Removal Of Inflammatory Cytokines Research Articles

Efficacy and safety of Tocilizumab, plasmapheresis and their combination in severe COVID-19: A randomized clinical trial

This study sought to evaluate and compare the effectiveness of plasmapheresis, Tocilizumab, and Tocilizumab with plasmapheresis treatment on the removal of inflammatory cytokines and improvement clinically of patients with severe COVID-19 in Intensive Care Units (ICU) due to the association between increased cytokine release and the severity of COVID-19. This clinical trial study was conducted in three treatment arms in Iran. All patients received standard care and randomization into one of three treatment groups; Tocilizumab (TCZ) alone, plasmapheresis alone, or a combination of Tocilizumab and plasmapheresis. Demographics, clinical evaluation, oxygenation status, laboratory tests and imaging data were evaluated in the three groups and re-checked 48h after the end of treatment trials. Primary outcomes were oxygenation status, the need for mechanical ventilation and the rate of death. Ninety-four patients were included in the trial after meeting the eligibility requirements. Twenty-eight patients received Tocilizumab alone, 33 had plasmapheresis alone, and 33 received both Tocilizumab and plasmapheresis. Baseline characteristics did not differ between three groups that included demographic, clinical and laboratory parameters. Following therapy, there was no difference between the three groups for CRP, ferritin, d-dimer, IL-6, pro-calcitonin and neutrophil to lymphocyte ratio (NLR) (P>0.05). While a significant reduction was found in CRP levels within each group (32.04±42.43 to 17.40±38.11, 51.28±40.96 to 26.36±33.07 and 41.20±34.27 to 21.56±24.96 in the tocilizumab, plasmapheresis, and combined group, respectively) (p<0.05), procalcitonin levels were elevated significantly in the Tocilizumab group (0.28±0.09 to 0.37±0.11) (p<0.05). Clinically there was no difference between the three groups following treatment for O2 saturation levels with supplementary oxygen at discharge, endotracheal intubation rate, use of NIVPP, mortality, mean hospital and ICU length of stay (p>0.05). Study results showed that the reduction of serum inflammatory markers, the rate of intubation and therapeutic complications including death were no different between the three groups; however, CRP levels were significantly reduced in all three groups, indicating that the interventions reduced inflammation likely through a reduction in the cytokine storm, though clinical outcomes were unaffected.

Hemoperfusion Therapy’s Efficiency in Reducing Serum IL-6 Levels and Disease Severity in COVID-19 Patients

Background: Interleukin (IL)-6, one of the inflammatory mediators involved in severe cases of coronavirus disease-19 (COVID-19), has been implicated in the pathogenesis of this disease. Extracorporeal blood purification has been suggested as one of the therapeutic strategies for COVID-19 patients, due to its favorable effect on the removal of inflammatory cytokines. Here, we investigated the impact of hemoperfusion (HP), a type of extracorporeal blood purification, in serum IL-6 levels and disease severity in COVID-19 patients. Methods: 35 patients with severe COVID-19 were enrolled in this study at the Imam-Reza Hospital, Tabriz University of Medical Sciences, between April 2020 and June 2020. The HA330 disposable HP cartridge was utilized (Jafron Biomedical Company, China). After a hemodialysis catheter was placed, patients underwent HP for at least three days in a row. Results: Our results indicated that COVID-19 patients’ serum levels of IL-6 significantly diminished following HP (P value≤0.001). Furthermore, a decrease in IL-6 levels following HP demonstrated the effectiveness of this approach (area under the curve [AUC]=0.7102 and P=0.0025). Conclusion: Taken together, our findings suggest HP as a promising therapeutic option in COVID-19. However, a detailed evaluation of HP’s efficacy is required in large prospective multicenter trials.

Extracorporeal Strategies in Sepsis Treatment: Role of Therapeutic Plasma Exchange

Mortality in sepsis remains high. Various techniques for extracorporeal cytokine removal have been investigated as additional therapeutic measures in sepsis and septic shock. To summarize a selection of extracorporeal blood purification techniques, with a special focus on therapeutic plasma exchange, and their current evidence in clinical use. Non-systematic literature review. Various extracorporeal blood purification techniques with different levels of evidence regarding cytokine removal, vasopressor sparing effects and reduction of mortality are currently in clinical use. Most extensively studied modalities include high-volume hemofiltration/dialysis with and without high cut-off filters a well as hemoadsorption techniques (including CytoSorb, and polymyxin-B filters). Despite partly encouraging observations regarding removal of inflammatory cytokines and hemodynamic stabilization, results from randomized studies did not show an effect on survival. Due to use of donor plasma as substitution fluid, therapeutic plasma exchange represents the only modality able to additionally replace protective and consumed factors. The use of extracorporeal blood purification methods cannot be recommended for sepsis patients outside of clinical trials given the current lack of evidence of their efficacy. Future investigations should aim to homogenize the studied patient collective in respect to clinical sepsis severity, time point of intervention and different inflammatory (sub-)phenotypes.

