Evolution of NETosis markers and DAMPs have prognostic value in critically ill COVID-19 patients

Huckriede, Joram; Anderberg, Sara Bülow; Morales, Albert; Vries, Femke de; Hultström, Michael; Bergqvist, Anders; Ortiz-Pérez, Josè T.; Sels, Jan Willem; Wichapong, Kanin; Lipcsey, Miklós; Poll, Marcel van de; Larsson, Anders; Luther, Tomas; Reutelingsperger, Chris; Frutos, Pablo Garcı́a de; Frithiof, Robert; Nicolaes, Gerry A. F.

doi:10.1038/s41598-021-95209-x

Cited by 68 publications

(82 citation statements)

References 53 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…STROBE guidelines were followed for reporting. An initial description of this study could be found in Huckriede et al (2021). All 117 patients admitted to the central intensive care unit at Uppsala University hospital during the first wave of the pandemic in 2020, with suspected COVID-19 infection, were screened for inclusion.…”

Section: Collection Of Patient Samplesmentioning

confidence: 99%

Histone H3 Cleavage in Severe COVID-19 ICU Patients

Huckriede

Vries

Hultström

et al. 2021

Front. Cell. Infect. Microbiol.

Self Cite

View full text Add to dashboard Cite

The severity of coronavirus disease 19 (COVID-19) is associated with neutrophil extracellular trap (NET) formation. During NET formation, cytotoxic extracellular histones are released, the presence of which is linked to the initiation and progression of several acute inflammatory diseases. Here we study the presence and evolution of extracellular histone H3 and several other neutrophil-related molecules and damage-associated molecular patterns (DAMPs) in the plasma of 117 COVID-19-positive ICU patients. We demonstrate that at ICU admission the levels of histone H3, MPO, and DNA-MPO complex were all significantly increased in COVID-19-positive patients compared to control samples. Furthermore, in a subset of 54 patients, the levels of each marker remained increased after 4+ days compared to admission. Histone H3 was found in 28% of the patients on admission to the ICU and in 50% of the patients during their stay at the ICU. Notably, in 47% of histone-positive patients, we observed proteolysis of histone in their plasma. The overall presence of histone H3 during ICU stay was associated with thromboembolic events and secondary infection, and non-cleaved histone H3 was associated with the need for vasoactive treatment, invasive ventilation, and the development of acute kidney injury. Our data support the validity of treatments that aim to reduce NET formation and additionally underscore that more targeted therapies focused on the neutralization of histones should be considered as treatment options for severe COVID-19 patients.

show abstract

Section: Collection Of Patient Samplesmentioning

confidence: 99%

Histone H3 Cleavage in Severe COVID-19 ICU Patients

Huckriede

Vries

Hultström

et al. 2021

Front. Cell. Infect. Microbiol.

Self Cite

View full text Add to dashboard Cite

show abstract

“…The unique inflammatory response exhibited by neutrophils whereby they release NETs as an effector mechanism is associated with poor clinical outcome in COVID-19 [34]. Several studies revealed the role of neutrophils in the pathology of the disease as levels of blood neutrophils and NETs released in COVID-19 patients were higher than those in a healthy cohort [35,36].…”

Section: Discussionmentioning

confidence: 99%

Systemic Inflammation and Complement Activation Parameters Predict Clinical Outcome of Severe SARS-CoV-2 Infections

Huber

Massri

Grasse

et al. 2021

Viruses

View full text Add to dashboard Cite

Overactivation of the complement system has been characterized in severe COVID-19 cases. Complement components are known to trigger NETosis via the coagulation cascade and have also been reported in human tracheobronchial epithelial cells. In this longitudinal study, we investigated systemic and local complement activation and NETosis in COVID-19 patients that underwent mechanical ventilation. Results confirmed significantly higher baseline levels of serum C5a (24.5 ± 39.0 ng/mL) and TCC (11.03 ± 8.52 µg/mL) in patients compared to healthy controls (p < 0.01 and p < 0.0001, respectively). Furthermore, systemic NETosis was significantly augmented in patients (5.87 (±3.71) × 106 neutrophils/mL) compared to healthy controls (0.82 (±0.74) × 106 neutrophils/mL) (p < 0.0001). In tracheal fluid, baseline TCC levels but not C5a and NETosis, were significantly higher in patients. Kinetic studies of systemic complement activation revealed markedly higher levels of TCC and CRP in nonsurvivors compared to survivors. In contrast, kinetic studies showed decreased local NETosis in tracheal fluid but comparable local complement activation in nonsurvivors compared to survivors. Systemic TCC and NETosis were significantly correlated with inflammation and coagulation markers. We propose that a ratio comprising systemic inflammation, complement activation, and chest X-ray score could be rendered as a predictive parameter of patient outcome in severe SARS-CoV-2 infections.

show abstract

“…Two possible reasons may explain this discrepancy. First, besides plasma gp96, viral RNA and multiple other elevated DAMPs could also induce IL-6 expression, including cell-free DNA, extracellular histone H3, and neutrophil elastase, as well as the immune modulators GAS6 and AXL ( 11 , 25 ). In addition, in severe COVID-19, the levels of circulating mitochondrial DNA, S100A8/A9, and high mobility group box 1 were also significantly increased and were correlated with inferior clinical outcomes ( 11 , 26 ).…”

Section: Discussionmentioning

confidence: 99%