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

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.

Complement activation in COVID-19 and targeted therapeutic options: A scoping review

“…None deaths were deemed likely study related. Zelek [ 132 ], 2020 Case series ICU Until discharge COVID-19 patients requiring intensive care and ventilation support (n = 5) – Severe Single 1500 mg IV dose of LFG316 (tesidolumab) Hydrocortisone, antibiotic prophylaxis (phenoxymethylpenicillin or clarithromycin) C5 Mortality of 20% (n = 1). In four of five patients, there was sustained improvement in clinical state.…”

“…Anaphylatoxins C3a and notably C5a were elevated and correlated with disease severity, ICU admission and mortality [ 12 , 14 , 65 , 68 , 85 , [119] , [120] , [121] , [122] , [123] , [124] , [125] , [126] , [127] , [128] ]. Soluble C5b-9 levels were also increased and correlated with C5a, markers of inflammation and coagulation [ 12 , 33 , 36 , 68 , 70 , 71 , 78 , 120 , 125 , [129] , [130] , [131] , [132] , [133] , [134] ]. C5 was only elevated in three studies measuring C5 levels [ 66 , 135 , 136 ].…”

Remodeling of T Cell Dynamics During Long COVID Is Dependent on Severity of SARS-CoV-2 Infection

“…First, to assess whether the cytokine storm (one of the hallmarks of COVID-19 disease (25,26) is still present in convalescent patients, we measured levels of 13 cytokines, chemokines and other immune mediators in plasma of convalescent patients and healthy controls (Figure 2). The cytokine storm has already been attenuated following recovery from COVID-19, as levels of TNFa, free active TGF-b, IFN-g, IL-1b, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12p70, IL-17 and MCP-1/CCL2 during convalescence were not higher compared to healthy volunteers.…”

“…The immune system immediately responds to infection with SARS-CoV-2 (19), and several perturbations in individuals with severe infection have been described in detail since the earliest moments of the pandemic (20)(21)(22)(23)(24). Systemic inflammation and markedly high levels of proinflammatory cytokines in plasma, named "cytokine storm", are characteristic for COVID-19 severe patients and are recognized as clinical predictors of disease outcome and mortality (25,26). Therefore coordinated resolution of inflammation is necessary for successful recovery from acute infection, as persistent inflammatory state can lead to dysregulated immune responses (27)(28)(29).…”

Biomarkers in Pediatric Nephrology—From Bedside to Bench and Back Again

“…In order to highlight the pathological background of a newly discovered disease, the molecular mechanisms of SARS-CoV-2 toxicity were analyzed within the clinical context. The first reports on the increased chemokine concentration, complement and coagulation overactivity stimulated a search for the molecular background of symptoms such as acute respiratory distress syndrome, thrombotic events or acute kidney injury [ 16 , 17 ]. Tracing the development of COVID-19 infection throughout various virus mutations enabled the acquisition of knowledge of SARS-CoV-2 structure, receptors, mechanisms of cell invasion and the way of systemic expansion with multiorgan affectation [ 14 ].…”