NETosis induction reflects COVID-19 severity and long COVID: insights from a 2-center patient cohort study in Israel, 2023, Nitzan Krinsky et al

[Mij]

Essentials

• Neutrophil extracellular trap formation (NETosis) induction levels by COVID-19 plasma correlate with illness severity, duration, platelet activation and coagulation factors.
• Long COVID syndrome is identified by elevated NETosis induction measurement in convalescent plasma of patients who sought medical care.
• NETosis induction level is a sensitive measurement to predict COVID-19 severity and long COVID.
• Neutrophil-targeted therapy may be an attractive approach in acute and chronic COVID-19.

Abstract
Background
COVID-19 severity and its late complications continue to be poorly understood. Neutrophil extracellular traps (NETs) form in acute COVID-19, likely contributing to morbidity and mortality.
Objectives
This study evaluated immunothrombosis markers in a comprehensive cohort of acute and recovered COVID-19 patients, including the association of NETs with long COVID.
Methods
One-hundred-seventy-seven patients were recruited from clinical cohorts at 2 Israeli centers: acute COVID-19 (mild/moderate, severe/critical), convalescent COVID-19 (recovered and long COVID), along with 54 non-COVID controls. Plasma was examined for markers of platelet activation, coagulation, and NETs. Ex vivo NETosis induction capability was evaluated after neutrophil incubation with patient plasma.
Results
Soluble P-selectin, factor VIII, von Willebrand factor, and platelet factor 4 were significantly elevated in patients with COVID-19 versus controls. Myeloperoxidase (MPO)-DNA complex levels were increased only in severe COVID-19 and did not differentiate between COVID-19 severities or correlate with thrombotic markers. NETosis induction levels strongly correlated with illness severity/duration, platelet activation markers, and coagulation factors, and were significantly reduced upon dexamethasone treatment and recovery. Patients with long COVID maintained higher NETosis induction, but not NET fragments, compared to recovered convalescent patients.
Conclusions
Increased NETosis induction can be detected in patients with long COVID. NETosis induction appears to be a more sensitive NET measurement than MPO-DNA levels in COVID-19, differentiating between disease severity and patients with long COVID. Ongoing NETosis induction capability in long COVID may provide insights into pathogenesis and serve as a surrogate marker for persistent pathology. This study emphasizes the need to explore neutrophil-targeted therapies in acute and chronic COVID-19.

https://www.jthjournal.org/article/S1538-7836(23)00274-X/fullte

 

[SNT Gatchaman]

Minor error in link, see: https://www.jthjournal.org/article/S1538-7836(23)00274-X/fulltext

 

[SNT Gatchaman]

A commentary was written on this paper at the time of publication in June: Poised to cast wide NETs in long COVID (2023, Journal of Thrombosis and Haemostasis, paywalled)

This was written by Stavros Giaglis, Laboratory for Experimental Rheumatology, Department of Biomedicine, University of Basel. I'm quoting some parts that illustrate the turn away from the BPS model.

Syndromes such as long COVID are not a new phenomenon. Despite the multifactorial pathogenesis, long COVID appears to be a typical organic postacute infection syndrome, with strong physiological dysfunction, and often not clearly obvious using standard diagnostic testing.

Other postacute infection syndromes, namely myalgic encephalomyelitis, chronic fatigue syndrome, postinfluenza syndrome, and posttreatment Lyme disease syndrome, share symptoms overlapping with those of long COVID. Inclusion of patients with such syndromes as control groups in long COVID studies might, therefore, prove significant for extending our overall comprehension and fortifying the impact of this field of research.

We may not yet adequately appreciate the precise nature and causes of disturbances in COVID-19 and long COVID and, consequently, may have failed so far to conceptualize and develop the proper means to confront them. The main concern appears to be a strong and persistent prothrombotic state and a particularly complex condition involving multiple interactions between cellular and humoral systems.