Untuned antiviral immunity in COVID-19 revealed by temporal type I/III interferon patterns and flu comparison

Andreakos and colleagues provide a longitudinal study comparing patients with COVID-19 to patients infected with influenza. They report a dysregulated interferon response whereby IFN-lambda and type I IFN production were diminished and delayed in patients with COVID-19, exhibiting a response that is 'untuned' with other inflammatory cytokines. A central paradigm of immunity is that interferon (IFN)-mediated antiviral responses precede pro-inflammatory ones, optimizing host protection and minimizing collateral damage(1,2). Here, we report that for coronavirus disease 2019 (COVID-19) this paradigm does not apply. By investigating temporal IFN and inflammatory cytokine patterns in 32 moderate-to-severe patients with COVID-19 hospitalized for pneumonia and longitudinally followed for the development of respiratory failure and death, we reveal that IFN-lambda and type I IFN production were both diminished and delayed, induced only in a fraction of patients as they became critically ill. On the contrary, pro-inflammatory cytokines such as tumor necrosis factor (TNF), interleukin (IL)-6 and IL-8 were produced before IFNs in all patients and persisted for a prolonged time. This condition was reflected in blood transcriptomes wherein prominent IFN signatures were only seen in critically ill patients who also exhibited augmented inflammation. By comparison, in 16 patients with influenza (flu) hospitalized for pneumonia with similar clinicopathological characteristics to those of COVID-19 and 24 nonhospitalized patients with flu with milder symptoms, IFN-lambda and type I IFN were robustly induced earlier, at higher levels and independently of disease severity, whereas pro-inflammatory cytokines were only acutely produced. Notably, higher IFN-lambda concentrations in patients with COVID-19 correlated with lower viral load in bronchial aspirates and faster viral clearance and a higher IFN-lambda to type I IFN ratio correlated with improved outcome for critically ill patients. Moreover, altered cytokine patterns in patients with COVID-19 correlated with longer hospitalization and higher incidence of critical disease and mortality compared to flu. These data point to an untuned antiviral response in COVID-19, contributing to persistent viral presence, hyperinflammation and respiratory failure.

Automated summary

Andreakos and colleagues conducted a study comparing patients with COVID-19 and influenza, finding that COVID-19 patients exhibited a dysregulated interferon response with diminished and delayed interferon production compared to flu patients. In COVID-19 patients, pro-inflammatory cytokines were produced before interferons and persisted longer, leading to worsened clinical outcomes.