Vascular neutrophilic inflammation and immunothrombosis distinguish severe COVID-19 from influenza pneumonia

J Thromb Haemost. 2021 Feb;19(2):574-581. doi: 10.1111/jth.15179. Epub 2020 Dec 20.


Objective: Infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can lead to severe pneumonia, but also thrombotic complications and non-pulmonary organ failure. Recent studies suggest intravascular neutrophil activation 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) pneumonia, as well as to better understand its upstream regulation.

Approach and results: By comparing histopathological specimens of SARS-CoV-2 with influenza-affected lungs, we show that vascular neutrophil recruitment, NETosis, and subsequent immunothrombosis are typical features of severe COVID-19, but less prominent in influenza pneumonia. Activated neutrophils were typically found in physical association with monocytes. To explore this further, we combined clinical data of COVID-19 cases with comprehensive immune cell phenotyping and bronchoalveolar lavage fluid scRNA-seq data. We show that a HLADRlow CD9low monocyte population expands in severe COVID-19, which releases neutrophil chemokines in the lungs, and might in turn explain neutrophil expansion and pulmonary recruitment in the late stages of severe COVID-19.

Conclusions: Our data underline an innate immune cell axis causing vascular inflammation and immunothrombosis in severe SARS-CoV-2 infection.

Keywords: COVID-19; SARS-CoV-2; immunopathology; immunothrombosis; monocytes; neutrophils.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • COVID-19 / diagnosis
  • COVID-19 / immunology*
  • COVID-19 / virology
  • Diagnosis, Differential
  • Host-Pathogen Interactions
  • Humans
  • Immunity, Innate*
  • Influenza, Human / diagnosis
  • Influenza, Human / immunology*
  • Influenza, Human / virology
  • Lung / immunology*
  • Lung / pathology
  • Lung / virology
  • Neutrophils / immunology*
  • Neutrophils / virology
  • Predictive Value of Tests
  • SARS-CoV-2 / immunology
  • SARS-CoV-2 / pathogenicity
  • Thrombosis / immunology*
  • Thrombosis / virology
  • Vasculitis / immunology*
  • Vasculitis / virology