Abstract
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.
Highlights
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) belongs to the family of Coronaviridae, a large family of single-stranded RNA viruses that are pathogenic in humans and several animal species [1,2]
The complement system triggers the production of anaphylatoxins (C3a and C5a) and the formation of the terminal complement complex and is known to interact with the coagulation cascade, thereby instigating neutrophil activation and NETosis
These results have been reflected in a study where higher baseline levels of terminal complement complex (TCC) were reported in COVID-19 patients, albeit C5a levels remained under the detection limit [24]
Summary
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) belongs to the family of Coronaviridae, a large family of single-stranded RNA viruses that are pathogenic in humans and several animal species [1,2]. The SARS-CoV-2 infection, responsible for COVID-19 (coronavirus disease 2019), was described by mid-December 2019. It has spread globally ever since, and the outbreak was eventually declared a pandemic by mid-March 2020 [3]. In Austria, the reported number of infected individuals has surpassed 775,000 cases [4,5]. The majority of presented infections are asymptomatic or are defined by mild respiratory symptoms, some infected individuals develop severe viral pneumonia, leading to acute respiratory distress syndrome (ARDS), resulting in the patient’s hospitalization and potential requirement of mechanical ventilation in the intensive care unit (ICU) [6,7]
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