Coronavirus disease 2019 (COVID-19) is characterized by a high incidence of acute
respiratory failure. The underlying immunopathology of that failure and how it compares to other causes of severe respiratory distress, such as influenza virus
infection, are not fully understood. Here we addressed this by developing a prospective observational cohort of
COVID-19 and
influenza subjects with varying degrees of disease severity and assessing the quality and magnitude of their immune responses at the cellular and
protein level. Additionally, we performed single-cell
RNA transcriptional profiling of peripheral blood mononuclear cells from select subjects. The cohort consists of 79
COVID-19 subjects, 26
influenza subjects, and 15 control subjects, including 35
COVID-19 and 7
influenza subjects with acute
respiratory failure. While
COVID-19 subjects exhibited largely equivalent or greater activated lymphocyte counts compared to
influenza subjects, they had fewer monocytes and lower surface HLA-class II expression on monocytes compared to
influenza subjects and controls. At least two distinct immune profiles were observed by
cytokine levels in severe
COVID-19 patients: 3 of 71 patients were characterized by extreme
inflammation, with greater than or equal to ~50% of the 35
cytokines measured greater than 2 standard deviations from the mean level of other severe patients (both
influenza and
COVID-19); the other immune profile, which characterized 68 of 71 subjects, had a mixed inflammatory signature, where 28 of 35
cytokines in
COVID-19 patients had lower mean
cytokine levels, though not all were statistically significant. Only 2
cytokines were higher in
COVID-19 subjects compared to
influenza subjects (IL-6 and IL-8).
Influenza and
COVID-19 patients could be distinguished statistically based on
cytokine module expression, particularly after controlling for the significant effects of age on
cytokine expression, but again with lower levels of most
cytokines in
COVID-19 subjects. Further, high circulating levels of
IL-1RA and
IL-6 were associated with increased odds of intubation in the combined
influenza and
COVID-19 cohort [OR = 3.93 and 4.30, respectively] as well as among only
COVID-19 patients. Single cell transcriptional profiling of
COVID-19 and
influenza subjects with
respiratory failure identified profound suppression in type I and
type II interferon signaling in
COVID-19 patients across multiple clusters. In contrast,
COVID-19 cell clusters were enriched for alterations in metabolic, stress, and apoptotic pathways. These alterations were consistent with an increased
glucocorticoid response in
COVID-19 patients compared to
influenza. When considered across the spectrum of innate and adaptive immune profiles, the immune pathologies underlying severe
influenza and
COVID-19 are substantially distinct. The majority of
COVID-19 patients with acute
respiratory failure do not have a
cytokine storm phenotype but instead exhibit profound type I and type II IFN immunosuppression when compared to patients with acute
influenza. Upregulation of a small number of inflammatory mediators, including
IL-6, predicts acute
respiratory failure in both
COVID-19 and
influenza patients.