Background Excessive activation of immune responses in coronavirus disease 2019 (COVID-19) is considered to be related to disease severity, complications and mortality. The complement system is an important component of innate immunity and can stimulate inflammation, but its role in COVID-19 is unknown. Methods A prospective, longitudinal, single center study was performed in hospitalized COVID-19 patients. Plasma concentrations of complement factors C3a, C3c, and terminal complement complex (TCC) were assessed at baseline and during hospital admission. In parallel, routine laboratory and clinical parameters were collected from medical files and analyzed. Results Complement factors C3a, C3c and TCC were significantly increased in plasma of COVID-19 patients compared to healthy controls (p<0.05). These complement factors were especially elevated in ICU patients during the entire disease course (p<0.005 for C3a and TCC). More intense complement activation was observed in patients that deceased and in patients with thromboembolic events. Conclusions COVID-19 patients demonstrate activation of the complement system, which is related to disease severity. This pathway may be involved in the dysregulated pro-inflammatory response associated with increased mortality and thromboembolic complications. Components of the complement system might have potential as prognostic markers for disease severity and as therapeutic targets in COVID-19.

Reports suggest a role of endothelial dysfunction and loss of endothelial barrier function in COVID-19. It is well established that the endothelial glycocalyx-degrading enzyme heparanase contributes to vascular leakage and inflammation. Low molecular weight heparins (LMWH) serve as an inhibitor of heparanase. We hypothesize that heparanase contributes to the pathogenesis of COVID-19, and that heparanase may be inhibited by LMWH. To test this hypothesis, heparanase activity and heparan sulfate levels were measured in plasma of healthy controls (n = 10) and COVID-19 patients (n = 48). Plasma heparanase activity and heparan sulfate levels were significantly elevated in COVID-19 patients. Heparanase activity was associated with disease severity including the need for intensive care, lactate dehydrogenase levels, and creatinine levels. Use of prophylactic LMWH in non-ICU patients was associated with a reduced heparanase activity. Since there is no other clinically applied heparanase inhibitor currently available, therapeutic treatment of COVID-19 patients with low molecular weight heparins should be explored.

Background A subset of critically ill COVID-19 patients develop a hyperinflammatory state. Anakinra, a recombinant interleukin-1 receptor antagonist, is known to be effective in several hyperinflammatory diseases. We investigated the effects of anakinra on inflammatory parameters and clinical outcomes in critically ill, mechanically ventilated COVID-19 patients with clinical features of hyperinflammation. Methods In this prospective cohort study, 21 critically ill COVID-19 patients treated with anakinra were compared to a group of standard care. Serial data of clinical inflammatory parameters and concentrations of multiple circulating cytokines were determined and aligned on start day of anakinra in the treatment group, and median start day of anakinra in the control group. Analysis was performed for day − 10 to + 10 relative to alignment day. Clinical outcomes were analyzed during 28 days. Additionally, three sensitivity analyses were performed: (1) using propensity score-matched groups, (2) selecting patients who did not receive corticosteroids, and (3) using a subset of the control group aimed to match the criteria (fever, elevated ferritin) for starting anakinra treatment. Results Baseline patient characteristics and clinical parameters on ICU admission were similar between groups. As a consequence of bias by indication, plasma levels of aspartate aminotransferase (ASAT) (p = 0.0002), ferritin (p = 0.009), and temperature (p = 0.001) were significantly higher in the anakinra group on alignment day. Following treatment, no relevant differences in kinetics of circulating cytokines were observed between both groups. Decreases of clinical parameters, including temperature (p = 0.03), white blood cell counts (p = 0.02), and plasma levels of ferritin (p = 0.003), procalcitonin (p = 0.001), creatinine (p = 0.01), and bilirubin (p = 0.007), were more pronounced in the anakinra group. No differences in duration of mechanical ventilation or ICU length of stay were observed between groups. Sensitivity analyses confirmed these results. Conclusions Anakinra is effective in reducing clinical signs of hyperinflammation in critically ill COVID-19 patients. A randomized controlled trial is warranted to draw conclusion about the effects of anakinra on clinical outcomes.

The clinical spectrum of COVID-19 varies and the differences in host response characterizing this variation have not been fully elucidated. COVID-19 disease severity correlates with an excessive pro-inflammatory immune response and profound lymphopenia. Inflammatory responses according to disease severity were explored by plasma cytokine measurements and proteomics analysis in 147 COVID-19 patients. Furthermore, peripheral blood mononuclear cell cytokine production assays and whole blood flow cytometry were performed. Results confirm a hyperinflammatory innate immune state, while highlighting hepatocyte growth factor and stem cell factor as potential biomarkers for disease severity. Clustering analysis reveals no specific inflammatory endotypes in COVID-19 patients. Functional assays reveal abrogated adaptive cytokine production (interferon-gamma, interleukin-17 and interleukin-22) and prominent T cell exhaustion in critically ill patients, whereas innate immune responses were intact or hyperresponsive. Collectively, this extensive analysis provides a comprehensive insight into the pathobiology of severe to critical COVID-19 and highlight potential biomarkers of disease severity.

Reports suggest a role of endothelial dysfunction and loss of endothelial barrier function in COVID-19. It is well established that the endothelial glycocalyx-degrading enzyme heparanase contributes to vascular leakage and inflammation. Low molecular weight heparins (LMWH) serve as an inhibitor of heparanase. We hypothesize that heparanase contributes to the pathogenesis of COVID-19, and that heparanase may be inhibited by LMWH. Heparanase activity and heparan sulfate levels were measured in plasma of healthy controls (n=10) and COVID-19 patients (n=48). Plasma heparanase activity and heparan sulfate levels were significantly elevated in COVID-19 patients. Heparanase activity associated with disease severity including the need for intensive care and mechanical ventilation, lactate dehydrogenase levels and creatinine levels. Use of prophylactic LMWH in non-ICU patients was associated with a reduced heparanase activity. Since there is no other clinically applied heparanase inhibitor currently available, therapeutic treatment of COVID-19 patients with low molecular weight heparins should be explored.

No abstract

Sepsis is characterized as a life-threatening organ dysfunction syndrome that is caused by a dysregulated host response to infection. The main etiological causes of sepsis are bacterial, fungal, and viral infections. Last decades clinical and preclinical research contributed to a better understanding of pathophysiology of sepsis. The dysregulated host response in sepsis is complex, with both pathogen-related factors contributing to disease, as well as immune-cell mediated inflammatory responses that can lead to adverse outcomes in early or advanced stages of disease. Due to its heterogenous nature, clinical diagnosis remains challenging and sepsis-specific treatment options are still lacking. Classification and early identification of patient subgroups may aid clinical decisions and improve outcome in sepsis patients. The initial clinical presentation is rather similar in sepsis of different etiologies, however, inflammatory profiles may be able to distinguish between different etiologies of infections. In this review, we summarize the role and the discriminating potency of host-derived inflammatory biomarkers in the context of the main etiological types of sepsis.

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