Nasal Biomarkers of Acute Illness Severity and Predictors of Recurrent Wheeze in Infants Infected With Respiratory Syncytial Virus

BACKGROUND: 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 primary RSV infection to test associations with illness severity and identify infants with recurrent wheeze. METHODS: Previously healthy infants with RSV infection were enrolled (December 2019-December 2023). Clinical and demographic data were collected, as were 2 anterior nasal swabs and a nasal wash for metagenome and transcriptome sequencing. Disease severity was measured by the improved Global Respiratory Severity Score (iGRSS). Participants were followed for approximately 1 year to identify recurrent wheeze. Multivariate regression models were developed to identify correlates and predictors of disease severity and recurrent wheeze, respectively. RESULTS: One hundred infants (90 hospitalized) were enrolled (mean ± SD age, 3.2 ± 2.3 months; 61% male). An overall 405 genes (false discovery rate, 0.10) were significantly and consistently associated with illness severity (iGRSS), implicating innate immune and interleukin signaling pathways. The abundance of nasal Dolosigranulum was inversely associated with iGRSS, while the abundance of Haemophilus was directly associated with iGRSS. Predictive models based on nasal gene expression during infection had the power to classify recurrent wheeze (in-sample area under the curve, 0.992; cross-validated area under the curve, 0.882), while metagenomic features did not improve predictive performance. CONCLUSIONS: We prospectively followed infants with primary RSV infection and identified associations among 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.