Introduction
Influenza A virus (IV) infections cause seasonal epidemics, which remain a major cause of morbidity and mortality worldwide. Disease severity depends on virological and host factors including age, immune status and comorbidities. The molecular signatures regulating host response dynamics that influence disease progression are poorly understood.

Methods
We analyzed and integrated cytokine and multi-Omic data (transcriptomic, cell deconvolution, metabolomic and lipidomic) from severe (n?=?135) and mild (n?=?126) influenza patients. Using MOFA (a factor analysis model) and Lasso regression, three factors (1, 4, and 6) were selected in a model predicting disease severity, adjusted for hypertension, a significant more prevalent condition among severe individuals, when considering the acute and post-infection time points.

Results
Two of the selected factors were strongly associated with hypertension. Enrichment scores for top cell type subsets showed significantly higher values for CD8+ T-cells, CD8+ Tcm (factor 1) in mild vs severe individuals at the acute phase and B-cells (factor 7) post-infection. Pathway enrichment on factors with transcriptomic signatures (factor 1 and 6) showed neutrophil degranulation and complement/coagulation cascades with a higher score in severe vs mild patients at early timepoints, meanwhile TCR signaling/T cell activation and IFN signaling were significantly lower in severe vs. mild individuals. Interestingly, antibody responses assessed against the globular head and stalk regions of the hemagglutinin glycoprotein showed that, regardless of disease severity, most individuals developed robust humoral responses against either H1 or H3 IV infection, indicating that antibody titers alone are a limited correlate of protection.

Conclusion
These findings suggest that early dysregulation of innate and cellular immune responses plays a crucial role in modulating disease outcome in individuals with hypertension, providing mechanistic insights into severity in this at-risk population.