NET Biomarkers in COVID-19 and Post-COVID Syndrome: a Comprehensive Analysis

TL;DR

This study shows that neutrophil extracellular traps (NETs) remain elevated in some patients after recovering from COVID-19, possibly contributing to long-term symptoms known as post-COVID syndrome.

Contribution

The study identifies persistent NET biomarkers in post-COVID syndrome patients and links them to ongoing inflammation and immune responses.

Findings

NET biomarkers were significantly elevated in acute COVID-19 and remained high in post-COVID syndrome patients.

A NETosis-based model accurately distinguished acute and post-COVID syndrome patients from healthy controls.

NET biomarkers correlated with neutrophil counts, cytokines, and inflammatory markers in both acute and post-COVID phases.

Abstract

SARS-CoV-2 triggers immune responses, including neutrophil activation and neutrophil extracellular trap (NET) release, contributing to COVID-19 severity. A significant proportion of patients experience persistent or new symptoms after recovery, referred to as post-COVID syndrome (PCS), which may be associated with NET release persistence. This study aimed to investigate whether NET-related biomarkers remain elevated after acute SARS-CoV-2 infection and to explore their association with PCS. We conducted an analytical descriptive cohort study including patients with acute COVID-19 (n = 35), PCS (n = 35), and a pre-pandemic healthy control group (PPC; n = 35). Serum samples from participants were used to measure NET biomarkers, including MPO-DNA complexes, elastase-DNA complexes, and MPO levels. The capacity to induce NETosis in vitro was evaluated by incubating neutrophils with participant serum. Additionally, soluble immune markers, including cytokines, anti-SARS-CoV-2 antibodies, and autoantibodies, were assessed. A NETosis-based model was developed using NET biomarkers to distinguish between acute COVID-19 or PCS patients and PPC individuals. Our findings revealed a significant increase in NET biomarkers during acute COVID-19 that persisted in PCS. This pattern was consistent with the in vitro study, where sera from PCS patients induced NET release. Additionally, NET biomarkers correlated with neutrophil counts, cytokines, autoantibodies, and inflammatory markers during acute COVID-19 and PCS. The multivariate model of NET biomarkers exhibited a high accuracy in distinguishing acute COVID-19 with an area under the curve (AUC) of 0.99 (CI = 0.98–1.00) and PCS patients with an AUC of 0.91 (CI = 0.84–0.99) from PPC. These findings suggest that persistent NETosis may contribute to PCS pathophysiology, highlighting NETs as potential biomarkers and therapeutic targets in post-viral syndromes.

The online version contains supplementary material available at 10.1007/s10875-026-01980-9.

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