New Decade, Old Debate: Blocking the Cytokine Pathways in Infection-Induced Cytokine Cascade

Rizvi, Mahrukh; Moraes, Alice Gallo De

doi:10.1097/cce.0000000000000364

Cited by 20 publications

(11 citation statements)

References 49 publications

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“…Another study [ 13 ] showed that the administration of celecoxib (CLX), a selective COX -2 inhibitor, after CLP also resulted in a reduced mortality rate. The survival rates reported in these studies were 57% and 43%, respectively, which might be improved by changing the dose and/or timing of the treatment, factors considered to be critical in the management of sepsis [ 14 , 15 , 16 ].…”

Section: Introductionmentioning

confidence: 99%

Effect of Celecoxib and Infliximab against Multiple Organ Damage Induced by Sepsis in Rats: A Comparative Study

et al. 2022

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In cases of sepsis, the immune system responds with an uncontrolled release of proinflammatory cytokines and reactive oxygen species. The lungs, kidneys, and liver are among the early impacted organs during sepsis and are a direct cause of mortality. The aim of this study was to compare the effects of infliximab (IFX) and celecoxib (CLX) on septic rats that went through a cecal ligation and puncture (CLP) surgery to induce sepsis. This study included four groups: sham, CLP (untreated), and CLP-treated with CLX or IFX. The administration of “low dose” CLX or IFX was performed after 2 h following the induction of sepsis. Twenty-four hours following the induction of sepsis, the rats were sacrificed and blood samples were collected to evaluate kidney, liver, and lung injuries. MDA and NOx content, in addition to SOD activity and GSH levels, were evaluated in the tissue homogenates of each group. Tissue samples were also investigated histopathologically. In a separate experiment, the same groups were employed to evaluate the survival of septic rats in a 7-day observation period. The results of this study showed that treatment with either CLX or IFX ameliorated the three organs’ damage compared to septic-untreated rats, decreased oxidative stress, enhanced the antioxidant defense, and reduced serum cytokines. As a result, a higher survival rate resulted: 62.5% and 37.5% after the administration of CLX and IFX, respectively, compared to 0% in the CLP group after 7 days. No significant differences were observed between the two agents in all measured parameters. Histopathological examination confirmed the observed results. In conclusion, CLX and IFX ameliorated lung, kidney, and liver injuries associated with sepsis through anti-inflammatory and antioxidant actions, which correlated to the increase in survival observed with both of them.

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Section: Introductionmentioning

confidence: 99%

Effect of Celecoxib and Infliximab against Multiple Organ Damage Induced by Sepsis in Rats: A Comparative Study

et al. 2022

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“…Severe and critical coronavirus disease 2019 (COVID-19) can manifest as respiratory failure with elevated inflammatory markers, resulting in exaggerated cytokine release, for which interleukin-6 receptor antagonists (IL-6RAs) are approved as treatment [ 1 – 3 ]. Interest in IL-6RAs and corticosteroids has increased recently due to their potential role as immunomodulators [ 4 – 7 ].…”

Section: Introductionmentioning

confidence: 99%

Clinical characteristics and outcomes of critically ill mechanically ventilated COVID-19 patients receiving interleukin-6 receptor antagonists and corticosteroid therapy: a preliminary report from a multinational registry

et al. 2021

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Background Interleukin-6 receptor antagonists (IL-6RAs) and steroids are emerging immunomodulatory therapies for severe and critical coronavirus disease (COVID-19). In this preliminary report, we aim to describe the epidemiology, clinical characteristics, and outcomes of adult critically ill COVID-19 patients, requiring invasive mechanical ventilation (iMV), and receiving IL-6RA and steroids therapy over the last 11 months. Materials and methods International, multicenter, cohort study derived from Viral Infection and Respiratory Illness University Study registry and conducted through Discovery Network, Society of Critical Care Medicine. Data were collected between March 01, 2020, and January 10, 2021. Results Of 860 patients who met eligibility criteria, 589 received steroids, 170 IL-6RAs, and 101 combinations. Patients who received IL-6RAs were younger (median age of 57.5 years vs. 61.1 and 61.8 years in the steroids and combination groups, respectively). The median C-reactive protein level was > 75 mg/L, indicating a hyperinflammatory phenotype. The median daily steroid dose was 7.5 mg dexamethasone or equivalent (interquartile range: 6–14 mg); 80.8% and 19.2% received low-dose and high-dose steroids, respectively. Of the patients who received IL-6RAs, the majority received one dose of tocilizumab and sarilumab (dose range of 600–800 mg for tocilizumab and 200–400 mg for sarilumab). Regarding the timing of administration, we observed that steroid and IL-6RA administration on day 0 of ICU admission was only 55.6% and 39.5%, respectively. By day 28, when compared with steroid use alone, IL-6RA use was associated with an adjusted incidence rate ratio (aIRR) of 1.12 (95% confidence interval [CI] 0.88, 1.4) for ventilator-free days, while combination therapy was associated with an aIRR of 0.83 (95% CI 0.6, 1.14). IL-6RA use was associated with an adjusted odds ratio (aOR) of 0.68 (95% CI 0.44, 1.07) for the 28-day mortality rate, while combination therapy was associated with an aOR of 1.07 (95% CI 0.67, 1.70). Liver dysfunction was higher in IL-6RA group (p = 0.04), while the bacteremia rate did not differ among groups. Conclusions Discordance was observed between the registry utilization patterns (i.e., timing of steroids and IL-6RA administration) and new evidence from the recent randomized controlled trials and guideline recommendations. These data will help us to identify areas of improvement in prescribing patterns and enhance our understanding of IL-6RA safety with different steroid regimens. Further studies are needed to evaluate the drivers of hospital-level variation and their impact on clinical outcomes. Trial registration ClinicalTrials.gov: NCT04486521. Registered on July 2020

