Distinct peripheral inflammatory profiles distinguish COVID-19 from influenza infection, with limited contributions from cytokine storm

Abstract

Abstract We developed a prospective observational cohort of COVID-19 and influenza patients to assess the quality and magnitude of their immune responses at the cellular and protein levels. Although COVID-19 patients exhibited equivalent lymphocyte counts compared to influenza patients, they had fewer monocytes and lower surface HLA-class II expression on select monocyte populations compared to influenza patients and healthy controls. Decreased HLA-DR on intermediate monocytes was a significant predictor of COVID-19 disease severity. Protein cytokine levels were measured in two distinct COVID-19 cohorts, composed of 73 and 89 patients, revealing multiple inflammatory phenotypes. Only four percent of patients (7 of 162) exhibited a distinct Cytokine Storm Syndrome (CSS) phenotype. Furthermore, COVID-19 patients generally exhibited lower cytokine levels than influenza patients. Upregulation of a few innate inflammatory mediators, including IL-6, GCSF, IL-1RA, and MCP1, predicted death from acute respiratory failure among COVID-19 patients but were not statistically higher than those of influenza patients. Single-cell transcriptional profiling of 2 healthy controls as well as 3 COVID-19 and 3 influenza subjects with respiratory failure was concordant with the profound suppression in type I and type II interferon signaling in COVID-19 patients across multiple cell types. In contrast, COVID-19 cells were enriched for alterations in metabolic, stress, and apoptotic pathways. When considered across the spectrum of peripheral innate and adaptive immune profiles, the immune pathologies underlying severe influenza and COVID-19 are substantially distinct, with COVID-19 patients generally less inflamed than those with influenza.