Objective: Infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can lead to severe pneumonia and acute respiratory distress syndrome (ARDS), but also thrombotic complications along with non-pulmonary multi-organ failure. Recent studies suggest intravascular neutrophil hyperactivation and subsequent immune cell triggered immunothrombosis as a central pathomechanism linking the heterogenous clinical picture of Coronavirus Disease 2019 (COVID-19). We sought to study whether immunothrombosis is a pathognomonic factor in COVID-19 or a general feature of (viral) pneumonias, and to gain further insights into regulatory mechanisms upstream of the immune cell mediated prothrombotic state.

Approach and results: By comparing histopathological specimens of patients succumbed to pulmonary SARS-CoV-2 infection with lungs affected by H1N1 or seasonal influenza, we show that vascular neutrophil recruitment, neutrophil extracellular trap formation (NETosis), and subsequent immunothrombosis are typical features of severe COVID-19, but less prominent in H1N1 and seasonal influenza pneumonia. Activated neutrophils were typically found in close proximity to monocytes. To explore this interaction further, we combined clinical data of COVID-19 cases with comprehensive flow cytometry-based immune cell phenotyping and bronchoalveolar lavage fluid scRNA-seq data. We show that a HLADR^low CD9^low monocyte population expands in severe COVID-19, which releases neutrophil-attracting chemokines in the lung. This might in turn explain neutrophil expansion and activation as well as enhanced pulmonary neutrophil recruitment in the late stages of severe COVID-19.

Conclusions: In summary, our data underline an innate immune cell axis comprising a specific monocyte subpopulation and activated neutrophils, which together cause vascular inflammation and immunothrombosis in severe SARS-CoV-2 infection.