Abstract 5809: Fluorescence-guided spatiotemporal dynamics of epithelial-mesenchymal transition under inflammatory microenvironment during colorectal cancer progression

Abstract Background: Epithelial-mesenchymal transition (EMT) is a biological process, by which epithelial cancer cells acquire mesenchymal phenotype with malignant properties for invasion and metastasis, leading to poor prognosis. Inflammatory microenvironment has been shown to be responsible for the development and progression of colorectal cancer. However, the role of inflammatory microenvironment in the EMT-related tumor progression remains unclear. To explore the relationship between inflammatory microenvironment and EMT, a live imaging system for EMT is a promising strategy on the in vitro and in vivo experiments. In this study, we developed a fluorescence-guided live cell imaging system for the assessment of spatiotemporal dynamics of EMT, and investigated the potential of inflammatory microenvironment for the induction of EMT phenotype in human colorectal cancer. Methods: Two human colorectal cancer cell lines, HCT116 and RKO, were stably transfected with vimentin promoter-driven red fluorescence protein TurboFP635 expression vector. Both cell lines were treated with inflammatory cytokines, IL-1β (1 ng/ml) and TNF-α (20 ng/ml), or co-cultured with mouse macrophage cell line RAW264.7 in the presence of lipopolysaccharide (LPS) (200 ng/ml). The time-lapse live imaging was observed by confocal laser scanning microscope. Migration and invasion properties were examined by transwell chamber assays. The fluorescence intensity was measured by microplate reader and flow cytometric analysis. The expression of EMT-related markers was assessed by Western blot analysis and q-PCR. EMT-induced HCT116 and RKO cells were treated with anti-inflammatory agents, aspirin (1mM) and salicylic acid (1 mM), for the suppression of EMT. Results: Inflammatory cytokines (IL-1β and TNF-α) induced red fluorescence intensity and morphological change like mesenchymal phenotype in HCT116 and RKO cells. Removal of inflammatory cytokines attenuated red fluorescence intensity and morphological change in both cells. Inflammatory cytokines also induced the migration and invasion properties in association with EMT-related markers. Moreover, co-culture with LPS-stimulated inflammatory macrophages also induced red fluorescence intensity and morphological change as well as inflammatory cytokines. Anti-inflammatory agents significantly suppressed the fluorescence-related EMT phenotype under inflammatory microenvironment. Conclusions: These results suggest that inflammatory microenvironment has a great potential for the induction of EMT process during colorectal cancer progression. This unique fluorescence-guided EMT imaging system is useful method for the exploration of inflammation-mediated tumor progression. Citation Format: Takeshi Ieda, Hiroshi Tazawa, Satoru Kikuchi, Shinji Kuroda, Toshiaki Ohara, Kazuhiro Noma, Hiroyuki Kishimoto, Takeshi Nagasaka, Masahiko Nishizaki, Shunsuke Kagawa, Takeshi Imamura, Toshiyoshi Fujiwara. Fluorescence-guided spatiotemporal dynamics of epithelial-mesenchymal transition under inflammatory microenvironment during colorectal cancer progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5809. doi:10.1158/1538-7445.AM2017-5809

Cytokine Levels in the Serum of Patients with Chronic Kidney Insufficiency Before and After Hemodialysis

Chronic kidney insufficiency (CKI) is often the end point of a broad range of chronic kidney diseases and characterized with decreasing number of functionally active nephrons. Pathophysiological CKI is characterized by decreased glomerular filtration, which leads to accumulation of life-threatening toxic metabolites. Hemodialysis is the main therapeutic measure aimed to prolong patient’s life until kidney transplant is available. The goal of this study is to analyze serum level of 21 cytokines in CKI. We have found that the serum level of several (IL-2Rα, IL-3, IL-12 (p40), IL-16, IL-18, HGF, MIF, CSF-1, MCP-3, CXCL12, SCF, IFN-α2, LIF, β-NGF, and CXCL1) cytokines and chemokines was upregulated in CKI without hemodialysis as compared to controls (p = 0.005). Interestingly, serum cytokines were also upregulated in serum of CKI patients who received hemodialysis. Upregulated cytokines are associated with inflammation and activation of Th1 lymphocytes. We suggest that hemodialysis has limited effect on serum cytokine levels. It could be concluded that therapeutic effect of hemodialysis is not associated with removal of inflammatory cytokines from circulation. Further studies will help better define the underlying cause of an increased inflammation in CKI and identify the laboratory criteria for anti-inflammatory therapy.

Successful Combination Therapy Including Plasma Exchange for Severe Toxic Epidermal Necrolysis

Toxic epidermal necrolysis (TEN) is a rare life‐threatening disorder. Although its treatment is not standardised due to the unknown pathogenesis and the lack of randomized clinical trials, systemic corticosteroids, immunoglobulins (IVIG) and immunosuppressive drugs such as cyclophosphamide have been used in the treatment of TEN with some success. We present a case with severe TEN treated successfully with combination therapy including plasma exchange. Although it is expensive and requires venous access, use of plasma exchange may be an effective measure leading to rapid cessation of dermal necrolysis, by the removal of inflammatory cytokines, autoantibodies, immune complex or other unknown toxic substances.

