Neutrophilia and NETopathy as Key Pathologic Drivers of Progressive Lung Impairment in Patients With COVID-19.

Teluguakula Narasaraju,Martin Herrmann,Benjamin M Tang,Vincent T K Chow,Sylviane Muller,Marko Radic

doi:10.3389/fphar.2020.00870

Abstract

There is an urgent need for new therapeutic strategies to contain the spread of the novel coronavirus disease 2019 (COVID-19) and to curtail its most severe complications. Severely ill patients experience pathologic manifestations of acute respiratory distress syndrome (ARDS), and clinical reports demonstrate striking neutrophilia, elevated levels of multiple cytokines, and an exaggerated inflammatory response in fatal COVID-19. Mechanical respirator devices are the most widely applied therapy for ARDS in COVID-19, yet mechanical ventilation achieves strikingly poor survival. Many patients, who recover, experience impaired cognition or physical disability. In this review, we argue the need to develop therapies aimed at inhibiting neutrophil recruitment, activation, degranulation, and neutrophil extracellular trap (NET) release. Moreover, we suggest that currently available pharmacologic approaches should be tested as treatments for ARDS in COVID-19. In our view, targeting host-mediated immunopathology holds promise to alleviate progressive pathologic complications of ARDS and reduce morbidities and mortalities in severely ill patients with COVID-19.

Highlights

The recent coronavirus disease 2019 (COVID-19) pandemic that started in Hubei Province of China has spread rapidly around the world (Wu J. et al, 2020; Zhu et al, 2020)
COVID19 is caused by SARS-coronavirus-2 (SARS-CoV-2), which belongs to the coronavirus family and is related to severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS) viruses
Detailed analyses of bronchoalveolar lavage (BAL) for indicators of neutrophil activation and neutrophil extracellular trap (NET) release are urgently needed to determine if neutrophilic influx, and NETosis are important drivers of progressive pulmonary pathology in the most severe cases of COVID-19

Summary

INTRODUCTION

The recent coronavirus disease 2019 (COVID-19) pandemic that started in Hubei Province of China has spread rapidly around the world (Wu J. et al, 2020; Zhu et al, 2020). Found that critically ill patients develop high neutrophilia before succumbing to infection, confirming the association between excessive neutrophil loads and acute lung pathology in fatal COVID-19. In severe COVID-19, greater neutrophilia may drive elevated pulmonary influx of neutrophils and stimulate excessive NET release, which can exacerbate alveolar-capillary damage and lead to pathologic manifestation of ARDS (Figure 1). Detailed analyses of BAL for indicators of neutrophil activation and NET release are urgently needed to determine if neutrophilic influx, and NETosis are important drivers of progressive pulmonary pathology in the most severe cases of COVID-19. Administration of drugs that prevent neutrophil recruitment and activity may effectively attenuate the pathologic complications of alveolitis and vascular injury in patients with COVID-19 (Figure 1), and initial results of several treatment strategies have been reported (COVID-19 Treatment Guidelines Panel). The effect of P140 on the neutrophil influx in the bronchoalveolar space requires specific attention

Inhibitors of Neutrophil Migration and Activation

Inhibitors of Neutrophil Proteases

Inhibitors of Peptidylarginine Deiminase IV

Findings

Future Therapeutic Choices