Epithelial Pathobiology Underlie Viral Wheezing Illnesses in Young Children

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Abstract RATIONALE: Viral infections are common in early childhood, with most children either being asymptomatic or having only upper respiratory symptoms. However, some children develop lower respiratory symptoms, including wheezing, which can result in hospitalization. A subset of these children have repeated wheezing episodes, leading to a higher risk of asthma later in childhood. Wheezing illnesses are precipitated by host-virus interactions that remain poorly understood. This study investigates the viral and molecular factors differentiating viral wheezing illnesses from non-wheezing viral infections in young children with a history of with recurrent wheeze. METHODS: Children aged 18-36 months with public insurance or from high-poverty census tracts and ≥3 wheezing episodes were enrolled in the WINDOWS study during an acute wheezing illness at the emergency department (ED) or at a non-illness clinic visit. Nasal swabs were collected for RNA-sequencing, with data processed through a viral metagenomic pipeline. Viral infection rates were compared between wheezing illnesses and non-illness clinic visits. RNA-seq data was analyzed using co-expression network analysis, and gene network responses to viral infections during wheezing illnesses were compared to clinic detected, non-wheezing viral infections. RESULTS: 93.4% of children with wheezing illnesses (n=91) carried a virus compared to 39.2% without illness (n=102, OR: 26.2, p<0.001). Overall viral load was 3.3-fold higher in wheezing illness (p=0.06). HRV-C infections were more common in wheezing illnesses (57.6% vs. 42.5%, p=0.05), and HRV-A was more common without wheezing illness (16.5% vs. 32.5%, p=0.02). Eighteen of 21 networks were differentially expressed in either or both of the virus+ groups when compared to children without viral infection (Figure 1). Interferon signaling and neutrophilic/monocyte immune-response networks were similarly upregulated in both virus+ groups. In contrast, B-cell and CD8+ T-cell networks were strongly induced with virus+ non-illness group but weakly induced with virus+ wheezing illness group. The squamous/mucus secretory and T2 mast cell networks were specifically upregulated in virus+ wheezing illnesses, whereas ciliated cell networks were downregulated more strongly in this group. Notably, epithelial T2 and a mucus secretory network were downregulated in the virus+ non-illness group, but not with virus+ wheezing illness. CONCLUSIONS: Wheezing illnesses in young children are associated with HRV-C infections and higher viral loads. These viral illnesses cause normal adaptive immune responses to infection to be suppressed, but fail to suppress epithelial T2 inflammation and mucus production, resulting in squamous and mucus metaplasia. Our data suggest aberrant host airway responses to viral infection underlie wheezing illness development.

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