Dataset Information

Effects of IFIH1 rs1990760 variants on systemic inflammation and outcome in critically ill COVID-19 patients in an observational translational study.

ABSTRACT:

Background

Variants in IFIH1, a gene coding the cytoplasmatic RNA sensor MDA5, regulate the response to viral infections. We hypothesized that IFIH1 rs199076 variants would modulate host response and outcome after severe COVID-19.

Methods

Patients admitted to an intensive care unit (ICU) with confirmed COVID-19 were prospectively studied and rs1990760 variants determined. Peripheral blood gene expression, cell populations, and immune mediators were measured. Peripheral blood mononuclear cells from healthy volunteers were exposed to an MDA5 agonist and dexamethasone ex-vivo, and changes in gene expression assessed. ICU discharge and hospital death were modeled using rs1990760 variants and dexamethasone as factors in this cohort and in-silico clinical trials.

Results

About 227 patients were studied. Patients with the IFIH1 rs1990760 TT variant showed a lower expression of inflammation-related pathways, an anti-inflammatory cell profile, and lower concentrations of pro-inflammatory mediators. Cells with TT variant exposed to an MDA5 agonist showed an increase in IL6 expression after dexamethasone treatment. All patients with the TT variant not treated with steroids survived their ICU stay (hazard ratio [HR]: 2.49, 95% confidence interval [CI]: 1.29-4.79). Patients with a TT variant treated with dexamethasone showed an increased hospital mortality (HR: 2.19, 95% CI: 1.01-4.87) and serum IL-6. In-silico clinical trials supported these findings.

Conclusions

COVID-19 patients with the IFIH1 rs1990760 TT variant show an attenuated inflammatory response and better outcomes. Dexamethasone may reverse this anti-inflammatory phenotype.

Funding

Centro de Investigación Biomédica en Red (CB17/06/00021), Instituto de Salud Carlos III (PI19/00184 and PI20/01360), and Fundació La Marató de TV3 (413/C/2021).

SUBMITTER: Amado-Rodriguez L

PROVIDER: S-EPMC8782569 | biostudies-literature | 2022 Jan

REPOSITORIES: biostudies-literature

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Publications

Effects of IFIH1 rs1990760 variants on systemic inflammation and outcome in critically ill COVID-19 patients in an observational translational study.

Amado-Rodríguez Laura L Salgado Del Riego Estefania E Gomez de Ona Juan J López Alonso Inés I Gil-Pena Helena H López-Martínez Cecilia C Martín-Vicente Paula P Lopez-Vazquez Antonio A Gonzalez Lopez Adrian A Cuesta-Llavona Elias E Rodriguez-Garcia Raquel R Boga Jose Antonio JA Elena Alvarez-Arguelles Marta M Mayordomo-Colunga Juan J Vidal-Castineira Jose Ramon JR Crespo Irene I Fernandez Margarita M Criado Loreto L Salvadores Victoria V Jimeno-Demuth Francisco Jose FJ Blanch Lluis L Prieto Belen B Fernandez-Fernandez Alejandra A Lopez-Larrea Carlos C Coto Eliecer E Albaiceta Guillermo M GM

eLife 20220121

<h4>Background</h4>Variants in <i>IFIH1</i>, a gene coding the cytoplasmatic RNA sensor MDA5, regulate the response to viral infections. We hypothesized that <i>IFIH1</i> rs199076 variants would modulate host response and outcome after severe COVID-19.<h4>Methods</h4>Patients admitted to an intensive care unit (ICU) with confirmed COVID-19 were prospectively studied and rs1990760 variants determined. Peripheral blood gene expression, cell populations, and immune mediators were measured. Peripher ...[more]

PMID: 35060899

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Project description:ObjectiveAnalyze the outcomes of critically ill patients who developed new-onset organ dysfunction and received systemic chemotherapy during their ICU stay.DesignRetrospective cohort study.SettingA tertiary medical center in Germany with an Intensive Care Medicine department consists of 11 intensive care units comprising 140 beds, serving all subspecialties of adult intensive care medicine.Patients167 patients receiving systemic oncological treatment from January 1st, 2015 to December 31st, 2021, with a data cut-off on December 31st, 2022.InterventionsNone.Measurements and main resultsA total of 167 patients were included. The primary reasons for ICU admission were respiratory failure and shock/sepsis, each accounting for 34% of cases, while complications associated with oncological therapy accounted for less than 8%. The median age of hematological patients (n = 129) was 62 years (IQR 50-70), and for solid tumor patients (n = 38), it was 60 years (IQR 52-65). Predominant disease entities included lymphoma (43%) and acute myeloid leukemia (29%) among hematological patients, and lung cancer (47%) and gastrointestinal malignancies (17%) among solid tumor patients. Hematological patients had a significantly higher median Simplified Acute Physiology Score II (47 vs. 39 points; p=0.013), a higher need for invasive mechanical ventilation (59% vs. 50%; p=0.3), renal replacement therapy (54% vs. 24%; p < 0.001), and a higher 1-year mortality rate (64% vs. 53%; p=0.2) compared to solid tumor patients. The hazard ratio for 1 year survival for male sex was 2.34 (1.31-3.49), for mechanical ventilation 2.01 (1.33-3.04), for vasopressor therapy 1.98 (1.27-3.10), and for renal replacement therapy 1.51 (1.03-2.23), respectively.ConclusionAdministering intravenous chemotherapy in an ICU setting remains challenging, and the experience to establish an indication for systemic chemotherapy is still challenging. However, the study demonstrates that, after careful interdisciplinary decision-making, a substantial number of patients can benefit from it.

Dataset Information

Effects of IFIH1 rs1990760 variants on systemic inflammation and outcome in critically ill COVID-19 patients in an observational translational study.

Background

Methods

Results

Conclusions

Funding

Publications

Effects of IFIH1 rs1990760 variants on systemic inflammation and outcome in critically ill COVID-19 patients in an observational translational study.

Similar Datasets

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