Abstract Rationale Most infants develop only mild upper respiratory illnesses (URIs) in response to viral infections. However, in some children these illnesses extend into the lower airways (LRIs) and become severe, requiring urgent care/hospitalization. Early-life severe LRIs (sLRIs) are strongly associated with later asthma development, but it is unclear whether this reflects: (1) a pre-existing airway/immune abnormality that predisposes to both severe illnesses and asthma, or (2) persistent airway injury and immune reprogramming caused by the sLRI itself. We asked whether children who go on to experience sLRIs show airway mucosal dysfunction at birth, and/or whether lasting airway changes are detectable after sLRI recovery, but before asthma onset. Methods Newborns were enrolled into the PRIMERO study and monitored weekly for respiratory symptoms through age 2. Illnesses with cough, wheeze, or shortness of breath were classified as LRIs; LRIs requiring systemic corticosteroids or hospitalization were classified as severe. Whole-transcriptome RNA-sequencing was performed on nasal swabs collected at birth and at a year 2 well visit. We performed differential expression with DESeq2 at each timepoint between children with ≥1 sLRI and children with no LRIs. ChatGPT was used to improve abstract readability and search for expression patterns. Results Of 1,042 children with surveillance and RNA-seq data, 433 experienced ≥1 sLRI and 609 had none. At birth, infants who later developed an sLRI already showed large-scale transcriptional differences (1,509 up- and 327 down-regulated genes). The sLRI group exhibited baseline upregulation of neutrophil/monocyte recruitment and activation programs (CXCL8/IL8, CCR1/CCR5), type 2 cytokine signaling (IL4R, IL13RA1, CRLF2, IL7R), interferon-stimulated genes (CXCL10, IRF7, IFITM1/2/3), and tissue remodeling/protease pathways (MMP1/3). Cell type enrichment revealed strong upregulation of neutrophils and inflammatory secretory cells. After recovery, at ∼2 years of age, the sLRI group showed even broader transcriptional reprogramming (3,477 up- and 3,185 down-regulated genes). Upregulated genes reflected amplified neutrophilic IL-1/TREM1 signaling, interferon and T2 inflammatory gene upregulation, markers of activated/exhausted T cells (LAG3, HAVCR2, TIGIT), and epithelial stress responses (KRT6A/6B). Downregulated genes were strongly enriched for multi-ciliated cells and included important barrier genes (CLDN1, TJP1). Conclusions Children who experience sLRIs exhibit an inflamed, immune-activated airway mucosa at birth that is poised for exaggerated responses to infection. After experiencing sLRIs, these children retain an inflamed airway mucosa, with mucociliary remodeling and barrier disruption, all before asthma diagnosis. These findings support a two-hit model in which both (1) airway/immune predisposition and (2) persistent post-viral airway reprogramming converge to drive asthma risk. This abstract is funded by: U01HL138626
Everman et al. (Fri,) studied this question.