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Objectives The purpose of this study is to test the safety and effectiveness of individually or simultaneously blocking IL-6, IL-6 receptor and IL-1 versus standard of care on blood oxygenation and systemic cytokine release syndrome in patients with COVID-19 coronavirus infection and acute hypoxic respiratory failure and systemic cytokine release syndrome. Trial design A phase 3 prospective, multi-center, interventional, open label, 6-arm 2x2 factorial design study. Participants Subjects will be recruited at the specialized COVID-19 wards and/or ICUs at 16 Belgian participating hospitals. Only adult (≥18y old) patients will be recruited with recent (≤16 days) COVID-19 infection and acute hypoxia (defined as PaO2/FiO2 below 350mmHg or PaO2/FiO2 below 280 on supplemental oxygen and immediately requiring high flow oxygen device or mechanical ventilation) and signs of systemic cytokine release syndrome characterized by high serum ferritin, or high D-dimers, or high LDH or deep lymphopenia or a combination of those, who have not been on mechanical ventilation for more than 24 hours before randomisation. Patients should have had a chest X-ray and/or CT scan showing bilateral infiltrates within the last 2 days before randomisation. Patients with active bacterial or fungal infection will be excluded. Intervention and comparator Patients will be randomized to 1 of 5 experimental arms versus usual care. The experimental arms consist of Anakinra alone (anti-IL-1 binding the IL-1 receptor), Siltuximab alone (anti-IL-6 chimeric antibody), a combination of Siltuximab and Anakinra, Tocilizumab alone (humanised anti-IL-6 receptor antibody) or a combination of Anakinra with Tocilizumab in addition to standard care. Patients treated with Anakinra will receive a daily subcutaneous injection of 100mg for a maximum of 28 days or until hospital discharge, whichever comes first. Siltuximab (11mg/kg) or Tocilizumab (8mg/kg, with a maximum dose of 800mg) are administered as a single intravenous injection immediately after randomization. Main outcomes The primary end point is the time to clinical improvement defined as the time from randomization to either an improvement of two points on a six-category ordinal scale measured daily till day 28 or discharge from the hospital or death. This ordinal scale is composed of (1) Death; (2) Hospitalized, on invasive mechanical ventilation or ECMO; (3) Hospitalized, on non-invasive ventilation or high flow oxygen devices; (4) Hospitalized, requiring supplemental oxygen; (5) Hospitalized, not requiring supplemental oxygen; (6) Not hospitalized. Randomisation Patients will be randomized using an Interactive Web Response System (REDCap). A 2x2 factorial design was selected with a 2:1 randomization regarding the IL-1 blockade (Anakinra) and a 1:2 randomization regarding the IL-6 blockade (Siltuximab and Tocilizumab). Blinding (masking) In this open-label trial neither participants, caregivers, nor those assessing the outcomes are blinded to group assignment. Numbers to be randomised (sample size) A total of 342 participants will be enrolled: 76 patients will receive usual care, 76 patients will receive Siltuximab alone, 76 patients will receive Tocilizumab alone, 38 will receive Anakinra alone, 38 patients will receive Anakinra and Siltuximab and 38 patients will receive Anakinra and Tocilizumab. Trial Status COV-AID protocol version 3.0 (15 Apr 2020). Participant recruitment is ongoing and started on April 4 th 2020. Given the current decline of the COVID-19 pandemic in Belgium, it is difficult to anticipate the rate of participant recruitment. Trial registration The trial was registered on Clinical Trials.gov on April 1st, 2020 ( ClinicalTrials.gov Identifier: NCT04330638) and on EudraCT on April 3rd 2020 (Identifier: 2020-001500-41). Full protocol The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1 ). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.

Interleukin-6 (IL-6) plays a crucial role in host defense against infection and tissue injuries and is a bioindicator of multiple distinct types of cytokine storms. In this review, we present the current understanding of the diverse roles of IL-6, its receptors, and its signaling during acute severe systemic inflammation. IL-6 directly affects vascular endothelial cells, which produce several types of cytokines and chemokines and activate the coagulation cascade. Endothelial cell dysregulation, characterized by abnormal coagulation and vascular leakage, is a common complication in cytokine storms. Emerging evidence indicates that a humanized anti-IL-6 receptor antibody, tocilizumab, can effectively block IL-6 signaling and has beneficial effects in rheumatoid arthritis, juvenile systemic idiopathic arthritis, and Castleman’s disease. Recent work has also demonstrated the beneficial effect of tocilizumab in chimeric antigen receptor T-cell therapy-induced cytokine storms as well as coronavirus disease 2019 (COVID-19). Here, we highlight the distinct contributions of IL-6 signaling to the pathogenesis of several types of cytokine storms and discuss potential therapeutic strategies for the management of cytokine storms, including those associated with sepsis and COVID-19. Inflammation: Stopping the storm Blocking interleukin-6, a signaling molecule known as a cytokine, may help in treatment of both chronic and acute inflammation. IL-6 is part of a healthy immune response, but is also implicated in chronic inflammatory diseases such as rheumatoid arthritis and in ‘cytokine storms’, when the inflammatory response spirals out of control. Sujin Kang and Tadamitsu Kishimoto at Osaka University in Japan have reviewed the roles IL-6 plays in chronic and acute inflammation, and how an antibody to the IL-6 receptor, tocilizumab, shows therapeutic potential. They report that tocilizumab successfully blocks IL-6 signaling and has beneficial effects against rheumatoid and juvenile systemic idiopathic arthritis, and other chronic inflammatory conditions. Tocilizumab has also been shown to suppress cytokine storms brought on by CAR-T cell therapy and COVID-19. These results pave the way for better treatments for inflammatory conditions.