Decreased levels of inflammatory cytokines in immunoglobulin-resistant Kawasaki disease after plasma exchange

The pathogenesis of coronary artery aneurysm (CAA) formation in Kawasaki disease (KD) remains unknown. However, inflammatory cytokines are thought to play an important role in KD. Patients with intravenous immunoglobulin (IVIG)-resistant KD are more likely to develop CAA. For such refractory patients, steroids and emerging infliximab (IFX) are used; however, further verification is required for their efficacy and safety. Plasma exchange (PE), which removes various inflammatory cytokines, has been used in Japan for over 15years to prevent CAA in IVIG-resistant KD patients. The sequential change in inflammatory cytokines during the time course of PE has yet to be investigated. In this study, we measured plasma levels of 13 cytokines in nine children with IVIG-resistant KD before the start of PE (day 0: D0), as well as at 1 or 2days (D1/2), and 4 or 5days (D4/5) after starting PE. The median age of onset was 8months (range: 3–53months). Before PE, patients were treated with IVIG (median dose: 4g/kg, range: 3–4g/kg). The median starting period of PE was 8days after the onset of fever (range: 6–21days), while its duration was 3days (range: 2–5days). Among the 13 cytokines, interleukin-6, tumor necrosis factor-α, tumor necrosis factor receptor I (TNFR1), TNFR2, granulocyte colony-stimulating factor, and IL-17 were significantly lower at D4/5 compared with D0 and/or D1/2, reflecting the potential central efficacy of PE. While three patients developed moderate CAA, their condition regressed within 1year. The removal of inflammatory cytokines could be the central efficacy of PE against refractory KD.

Suppression of Inflammatory Cytokines During Ex Vivo Lung Perfusion With an Adsorbent Membrane

Lung grafts can be perfused ex vivo for 2 hours without edema formation; however, prolonged ex vivo lung perfusion (EVLP) eventually induces lung injury. This study evaluated the change in proinflammatory cytokines of the perfusate during EVLP and investigated the effect of cytokine removal using an adsorbent membrane. Porcine heart-lung blocks were harvested after electrically induced cardiac arrest and underwent 12-hour EVLP with an adsorbent membrane (membrane group: n = 5) and without an adsorbent membrane (control group: n = 6). In the control group, both tumor necrosis factor-alpha and interleukin 8 levels were elevated in the perfusate 2 hours after perfusion. Although tumor necrosis factor-alpha and interleukin 8 levels were significantly lower in the membrane group than in the control group during the EVLP period, there was no significant difference in oxygenation, pulmonary vascular resistance, edema formation, or myeloperoxidase activity between the two groups. Tumor necrosis factor-alpha and interleukin 8 levels of the perfusate were elevated during EVLP. Although adverse effects of these inflammatory cytokines were anticipated, removal of inflammatory cytokines by the adsorbent membrane did not improve lung function during prolonged EVLP. Factors other than the cytokines may play a major role in causing lung injury during EVLP. Further research is needed to investigate the real mechanism of lung graft injury during prolonged EVLP and to establish longer EVLP duration for graft treatment. This strategy could contribute to the salvage of potentially damaged lungs, especially from cardiac death donors, and to expansion of the donor pool.

Removal of inflammatory cytokines with high volume hemofiltration

Removal of inflammatory cytokines with high volume hemofiltration

Removal of inflammatory cytokines and endotoxin by veno-venous continuous renal replacement therapy for burned patients with sepsis

Removal of inflammatory cytokines and endotoxin by veno-venous continuous renal replacement therapy for burned patients with sepsis

Removal of inflammatory cytokines and endotoxin by veno-venous continuous renal replacement therapy for burned patients with sepsis

Objective: To evaluate the effect of veno-venous continuous renal replacement therapy (CRRT) on the plasma levels of endotoxin and cytokines in severely burned patients with sepsis. Methods: Twenty adult severely burned patients with sepsis were studied. For the diagnosis of sepsis, patients were randomly divided into CRRT ( n = 10) and Control ( n = 10). Both groups received conventional therapy after admission. Veno-venous CRRT was administered to 10 patients in the CRRT group whenever patients were determined to be septic. The plasma level of endotoxin, TNF-alpha, IL-1 beta, IL-6 and IL-8 were measured at 0, 1, 2, 6, 12, 36 and 60 h after CRRT initiation, and at 0, 12, 36 and 60 h after the patients were diagnosed as having sepsis in the Control group. Main Results: Plasma level of endotoxin and all the cytokines after CRRT initiation were significantly lower than those before the treatment ( P < 0.01). The serial change of endotoxin, IL-1 beta, IL-6 and IL-8 was significantly lower at 12, 36 and 60 h after treatment compared with Control groups ( P < 0.01). A significant decrease in plasma TNF-alpha levels was seen at 36 and 60 h after treatment compared with Control groups ( P < 0.01). Conclusion: Plasma endotoxin and cytokines (TNF-alpha, IL-1 beta, IL-6 and IL-8) can be removed effectively with CRRT in severely burned patients with sepsis.