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“…Furthermore, randomised trials have been performed aiming to remove IL-6 and other cytokines by using extracorporeal haemoadsorption devices. 42 In the largest trial (97 evaluable patients), the use of haemoadsorption in patients with severe sepsis was not associated with any reduction in plasma IL-6 levels and had no effect on mortality once adjusting for comorbidities (Hazard Ratio 1.67, 95% CI 0.77 - 3.61). 43 Given that this device is untargeted, did not successfully reduce IL-6 levels and the clinically relevant complications associated with usage of extracorporeal haemoadsorption, it is hard to interpret this evidence in evaluation of targeted IL-6 downregulation by either genetic variation or IL6RA.…”

Section: Discussionmentioning

confidence: 94%

Therapeutic potential of IL6R blockade for the treatment of sepsis and sepsis-related death: Findings from a Mendelian randomisation study

Hamilton

Thomas

Arnold

et al. 2022

Preprint

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Introduction Sepsis is characterised by dysregulated, life-threatening immune responses, which are thought to be driven by cytokines such as interleukin-6 (IL-6). Genetic variants in IL6R known to downregulate IL-6 signalling are associated with improved COVID-19 outcomes, a finding later confirmed in randomised trials of IL-6 receptor antagonists (IL6RA). We hypothesised that blockade of IL6R could also improve outcomes in sepsis. Methods We performed a Mendelian randomisation analysis using single nucleotide polymorphisms (SNPs) in and near IL6R to evaluate the likely causal effects of IL6R blockade on sepsis, sepsis severity, other infections, and COVID-19. We weighted SNPs by their effect on CRP and combined results across them in inverse variance weighted meta-analysis, proxying the effect of IL6RA. Our outcomes were measured in UK Biobank, FinnGen, the COVID-19 Host Genetics Initiative (HGI), and the GenOSept and GainS consortium. We performed several sensitivity analyses to test assumptions of our methods, including utilising variants around CRP in a similar analysis. Results In the UK Biobank cohort (N=485,825, including 11,643 with sepsis), IL6R blockade was associated with a decreased risk of sepsis (OR=0.80; 95% CI 0.66-0.96, per unit of natural log transformed CRP decrease). The size of this effect increased with severity, with larger effects on 28-day sepsis mortality (OR=0.74; 95% CI 0.38-0.70); critical care admission with sepsis (OR=0.48, 95% CI 0.30-0.78) and critical care death with sepsis (OR=0.37, 95% CI 0.14 - 0.98) Similar associations were seen with severe respiratory infection: OR for pneumonia in critical care 0.69 (95% CI 0.49 - 0.97) and for sepsis survival in critical care (OR=0.22; 95% CI 0.04- 1.31) in the GainS and GenOSept consortium. We also confirm the previously reported protective effect of IL6R blockade on severe COVID-19 (OR=0.69, 95% 0.57 - 0.84) in the COVID-19 HGI, which was of similar magnitude to that seen in sepsis. Sensitivity analyses did not alter our primary results. Conclusions IL6R blockade is causally associated with reduced incidence of sepsis, sepsis related critical care admission, and sepsis related mortality. These effects are comparable in size to the effect seen in severe COVID-19, where IL-6 receptor antagonists were shown to improve survival. This data suggests a randomised trial of IL-6 receptor antagonists in sepsis should be considered.

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New Decade, Old Debate: Blocking the Cytokine Pathways in Infection-Induced Cytokine Cascade

Cited by 20 publications

References 49 publications

Effect of Celecoxib and Infliximab against Multiple Organ Damage Induced by Sepsis in Rats: A Comparative Study

Effect of Celecoxib and Infliximab against Multiple Organ Damage Induced by Sepsis in Rats: A Comparative Study

Clinical characteristics and outcomes of critically ill mechanically ventilated COVID-19 patients receiving interleukin-6 receptor antagonists and corticosteroid therapy: a preliminary report from a multinational registry

Therapeutic potential of IL6R blockade for the treatment of sepsis and sepsis-related death: Findings from a Mendelian randomisation study

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