Nasal Biomarkers of Acute Illness Severity and Predictors of Recurrent Wheeze in Respiratory Syncytial Virus (RSV) Infected Infants.

Abstract

Respiratory syncytial virus (RSV) is a leading cause of hospitalization in infants and those with RSV disease appear more likely to develop recurrent wheeze. We examined nasal airway gene expression and microbiome composition during acute primary RSV infection to test associations with illness severity and identify infants with recurrent wheeze. Previously healthy infants with confirmed RSV infection were enrolled (Dec 2019 to Dec 2023). Clinical, demographic data, 2 anterior nasal swabs and a nasal wash were collected for metagenome and transcriptome sequencing. Disease severity was measured by the improved Global Respiratory Severity Score (iGRSS). Participants were followed for approximately 1 year after enrollment to identify recurrent wheeze. Multivariate regression models were developed to identify correlates and predictors of disease severity and recurrent wheeze, respectively. 100 (90 hospitalized) infants were enrolled (mean age 3.2±2.3 months; 61% male). 405 genes (false discovery rate 0.10) were significantly and consistently associated with illness severity (iGRSS), implicating Innate Immune and Interleukin Signaling pathways. An abundance of Dolosigranulum in the nares was inversely associated with iGRSS while the abundance of Haemophilus was directly associated with iGRSS. Predictive models using nasal gene expression during acute infection had the power to classify recurrent wheeze (in-sample AUC=0.992; cross-validated AUC=0.882) while metagenomic features did not improve predictive performance. We prospectively followed infants with primary RSV infection and identified associations between nasal gene expression, microbiome composition/function and acute disease severity and recurrent wheeze. Host transcriptional profiles during infection were predictive of recurrent wheeze within the following year.