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⇱ Persistence of neutrophil extracellular traps and anticardiolipin auto-antibodies in post-acute phase COVID-19 patients - PubMed

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Abstract

In the early phase of the pandemic, we were among the first to postulate that neutrophil extracellular traps (NETs) play a key role in COVID-19 pathogenesis. This exploratory prospective study based on 279 individuals showed that plasma levels of neutrophil elastase, myeloperoxidase and circulating DNA of nuclear and mitochondrial origins in nonsevere (NS), severe (S) and postacute phase (PAP) COVID-19 patients were statistically different as compared to the levels in healthy individuals, and revealed the high diagnostic power of these NETs markers in respect to the disease severity. The diagnostic power of NE, MPO, and cir-nDNA as determined by the Area Under Receiver Operating Curves (AUROC) was 0.95, 097, and 0.64; 0.99, 1.0, and 0.82; and 0.94, 1.0, and 0.93, in NS, S, and PAP patient subgroups, respectively. In addition, a significant fraction of NS, S as well as of PAP patients exhibited aCL IgM/IgG and anti-B2GP IgM/IgG positivity. We first demonstrate persistence of these NETs markers in PAP patients and consequently of sustained innate immune response imbalance, and a prolonged low-level pro-thrombotic potential activity highlighting the need to monitor these markers in all COVID-19 PAP individuals, to investigate postacute COVID-19 pathogenesis following intensive care, and to better identify which medical resources will ensure complete patient recovery.

Keywords: COVID-19; anti-cardiolipin; circulating DNA; diagnosis; long COVID; neutrophil extracellular traps.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

👁 Figure 1
Figure 1
Study flow chart. PBDD: post blood draw delay; PAP: postacute phase.
👁 Figure 2
Figure 2
Nneutrophil extracellular traps (NETs)' association with COVID‐19 and postacute phase of COVID‐19. (A) Comparison of concentrations of NETs biomarkers (NE, MPO, cirDNA, cir‐mtDNA, and MNR) in healthy individuals (HI), nonsevere (NS), severe (S) and postacute phase (PAP) COVID‐19 patients. Lines represent median. T‐test was performed to compare the values of NETs biomarkers in COVID‐19 patients and HI. CirDNA: circulating cell‐free DNA; MPO, myeloperoxidase; NE, neutrophil elastase; cir‐mtDNA, circulating cell‐free DNA of mitochondrial origin; MNR, ratio of mitochondrial to nuclear circulating DNA concentration. Data obtained when combining NS and S patient cohorts (N = 70) are shown in Supporting Information: Figure 3S. (B) Correlation matrix of concentrations of NETs biomarkers (NE, MPO in ng/ml of plasma) with cirDNA markers (cirDNA, cir‐mtDNA in ng/ml plasma, MNR) in HI and NS, S, and PAP COVID‐19 patients. Heatmap manifests the strength of the relationship by Pearson's correlation analysis (red: positive correlation; blue: negative correlation). As shown in Supporting Information: Figure 2S the same observations are made when normalizing the concentration values with the neutrophil number suggesting that they are not directly due to the number of neutrophils. A probability of less than 0.05* was considered statistically significant; **p < 0.01, ***p < 0.001, ****p < 0.0001. Each dot represents the value of a single patient or a single healthy individual.
👁 Figure 3
Figure 3
Presence of the anti‐cardiolipin autoantibodies (anticardiolipin [aCL], IgG/IgM) and Beta‐2‐glycoprotein I antibodies (anti‐B2GPI, IgG/IgM) in nonsevere (NS), S, and postacute phase (PAP) COVID‐19 patients. Positive patient number in these cohorts are indicated in Supporting Information: Figure 7S. Measurement of aCL and the B2GPI, IgG/IgM in plasma subjects was performed using an ELISA kit. B2GP binds anionic phospholipids and is considered to be the predominant antigen in anti‐phospholipid syndrome (APS), with anti‐B2GP recognized in the laboratory criteria for APS diagnosis. An increased prevalence of anti‐B2GP outside of APS has been reported in several infections, as well as in a variety of other disorders (Supporting Information: Supplementary 1). The rather low aCL test specificity is improved by the use of the ELISA as a confirmatory, specific test for B2GPI antibodies, usually being performed after a positive screening test result for aCL. Quantitative assessment of aCL antibodies was considered for IgG or IgM ≥ 3 UA/ml (upon the 99th percentile in healthy controls using the Orgentec Diagnostika Elisa kit). Quantitative assessment of anti‐B2GP antibodies was considered for IgG ≥ 4 UA/ml and IgG ≥ 5 UA/ml (upon the 90th percentile). Note, IgG and IgM of aCL and anti‐B2GP are statistically associated in several S and PAP subjects validating the use of the cutoffs. A probability of less than 0.05* was considered statistically significant; **p < 0.01, ***p < 0.001, ****p < 0.0001.
👁 Figure 4
Figure 4
Performance characteristics of the neutrophil extracellular traps (NETs) biomarkers for COVID‐19. Receiver operating curves (ROC) curves for neutrophil elastase (NE), myeloperoxidase (MPO), cir‐nDNA, cir‐mtDNA concentrations and MNR between healthy individuals and COVID‐19 patients (nonsevere [NS], S, and postacute phase [PAP]). ROC curves of these markers in combining both NS and S COVID‐19 patient cohorts versus HI (AUC of 0.97, 0.99, 0.98, and 1.0 for NE, MPO, cir‐nDNA, and MNR, respectively), and in differentiating NS and S (0.81, 0.81, 0.72, and 0.60 for NE, MPO, cir‐nDNA, and MNR, respectively) are shown in Supporting Information: Figure 4S and 5S, respectively. The improved diagnostic power (AUC of 0.98 and 0.99 in NS and S cohorts, respectively) by combining NE and MPO concentrations is shown in Supporting Information: Figure 6S. AUC, area under curve; cirDNA, circulating cell‐free DNA; cir‐mtDNA, circulating cell‐free DNA of mitochondrial origin; MNR, ratio of mitochondrial to nuclear circulating DNA concentration; MPO, myeloperoxidase; NE, neutrophil elastase; ROC, receiver operating characteristics.

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