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HGNC Genes

SARS-CoV-2 proteins

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    Clinical Characteristics and Outcomes of Critically ill Mechanically Ventilated MESHD COVID-19 MESHD Patients Receiving interleukin-6 HGNC Receptor Antagonists and/or Corticosteroid Therapy, the INTERACT study: A Multicenter International Observational Study

    Authors: Marwa R Amer; Mohammed Bawazeer; Khalid Maghrabi; Ahmed Mohamed Kamal; Abid Butt; Talal Dahhan; Eiad Kseibi; Mohammed Abujazar; Razan Alghunaim; Muath Rabee; Maal Abualkhair; Ali Al-Janoubi; Abeer AlFirm; Syed Moazzum Khurshid; Ognjen Gajic; Allan J. Walkey; Jarrod M Mosier; Igor Borisovich Zabolotskikh; Oscar Y Gavidia; Santiago Y. Teruel; Michael A. Bernstein; Karen Boman; Vishakha K. Kumar; Vikas Bansal; Rahul Kashyap

    doi:10.1101/2021.04.12.21255323 Date: 2021-04-13 Source: medRxiv

    Objectives: To compare the clinical characteristics and outcomes of critically ill coronavirus disease MESHD ( COVID-19 MESHD) patients requiring mechanical ventilation (MV), receiving interleukin 6 receptor ( IL6R HGNC) antagonists, steroids, or a combination of both. Design: An international, multicenter, observational study derived from the COVID-2019 Viral Infection and Respiratory Illness University Study (VIRUS) registry and conducted through the Discovery Network, the Society of Critical Care Medicine. Marginal structural modeling was used to adjust for time-dependent confounders, and observations were weighted using the inverse probability of treatment weight. Sensitivity analysis was conducted to emulate a target trial design. Setting: 168 hospitals in 16 countries. Patients: adult ICU patients ( > 18 years) requiring MV for COVID-19 MESHD between March 01, 2020, and January 10, 2021. Intervention: None. Measurements and Main Results: A total of 860 patients met eligibility criteria: 589 received steroids, 170 IL-6R HGNC antagonists, and 101 combination therapy, and the groups were balanced after adjustment. The median daily steroid dose was 7.5 mg dexamethasone or equivalent (IQR: 6 to 14 mg); 80.8% received low-dose and 19.2% high-dose steroids (> 15 mg/day of dexamethasone or equivalent). The median C-reactive protein HGNC level was > 75 mg/L in majority of our cohort. The use of IL6R HGNC antagonists alone or in combination was not associated with a significant difference in ventilator free days ( VFD MESHD) compared to steroids alone (adjusted incidence rate ratio [95% CI]): IL6R HGNC antagonists (1.12 [0.88,1.4]), combination (0.83 [0.6,1.14]). Patients treated with low or high-dose steroids had non-significant differences in VFD MESHD compared to IL6R HGNC antagonists (beta= 0.62, 95% CI -1.54, 2.78 for low-dose steroid; beta= -1.19, 95% CI -3.85, 1.47 for high-dose steroid). The use of IL6R HGNC antagonists alone or in combination was not associated with a significant difference in 28 day mortality compared to steroids alone (adjusted odds ratio [95% CI]): IL6R HGNC antagonists alone (0.68 [0.44,1.07]), combination (1.07 [0.67,1.7]). There was no difference in hospital mortality compared to steroids alone (aOR 0.68, 95% CI 0.43,1.09 for IL6R HGNC antagonist, aOR 1.23, 95 % CI 0.72,2.11 for combination). The findings of sensitivity analysis were consistent with the primary analysis. The rate of liver dysfunction MESHD was higher in the IL6R HGNC antagonist (p=0.038), while the rate of bacteremia MESHD did not differ among the three groups. Conclusions: We observed no difference in outcomes between mechanically ventilated adult ICU patients who received IL6R HGNC antagonists, steroids, or combination therapy and those who received IL6R HGNC antagonists or low or high dose steroids. Further trials are needed to evaluate high-dose steroids as substitutes for IL6R HGNC antagonists in resource-limited settings.

