NETosis induction reflects COVID-19 severity and long COVID: insights from a 2-center patient cohort study in Israel

Krinsky, Nitzan; Sizikov, Sofia; Nissim, Sivan; Dror, Adi; Sas, Anna; Prinz, Hodaya; Pri-Or, Ester; Perek, Shay; Raz-Pasteur, Ayelet; Lejbkowicz, Izabella; Cohen-Matsliah, Sivan Ida; Almog, Ronit; Chen, Nikanor; Kurd, Ramzi; Jarjoui, Amir; Rokach, Ariel; Ben‐Chetrit, Eli; Schroeder, Avi; Caulin, Aleah F.; Yost, Christian C.; Schiffman, Joshua D.; Goldfeder, Mor; Martinod, Kimberly

doi:10.1016/j.jtha.2023.02.033

Cited by 26 publications

(15 citation statements)

References 64 publications

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“… 3 The previous studies showed the association between the extent of NETosis and the COVID‐19 severity. 42 , 43 , 44 Since the role of NETs has been documented in the development of anti‐CCP, the higher production of anti‐CCP in severe forms of COVID‐19 patients in our study may be attributed to the extent of NETosis in severe forms of COVID‐19, which warrants further investigations. In contrast, we could not find higher levels of anti‐CCP in our critical patients, which may be attributed to the effects of other factors that provoke the development of anti‐CCP, including shared epitope (SE), PADI4 polymorphism, smoking status, and other genetic and environmental factors that affect the production of anti‐CCP.…”

Section: Discussionmentioning

confidence: 68%

The development of anticyclic citrullinated peptide (anti‐CCP) antibody following severe COVID‐19

Roghani,

Dastbaz,

Lotfi

et al. 2024

Immunity Inflam & Disease

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ObjectivesThe dysregulated immune response is one of the cardinal features of severe coronavirus disease 2019 (COVID‐19). This study was conducted to clarify the occurrence of autoantibodies (AABs) associated with systemic autoimmune rheumatic diseases (SARDs) in hospitalized patients with a moderate, severe, and critical form of COVID‐19.MethodsThe serum samples obtained from 176 hospitalized COVID‐19 patients were investigated in this study, including patients with moderate (N = 90), severe (N = 50), and critical (N = 36) forms of COVID‐19. Also, the serum samples collected from healthy subjects before the COVID‐19 pandemic were used as controls (N = 176). The antinuclear antibodies (ANAs), antidouble‐stranded DNA (anti‐dsDNA), cytoplasmic‐anti neutrophil cytoplasmic antibody (c‐ANCA), perinuclear ANCA (p‐ANCA), antiphospholipid antibodies (aPLs), and anticyclic citrullinated peptide (anti‐CCP) occurrence was evaluated using a solid‐phase enzyme‐linked immunosorbent assay (ELISA).ResultsThe results showed that the occurrence of ANAs, anti‐dsDNA, anti‐CCP, c‐ANCA, and p‐ANCA was significantly higher in the COVID‐19 patients compared to serum obtained from healthy subjects (p < .0001, p < .0001, p < .0001, p < .05, and p < .001, respectively). The positive number of anti‐CCP tests increased significantly in severe COVID‐19 compared to the moderate group (p < .01).ConclusionOur study further supports the development of autoantibodies related to systemic autoimmune rheumatologic diseases. To the best of our knowledge, this is the first study with a large sample size that reported the occurrence of anti‐CCP in a severe form of COVID‐19.

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Section: Discussionmentioning

confidence: 68%

The development of anticyclic citrullinated peptide (anti‐CCP) antibody following severe COVID‐19

Roghani,

Dastbaz,

Lotfi

et al. 2024

Immunity Inflam & Disease

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“…However, inhaled DNase1 may have limited efficacy in severe and critical patients where pulmonary microvessels may already be obstructed by microthrombi. In contrast, administering inhaled DNase1 to patients at an early stage of NET-DNase activity imbalance may be effective in preventing further clinical deterioration or development of long COVID [ 39 ]. Our results also encourage the development of systemic DNase administration, either subcutaneously, as recently demonstrated in a mouse model of COVID-19 [ 40 ], or intravenously, as proposed in mouse models where increased NETosis is involved.…”