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.

Background. Women in Africa, especially young women, have very high human immunodeficiency virus (HIV) incidence rates that cannot be fully explained by behavioral risks. We investigated whether genital inflammation influenced HIV acquisition in this group. Methods. Twelve selected cytokines, including 9 inflammatory cytokines and chemokines (interleukin [IL]-1α, IL-1β, IL-6, tumor necrosis factor-α, IL-8, interferon-γ inducible protein-10 [IP-10], monocyte chemoattractant protein-1, macrophage inflammatory protein [MIP]-1α, MIP-1β), hematopoietic IL-7, and granulocyte macrophage colony-stimulating factor, and regulatory IL-10 were measured prior to HIV infection in cervicovaginal lavages from 58 HIV seroconverters and 58 matched uninfected controls and in plasma from a subset of 107 of these women from the Centre for the AIDS Programme of Research in South Africa 004 tenofovir gel trial. Results. HIV seroconversion was associated with raised genital inflammatory cytokines (including chemokines MIP-1α, MIP-1β, and IP-10). The risk of HIV acquisition was significantly higher in women with evidence of genital inflammation, defined by at least 5 of 9 inflammatory cytokines being raised (odds ratio, 3.2; 95% confidence interval, 1.3–7.9; P = .014). Genital cytokine concentrations were persistently raised (for about 1 year before infection), with no readily identifiable cause despite extensive investigation of several potential factors, including sexually transmitted infections and systemic cytokines. Conclusions. Elevated genital concentrations of HIV target cell–recruiting chemokines and a genital inflammatory profile contributes to the high risk of HIV acquisition in these African women.

Depression is a common, severe and chronic psychiatric disease. Although the currently available antidepressants have been used in the treatment of depression, their beneficial effects are limited. Accumulating evidence suggests that pro-inflammatory cytokines such as interleukin-6 (IL-6) have an important role in the pathogenesis of depression. This study was undertaken to examine whether anti-mouse IL-6 receptor antibody (MR16-1) induces antidepressant effects in a social defeat stress model. Intravenous injection of MR16-1 induced rapid-onset and long-lasting antidepressant effects in susceptible mice after social defeat stress through its anti-inflammatory actions. In contrast, intracerebroventricular injection of MR16-1 induced no antidepressant effects in susceptible mice. Furthermore, treatment with MR16-1 could significantly normalize alterations in the expression of synaptic proteins (postsynaptic density protein 95 and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor 1) and dendritic spine density in the brain regions of susceptible mice. Gut microbiota analysis using 16S ribosomal RNA gene sequencing showed that MR16-1 significantly improved decreased Firmicutes/Bacteroidetes ratio in susceptible mice. It also significantly improved decreased levels of Oscillospira in susceptible mice. These findings suggest that peripheral IL-6 has a key role in the pathogenesis of depression and that the blockade of IL-6 receptor in the periphery might have rapid-onset and long-lasting antidepressant effects by normalizing the altered composition of gut microbiota in susceptible mice after social defeat stress. Therefore, the blockade of IL-6 receptor in the periphery shows promise as a novel therapeutic approach for depressed patients with higher IL-6 blood levels.

Relapse of neuromyelitis optica spectrum disorder occurred in 20% of patients who received satralizumab, a subcutaneous anti–interleukin-6 antibody, as compared with 43% of those in the placebo group. The drug may have been more effective in patients with anti–aquaporin-4 IgG antibody than in those without the antibody.

