Rhinovirus-infected preschool children with problematic wheeze have lung eosinophilic inflammation.

Abstract

Rhinovirus (RV) infections are important triggers of wheezing illnesses in children and in infants are associated with the later development of asthma. In preschool children with treatment-refractory wheeze, we reported ∼30% had an active but silent RV infection, most with mixed lung neutrophilia and eosinophilia. This led us to speculate that RV infection might support the future inception of asthma through type 2 (T2) inflammatory pathways. We sought to demonstrate that the presence of an indolent RV infection would identify infants with eosinophilic inflammation and a T2 inflammatory signature in their airways. Children (≤5 years old) including those without (n = 26) and with RV infection (n = 13) underwent bronchoalveolar lavage (BAL). Eosinophils were quantified in BAL cell pellets, and eosinophil-derived neurotoxin (EDN) was measured in BAL fluid via enzyme immunoassay. BAL fluid was also evaluated for T2 inflammation-associated proteins via proximity extension assays. RNA was extracted from bronchial wall scrapings and expression of T2 signature genes evaluated by bulk RNA sequencing. RV was not associated with increased numbers of intact eosinophils but rather was associated with elevated concentrations of EDN. However, increased EDN could not be linked to the presence of either transcripts or proteins associated with a T2-high phenotype. In infants with severe treatment-refractory wheeze, the presence of EDN without canonical T2 cytokines suggests that lung eosinophils are not part of a typical T2 inflammatory response and may be a component of an antiviral immune response. RV-associated wheeze in this age group may identify infants at high risk of developing asthma in whom therapies targeting RV instead of T2 inflammation may prove more beneficial.