The basis of the varied immune responses seen to SARS-CoV-2 and other respiratory infections remains unclear. This preprint by Mudd et al. used single-cell RNA sequencing of PBMCs from patients with COVID-19 or influenza to ascertain disease-specific signatures. The authors identified two select cytokine modules (namely, IL-1RA and IL-6) that correlated with COVID-19 disease severity and were predictive of poor outcomes. By contrast, patients with influenza exhibited higher generalized inflammation. Compared with patients with influenza, patients with COVID-19 had reduced monocyte subsets, as well as lymphopenia, and exhibited a suppressed type I interferon response across multiple immune cell types. Interestingly, these cells, and especially the monocytes, showed enriched glucocorticoid and metabolic stress signalling. These data provide key insights that may guide the design of disease-specific therapies before the start of a new flu season.