Cytokine release syndrome (CRS) is a life-threatening complication induced by systemic inflammatory responses to infections, including bacteria and chimeric antigen receptor T cell therapy. There are currently no immunotherapies with proven clinical efficacy and understanding of the molecular mechanisms of CRS pathogenesis is limited. Here, we found that patients diagnosed with CRS from sepsis, acute respiratory distress syndrome (ARDS), or burns showed common manifestations: strikingly elevated levels of the four proinflammatory cytokines interleukin (IL)-6, IL-8, monocyte chemotactic protein-1 (MCP-1), and IL-10 and the coagulation cascade activator plasminogen activator inhibitor-1 (PAI-1). Our in vitro data indicate that endothelial IL-6 trans-signaling formed an inflammation circuit for robust IL-6, IL-8, and MCP-1 production and promoted PAI-1 production; additionally, an IL-6 signaling blockade by the human monoclonal antibody tocilizumab blunted endothelial cell activation. Plasma from severe COVID-19 patients similarly exhibited increased IL-6, IL-10, and MCP-1 levels, but these levels were not as high as those in patients with CRS from other causes. In contrast, the PAI-1 levels in COVID-19 patients were as highly elevated as those in patients with bacterial sepsis or ARDS. Tocilizumab treatment decreased the PAI-1 levels and alleviated critical illness in severe COVID-19 patients. Our findings suggest that distinct levels of cytokine production are associated with CRS induced by bacterial infection and COVID-19, but both CRS types are accompanied by endotheliopathy through IL-6 trans-signaling. Thus, the present study highlights the crucial role of IL-6 signaling in endothelial dysfunction during bacterial infection and COVID-19.

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IntroductionCoronavirus disease 2019 (COVID-19) is a new viral disease. Uncontrolled inflammation called “cytokine storm” is reported to contribute to disease pathogenesis as well as sepsis. We aimed to identify cytokines related to the pathogenesis of COVID-19 through a proteomics analysis of 1463 plasma proteins, validate these cytokines, and compare them with sepsis.Materials and MethodsIn a derivation cohort of 306 patients with COVID-19, 1463 unique plasma proteins were measured on days 1, 4, and 8. Cytokines associated with disease severity and prognosis were derived. In a validation cohort of 62 COVID-19 patients and 38 sepsis patients treated in the intensive care unit [ICU], these derived cytokines were measured on days 1 (day of ICU admission), 2-3, and 6-8 (maximum: 3 time points/patient). Derived cytokines were compared with healthy controls and between COVID-19 and sepsis patients, and the associations with prognosis were evaluated. The time to wean off mechanical ventilation (MV) was evaluated only for COVID-19.ResultsIL-6, amphiregulin, and growth differentiation factor (GDF)-15 were associated with disease severity and prognosis in the derivation cohort. In the validation cohort, IL-6 and GDF-15 were elevated in COVID-19 and sepsis on day 1, and the levels of these cytokines were higher in sepsis than in COVID-19. IL-6 and GDF-15 were associated with prognosis in sepsis. Cox proportional hazards model with time as a dependent covariate showed a significant relationship between plasma GDF-15 level and time to wean off MV (hazard ratio, 0.549 [95% confidence level, 0.382–0.789]). The GDF-15 level at ICU admission predicted late recovery.ConclusionGDF-15 and IL-6 derived from proteomics analysis were related with disease severity of COVID-19. Their values were higher in sepsis than in COVID-19 and were associated with prognosis in sepsis. In COVID-19 patients treated in the ICU, GDF-15 was associated with the time to wean off MV and better predicted late recovery.

Introduction: Cytokines compose a network and play crucial roles in the pathogenesis and prognosis of sepsis. Adipose tissue is an important immune endocrine organ that releases adipocytokines. This study aimed to evaluate adipocytokines in sepsis from a network perspective. Materials and Methods: This retrospective study of 37 patients with sepsis and 12 healthy controls was conducted from February 2014 to July 2015. Blood samples were collected from patients on days 1 (within 24 h of diagnosis), 2, 4, 6, 8, 11, and 15 and from healthy controls. Adipocytokines (adiponectin, leptin, resistin, chemerin, visfatin, vaspin, CXCL-12/SDF-1, angiotensinogen), inflammatory cytokines (IL-1b, IL-4, IL-6, IL-8, IL-10, IL-12/IL-23p40, TNF-a, monocyte chemotactic protein [MCP-1]), and plasminogen activator inhibitor-1 were measured. Acute Physiology and Chronic Health Evaluation II score was evaluated on day 1, and Sequential Organ Failure Assessment (SOFA) score and Japanese Association for Acute Medicine (JAAM) and International Society of Thrombosis and Hemostasis overt disseminated intravascular coagulation (DIC) scores were assessed at the times of blood sampling. Results: Hierarchical clustering analysis showed the cluster formed by resistin, IL-6, IL-8, MCP-1, and IL-10 on days 1, 2, and 4 represented the cytokine network throughout the acute phase of sepsis. Each cytokine in this network was significantly associated with SOFA and JAAM DIC scores over the acute phase. A Cox proportional hazards model focusing on the acute phase showed a significant relation of these five cytokines with patient prognosis. Conclusions: Adipocytokines and an inflammatory cytokine profile assessed over time in sepsis patients showed that resistin was involved in an inflammatory cytokine network including IL-6, IL-8, IL-10, and MCP-1 in the acute phase of sepsis, and this network was associated with severity and prognosis of sepsis.

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