    Genetic inhibition of interleukin-6 HGNC receptor signaling and Covid-19 MESHD

    Authors: Jonas Bovijn; Cecilia M. Lindgren; Michael V. Holmes

    doi:10.1101/2020.07.17.20155242 Date: 2020-07-19 Source: medRxiv

    There are few effective therapeutic options for the treatment of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection MESHD. Early evidence has suggested that IL-6R HGNC blockers may confer benefit, particularly in severe coronavirus disease 2019 MESHD ( Covid-19 MESHD). We leveraged large-scale human genetic data to investigate whether IL6-R HGNC blockade may confer therapeutic benefit in Covid-19 MESHD. A genetic instrument consisting of seven genetic variants in or close to IL6R HGNC was recently shown to be linked to altered levels of c-reactive protein HGNC ( CRP HGNC), fibrinogen HGNC, circulating IL-6 HGNC and soluble IL-6R HGNC, concordant to known effects of pharmacological IL-6R HGNC blockade. We investigated the effect of these IL6R HGNC variants on risk of hospitalization for Covid-19 MESHD and other SARS-CoV-2-related outcomes using data from The Covid-19 MESHD Host Genetics Initiative. The IL6R HGNC variants were strongly associated with serum CRP HGNC levels in UK Biobank. Meta-analysis of scaled estimates revealed a lower risk of rheumatoid arthritis MESHD (OR 0.93 per 0.1 SD lower CRP HGNC, 95% CI, 0.90-0.96, P = 9.5 x 10-7), recapitulating this established indication for IL-6R HGNC blockers (e.g. tocilizumab and sarilumab). The IL-6R HGNC instrument was associated with lower risk of hospitalization for Covid-19 MESHD (OR 0.88 per 0.1 SD lower CRP HGNC, 95% CI, 0.78-0.99, P = 0.03). We found a consistent association when using a population-based control group (i.e. all non-cases; OR 0.91 per 0.1 SD lower CRP HGNC, 95% CI, 0.87-0.96, P = 4.9 x 10-4). Evaluation of further SARS-CoV-2-related outcomes suggested association with risk of SARS-CoV-2 infection MESHD, with no evidence of association with Covid-19 MESHD complicated by death MESHD or requiring respiratory support. We performed several sensitivity analyses to evaluate the robustness of our findings. Our results serve as genetic evidence for the potential efficacy of IL-6R HGNC blockade in Covid-19 MESHD. Ongoing large-scale RCTs of IL-6R HGNC blockers will be instrumental in identifying the settings, including stage of disease, in which these agents may be effective.

    Temporal clinical and laboratory response to interleukin-6 HGNC receptor blockade with Tocilizumab in 89 hospitalized patients with COVID-19 MESHD pneumonia

    Authors: Daria S Formina; Mar'yana A Lysenko; Irina P Beloglazova; zinaida Y Mutinova; Nataliya G Poteshkina; Inna V Samsonova; Tat'yana S Kruglova; Anton A Chernov; Alexander V Karaulov; Michael M Lederman

    doi:10.1101/2020.06.12.20122374 Date: 2020-06-12 Source: medRxiv

    Abstract: Background:. Emerging evidence links morbidity and mortality of pandemic COVID-19 MESHD pneumonia MESHD to an inflammatory cytokine storm. Methods: Eighty nine patients with COVID-19 MESHD pneumonia MESHD and heightened systemic inflammation MESHD (elevated serum C reactive protein HGNC and interleukin-6 HGNC levels) were treated with Tocilizumab (TCZ), a human monoclonal IgG1 antibody to the interleukin-6 receptor HGNC. Results: Clinical and laboratory improvement was seen comparing baseline and 1-2 day post-infusion indices. Among 72 patients not receiving mechanical ventilation, NEWS2 scores fell from 5 to 2 (p <0.001) C reactive protein HGNC levels fell from 95 to 14 mg/L (p <0.001) and lymphocyte counts rose from 900 to 1000/uL (p=0.036). Sixty three of 72 patients were discharged from hospital, one patient died, and 8 remained in hospital at time of writing. Among 17 patients receiving mechanical ventilation, despite a rapid decrease in CRP HGNC levels from 89 to 35 mg/L (p = 0.014) and early improvements in NEWS2 scores in 10 of 17, ten patients died and seven remain in hospital at time of writing. Overall, mortality was only seen in patients who had markedly elevated CRP HGNC levels (>30 mg/L) and low lymphocyte counts (<1000/uL) before TCZ administration. Conclusions: Inflammation MESHD and lymphocytopenia MESHD are linked to mortality in COVID-19 MESHD. Inhibition of IL-6 HGNC activity by administration of Tocilizumab, an anti IL-6 receptor antibody is associated with rapid improvement in both CRP HGNC and lymphocyte counts and in clinical indices. Controlled clinical trials are needed to confirm the utility of IL-6 HGNC blockade in this setting. Additional interventions will be needed for patients requiring mechanical ventilation.

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MeSH Disease
HGNC Genes
SARS-CoV-2 Proteins


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