IL-6 has context-dependent pro- and anti-inflammatory properties and is now regarded as a prominent target for clinical intervention. Hunter and Jones discuss the effect of IL-6 on innate and adaptive immunity, and consider how the immunobiology of IL-6 may inform clinical decisions. Interleukin 6 (IL-6) has a broad effect on cells of the immune system and those not of the immune system and often displays hormone-like characteristics that affect homeostatic processes. IL-6 has context-dependent pro- and anti-inflammatory properties and is now regarded as a prominent target for clinical intervention. However, the signaling cassette that controls the activity of IL-6 is complicated, and distinct intervention strategies can inhibit this pathway. Clinical experience with antagonists of IL-6 has raised new questions about how and when to block this cytokine to improve disease outcome and patient wellbeing. Here we discuss the effect of IL-6 on innate and adaptive immunity and the possible advantages of various antagonists of IL-6 and consider how the immunobiology of IL-6 may inform clinical decisions.

Cancer-associated fibroblasts (CAFs) are a crucial component in the tumor microenvironment (TME) of peritoneal metastasis (PM), where they contribute to tumor progression and metastasis via secretion of interleukin-6 (IL-6). Here, we investigated the role of IL-6 in PM of gastric cancer (GC) and assessed whether anti-IL-6 receptor antibody (anti-IL-6R Ab) could inhibit PM of GC. We conducted immunohistochemical analysis of IL-6 and α-smooth muscle (α-SMA) expressions in clinical samples of GC and PM, and investigated the interactions between CAFs and GC cells in vitro. Anti-tumor effects of anti-IL-6R Ab on PM of GC were investigated in an orthotopic murine PM model. IL-6 expression was significantly correlated with α-SMA expression in clinical samples of GC, and higher IL-6 expression in the primary tumor was associated with poor prognosis of GC. Higher IL-6 and α-SMA expressions were also observed in PM of GC. In vitro, differentiation of fibroblasts into CAFs and chemoresistance were observed in GC cells cocultured with fibroblasts. Anti-IL-6R Ab inhibited the progression of PM in GC cells cocultured with fibroblasts in the orthotopic mouse model but could not inhibit the progression of PM consisting of GC cells alone. IL-6 expression in the TME was associated with poor prognosis of GC, and CAFs were associated with establishment and progression of PM via IL-6. Anti-IL-6R Ab could inhibit PM of GC by the blockade of IL-6 secreted by CAFs, which suggests its therapeutic potential for PM of GC.

We report on the effect of hemoadsorption therapy to reduce cytokines in septic patients with respiratory failure. This was a randomized, controlled, open-label, multicenter trial. Mechanically ventilated patients with severe sepsis or septic shock and acute lung injury or acute respiratory distress syndrome were eligible for study inclusion. Patients were randomly assigned to either therapy with CytoSorb hemoperfusion for 6 hours per day for up to 7 consecutive days (treatment), or no hemoperfusion (control). Primary outcome was change in normalized IL-6-serum concentrations during study day 1 and 7. 97 of the 100 randomized patients were analyzed. We were not able to detect differences in systemic plasma IL-6 levels between the two groups (n = 75; p = 0.15). Significant IL-6 elimination, averaging between 5 and 18% per blood pass throughout the entire treatment period was recorded. In the unadjusted analysis, 60-day-mortality was significantly higher in the treatment group (44.7%) compared to the control group (26.0%; p = 0.039). The proportion of patients receiving renal replacement therapy at the time of enrollment was higher in the treatment group (31.9%) when compared to the control group (16.3%). After adjustment for patient morbidity and baseline imbalances, no association of hemoperfusion with mortality was found (p = 0.19). In this patient population with predominantly septic shock and multiple organ failure, hemoadsorption removed IL-6 but this did not lead to lower plasma IL-6-levels. We did not detect statistically significant differences in the secondary outcomes multiple organ dysfunction score, ventilation time and time course of oxygenation.

Interleukein-6 (IL-6), is produced locally from infectious or injured lesions and is delivered to the whole body via the blood stream, promptly activating the host defense system to perform diverse functions. However, excessive or sustained production of IL-6 is involved in various diseases. In diseases, the IL-6 inhibitory strategy begins with the development of the anti-IL-6 receptor antibody, tocilizumab (TCZ). This antibody has shown remarkable effects on Castleman disease, rheumatoid arthritis and juvenile idiopathic arthritis. In 2017, TCZ was proven to work effectively against giant cell arteritis, Takayasu arteritis and cytokine releasing syndrome, initiating a new era for the treatment of these diseases. In this study, the defensive functions of IL-6 and various pathological conditions are compared. Further, the diseases of which TCZ has been approved for treatment are summarized, the updated results of increasing off-label use of TCZ for various diseases are reviewed and the conditions for which IL-6 inhibition might have a beneficial role are discussed. Given the involvement of IL-6 in many pathologies, the diseases that can be improved by IL-6 inhibition will expand. However, the important role of IL-6 in host defense should always be kept in mind in clinical practice.