An abnormally strong proinflammatory response known as "cytokine storm" may play an important role in the pathophysiology of coronavirus disease 2019 (COVID-19), although cytokine storm remains ill defined. 1 Sinha and colleagues 2 reported that although IL-6 levels are elevated in severe COVID-19, they are lower than levels usually observed in (non-COVID-19) acute respiratory distress syndrome (ARDS). However, this comparison is limited by the use of different assays, which are not well standardized. 3 We compared cytokine levels in critically ill patients with COVID-19 vs levels in patients with other critical illnesses. Methods | All patients in this study were admitted to the intensive care unit (ICU) of Radboud University Medical Center. Plasma concentrations of the proinflammatory cytokines tumor necrosis factor (TNF), IL-6, and IL-8 were determined in consecutive mechanically ventilated patients with COVID-19 with ARDS (partial pressure of oxygen/fraction of inspired oxygen ratio <300; sampled within 48 hours after ICU admission), bacterial septic shock with or without ARDS (sampled within 24 hours after septic shock diagnosis), outof-hospital cardiac arrest (OHCA; sampled within 24 hours after ICU admission), and multiple traumas (sampled within 24 hours after trauma). The patients with sepsis and trauma are part of larger published cohorts, 4,5 whereas data of 14 patients with OHCA were previously published. 6 Sampling

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&lt;0.05). These complement factors were especially elevated in ICU patients during the entire disease course (p&lt;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.

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.

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Background The CytoSorb hemoadsorption device has been demonstrated to be capable of clearing inflammatory cytokines, but has not yet been shown to attenuate plasma cytokine concentrations. We investigated the effects of CytoSorb hemoperfusion on plasma levels of various cytokines using the repeated human experimental endotoxemia model, a highly standardized and reproducible human in vivo model of systemic inflammation and immunological tolerance induced by administration of bacterial lipopolysaccharide (LPS). Methods Twenty-four healthy male volunteers (age 18–35) were intravenously challenged with LPS (a bolus of 1 ng/kg followed by continuous infusion of 0.5 ng/kg/hr for three hours) twice: on day 0 to quantify the initial cytokine response and on day 7 to quantify the degree of endotoxin tolerance. Subjects either received CytoSorb hemoperfusion during the first LPS challenge (CytoSorb group), or no intervention (control group). Plasma cytokine concentrations and clearance rates were determined serially. This study was registered at ClinicalTrials.gov (NCT04643639, date of registration November 24th 2020). Results LPS administration led to a profound increase in plasma cytokine concentrations during both LPS challenge days. Compared to the control group, significantly lower plasma levels of tumor necrosis factor (TNF, − 58%, p < 0.0001), interleukin (IL)-6 ( − 71%, p = 0.003), IL-8 ( − 48%, p = 0.02) and IL-10 ( − 26%, p = 0.03) were observed in the CytoSorb group during the first LPS challenge. No differences in cytokine responses were observed during the second LPS challenge. Conclusions CytoSorb hemoperfusion effectively attenuates circulating cytokine concentrations during systemic inflammation in humans in vivo, whereas it does not affect long-term immune function. Therefore, CytoSorb therapy may be of benefit in conditions characterized by excessive cytokine release.