Using this balanced, multi-omics approach, we describe shared and diverging transcriptional and phenotypic patterns—including increased levels of type I interferon-stimulated natural killer cells in COVID-19, cytotoxic CD8 T EMRA cells in both COVID-19 and influenza, and distinctive monocyte compositions between all groups—and thereby expand our understanding of the peripheral immune response in different etiologies of pneumonia. Here, CD8A is linked to susceptibility to pneumonia measurement.