Section: Discussionmentioning

confidence: 99%

Impaired balance between neutrophil extracellular trap formation and degradation by DNases in COVID-19 disease

Garcia,

Labrouche-Colomer,

Duvignaud

et al. 2024

J Transl Med

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Background Thrombo-inflammation and neutrophil extracellular traps (NETs) are exacerbated in severe cases of COVID-19, potentially contributing to disease exacerbation. However, the mechanisms underpinning this dysregulation remain elusive. We hypothesised that lower DNase activity may be associated with higher NETosis and clinical worsening in patients with COVID-19. Methods Biological samples were obtained from hospitalized patients (15 severe, 37 critical at sampling) and 93 non-severe ambulatory cases. Our aims were to compare NET biomarkers, functional DNase levels, and explore mechanisms driving any imbalance concerning disease severity. Results Functional DNase levels were diminished in the most severe patients, paralleling an imbalance between NET markers and DNase activity. DNase1 antigen levels were higher in ambulatory cases but lower in severe patients. DNase1L3 antigen levels remained consistent across subgroups, not rising alongside NET markers. DNASE1 polymorphisms correlated with reduced DNase1 antigen levels. Moreover, a quantitative deficiency in plasmacytoid dendritic cells (pDCs), which primarily express DNase1L3, was observed in critical patients. Analysis of public single-cell RNAseq data revealed reduced DNase1L3 expression in pDCs from severe COVID-19 patient. Conclusion Severe and critical COVID-19 cases exhibited an imbalance between NET and DNase functional activity and quantity. Early identification of NETosis imbalance could guide targeted therapies against thrombo-inflammation in COVID-19-related sepsis, such as DNase administration, to avert clinical deterioration. Trial registration: COVERAGE trial (NCT04356495) and COLCOV19-BX study (NCT04332016). Graphical Abstract

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“…68 Moreover, a recent study examined a cohort of different severities of convalescent patients, including long-COVID patients ( n = 46), and found NETosis induction significantly elevated in long-COVID patients along with markers of platelet, endothelial, and clotting activation. 69 Of note, NET levels strongly correlated with illness duration, platelet activation markers, and coagulation factors and were significantly reduced upon dexamethasone treatment. 69…”

Section: Mechanism Of Diseasementioning

confidence: 94%

“…69 Of note, NET levels strongly correlated with illness duration, platelet activation markers, and coagulation factors and were significantly reduced upon dexamethasone treatment. 69…”

Section: Mechanism Of Diseasementioning

confidence: 94%

COVID-19 and Long-COVID Thrombosis: From Clinical and Basic Science to Therapeutics

Violi,

Harenberg,

Pignatelli

et al. 2023

Thromb Haemost

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Coronavirus infectious disease-19 (COVID-19) is a pandemic characterized by serious lung disease and thrombotic events in the venous and circulation trees, which represent a harmful clinical sign of poor outcome. Thrombotic events are more frequent in patients with severe disease requiring intensive care units and are associated with platelet and clotting activation. However, after resolution of acute infection, patients may still have clinical sequelae, the so-called long-COVID-19, including thrombotic events again in the venous and arterial circulation. The mechanisms accounting for thrombosis in acute and long COVID-19 have not been fully clarified; interactions of COVID-19 with angiotensin converting enzyme 2 or toll-like receptor family or infection-induced cytokine storm have been suggested to be implicated in endothelial cells, leucocytes, and platelets to elicit clotting activation in acute as well in chronic phase of the disease. In acute COVID-19, prophylactic or full doses of anticoagulants exert beneficial effects even if the dosage choice is still under investigation; however, a residual risk still remains suggesting a need for a more appropriate therapeutic approach. In long COVID-19 preliminary data provided useful information in terms of antiplatelet treatment but definition of candidates for thrombotic prophylaxis is still undefined.

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NETosis induction reflects COVID-19 severity and long COVID: insights from a 2-center patient cohort study in Israel

Cited by 26 publications

References 64 publications

The development of anticyclic citrullinated peptide (anti‐CCP) antibody following severe COVID‐19

The development of anticyclic citrullinated peptide (anti‐CCP) antibody following severe COVID‐19

Impaired balance between neutrophil extracellular trap formation and degradation by DNases in COVID-19 disease

COVID-19 and Long-COVID Thrombosis: From Clinical and Basic Science to Therapeutics

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