Abstract
Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a poorly understood disease involving a high inflammatory status. Neutrophil extracellular traps (NETs) have been described as a new pathway to contain infectious diseases but can also participate in the imbalance of the inflammatory and the coagulation systems. NETs could be a therapeutic target in COVID-19 patients.Methods: Consecutive patients with SARS-CoV2 related pneumonia admitted to the intensive care unit were included in a prospective bicentric study. Neutrophil extracellular trap concentrations were quantified in whole blood samples at day-1 and day-3 by flow cytometry. The primary outcome was the association between the blood NET quantification at ICU admission and the number of days with refractory hypoxemia defined by a PaO2/FIO2 ratio ≤100 mmHg.Results: Among 181 patients admitted to the ICUs for acute respiratory failure related to SARS-CoV2 pneumonia, 58 were included in the analysis. Patients were 62 [54, 69] years old in median, mostly male (75.9%). The median number of days with severe hypoxemia was 4 [2, 6] days and day-28 mortality was 27.6% (n = 16). The blood level of NETs significantly decreased between day-1 and day-3 in patients who survived (59.5 [30.5, 116.6] to 47 [33.2, 62.4] p = 0.006; 8.6 [3.4, 18.0] to 4 [1.4, 10.7] p = 0.001 and 7.4 [4.0, 16.7] to 2.6 [1.0, 8.3] p = 0.001 for MPO+, Cit-H3+, and MPO+ Cit-H3+ NETs, respectively) while it remained stable in patients who died (38.4 [26.0, 54.8] to 44.5 [36.4, 77.7] p = 0.542; 4.9 [1.3, 13.0] to 5.5 [2.8, 6.9] p = 0.839 and 4 [1.3, 13.6] to 2.7 [1.4, 4.5] p = 0.421 for MPO+, Cit-H3+, and MPO+ Cit-H3+ NETs, respectively). In multivariable negative binomial regression, the blood level of MPO+ NETs was negatively associated with the number of days with severe hypoxemia within 7 days (0.84 [0.73, 0.97]), while neither Cit-H3+ NETs nor double-positive NETs were significantly associated with the primary outcome.Conclusion: The whole blood level of NETs at day-1 was negatively associated with the number of days with severe hypoxemia in patients admitted to the intensive care unit for SARS-CoV2 related pneumonia. The lack of decrease of the blood level of NETs between day-1 and day-3 discriminated patients who died within day-28.
Highlights
Neutrophils extracellular traps (NETs) are the result of neutrophil extrusion of extracellular fibers composed of DNA, histones, and granule-derived proteins released by neutrophils, which trap and kill extracellular pathogens [1]
Similar results were obtained in patients with vs. without acute cor pulmonale (36.3 [33.5, 55.1] vs. 60.3 [36.3, 101.2] p < 0.001, 0 [0, 0.1] vs. 2.3 [0.3, 4.6] p < 0.001, and 1.3 [0.7, 8.2] vs. 5.8 [1.9, 14.4] p < 0.001 for MPO+, Cit-H3+, and MPO+ Cit-H3+ NETs, respectively). In this prospective observational study including 58 patients admitted to the intensive care unit for acute respiratory failure related to SARS-CoV2 pneumonia, we observed a negative association between the blood level of NETs at day-1 and [1] the severity of the respiratory status, [2] the occurrence of thrombotic events, and [3] the occurrence of right ventricular failure assessed by echocardiography
The whole blood level of NETs at day-1 was negatively associated with the number of days with severe hypoxemia in patients admitted to the intensive care unit for SARSCoV2 related pneumonia
Summary
Neutrophils extracellular traps (NETs) are the result of neutrophil extrusion of extracellular fibers composed of DNA, histones, and granule-derived proteins released by neutrophils, which trap and kill extracellular pathogens [1]. NETs are important players in the genesis, growth and resolution of the coagulation cascade [4, 5] and may participate in the imbalance of inflammation and coagulation in sepsis [6] This is well-described in the context of acute respiratory distress syndrome (ARDS) related to bacterial [7,8,9,10] or influenza pneumonia [11,12,13], linked to the massive invasion of alveoli by an inflammatory infiltrate containing neutrophils, monocytes, macrophages, altered epithelial cells and numerous pro-inflammatory markers [14] Blood and alveoli levels of NETs in ARDS patients strongly correlate with the severity of respiratory disease [7, 15]. NETs could be a therapeutic target in COVID-19 patients
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