J Thromb Haemost . Vascular neutrophilic inflammation and immunothrombosis distinguish severe COVID-19 from influenza pneumonia

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J Thromb Haemost


. 2020 Nov 20.
doi: 10.1111/jth.15179. Online ahead of print.
Vascular neutrophilic inflammation and immunothrombosis distinguish severe COVID-19 from influenza pneumonia


Leo Nicolai ^{1 2 3} , Alexander Leunig ^{1 2} , Sophia Brambs ¹ , Rainer Kaiser ^{1 2 3} , Markus Joppich ⁴ , Marie Hoffknecht ¹ , Christoph Gold ¹ , Anouk Engel ¹ , Vivien Polewka ¹ , Maximilian Muenchhoff ^{3 5 6} , Johannes C Hellmuth ^{3 7 8} , Adrian Ruhle ^{3 5} , Stephan Ledderose ⁹ , Tobias Weinberger ^{1 2 3} , Heiko Schulz ⁹ , Clemens Scherer ^{1 2 3} , Martina Rudelius ⁹ , Michael Zoller ¹⁰ , Oliver T Keppler ^{3 5 6} , Bernhard Zwi?ler ¹⁰ , Michael von Bergwelt-Baildon ^{3 7 8} , Stefan K??b ^{1 2 3} , Ralf Zimmer ⁴ , Roman D B?low ¹¹ , Saskia von Stillfried ¹¹ , Peter Boor ^{11 12} , Steffen Massberg ^{1 2 3} , Kami Pekayvaz ^{1 2 3} , Konstantin Stark ^{1 2 3}



Affiliations

• PMID: 33217134
• DOI: 10.1111/jth.15179

Abstract

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 HLADR^low CD9^low monocyte population expands in severe COVID-19, which releases neutrophil chemokines in the lung, and might in turn explain neutrophil expansion and pulmonary recruitment in the late stages of severe COVID-19.
Conclusions: In summary, 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.