Identification of immune correlates of fatal outcomes in critically ill COVID-19 patients
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE178404 | GEO | 2021/06/18
REPOSITORIES: GEO
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Project description:Background: Outcomes in patients with severe SARS-CoV-2 infection (COVID-19) are conditioned by viral control and regulation of inflammation. Variants in IFIH1, a gene coding the cytoplasmatic RNA sensor MDA5, regulate the response to viral infections. Methods: Patients admitted to an intensive care unit (ICU) with documented COVID-19 were prospectively included and IFIH1 rs1990760 genotypes determined. Peripheral blood gene expression, cell populations and immune mediators were measured during the first day after ICU admission before steroid therapy. Peripheral blood mononuclear cells from healthy volunteers were exposed ex-vivo to an MDA5 agonist and dexamethasone, and changes in gene expression assessed. ICU discharge and hospital death were modelled using rs1990760 variants and dexamethasone therapy as factors. Findings: 237 patients were studied. Patients with the IFIH1 rs1990760 TT variant showed a decrease in expression of inflammation-related pathways, an anti-inflammatory cell profile and a decrease in pro-inflammatory mediators. Cells with TT variant exposed to an MDA5 agonist ex-vivo showed an increase in FOXO3 and IL6 when dexamethasone was added. All patients with the TT variant not treated with steroids (n=14) survived their ICU stay (HR 2.49 95% confidence interval 1.29 – 4.79). Dexamethasone therapy in this subgroup (N=50) delayed ICU discharge and increased hospital mortality (HR 2.19, 95% confidence interval 1.01 – 4.87) and serum IL-6 concentrations. Interpretation: COVID-19 ICU patients with the IFIH1 rs1990760 TT variant show an ameliorated inflammatory response that results in better outcomes than CC/CT variants. Dexamethasone can reverse this anti-inflammatory phenotype, worsening the outcome. Funding: Instituto de Salud Carlos III.
2021-07-03 | GSE168400 | GEO
Project description:Infections caused by SARS-CoV-2 may cause a severe disease, termed COVID-19, with significant mortality. Host responses to this infection, mainly in terms of systemic inflammation, have emerged as key pathogenetic mechanisms, and their modulation is the only therapeutic strategy that has shown a mortality benefit. Herein, we used peripheral blood transcriptomes of critically-ill COVID-19 patients obtained at admission in an Intensive Care Unit, to identify two clusters that, in spite of no major clinical differences, have different gene expression profiles that reveal different underlying pathogenetic mechanisms and ultimately have different ICU outcome. A transcriptomic signature was used to identify these clusters in an external validation cohort, yielding a similar result. These results illustrate the potential of transcriptomic profiles to identify patient endotypes and point to relevant pathogenetic mechanisms in COVID-19.
2023-04-29 | GSE206264 | GEO
Project description:Infections caused by SARS-CoV-2 may cause a severe disease, termed COVID-19, with significant mortality. Host responses to this infection, mainly in terms of systemic inflammation, have emerged as key pathogenetic mechanisms, and their modulation is the only therapeutic strategy that has shown a mortality benefit. Herein, we used peripheral blood transcriptomes of critically-ill COVID-19 patients obtained at admission in an Intensive Care Unit, to identify two clusters that, in spite of no major clinical differences, have different gene expression profiles that reveal different underlying pathogenetic mechanisms and ultimately have different ICU outcome. A transcriptomic signature was used to identify these clusters in an external validation cohort, yielding a similar result. These results illustrate the potential of transcriptomic profiles to identify patient endotypes and point to relevant pathogenetic mechanisms in COVID-19.
2022-02-28 | GSE197258 | GEO
Project description:Infections caused by SARS-CoV-2 may cause a severe disease, termed COVID-19, with significant mortality. Host responses to this infection, mainly in terms of systemic inflammation, have emerged as key pathogenetic mechanisms, and their modulation is the only therapeutic strategy that has shown a mortality benefit. Herein, we used peripheral blood transcriptomes of critically-ill COVID-19 patients obtained at admission in an Intensive Care Unit, to identify two clusters that, in spite of no major clinical differences, have different gene expression profiles that reveal different underlying pathogenetic mechanisms and ultimately have different ICU outcome. A transcriptomic signature was used to identify these clusters in an external validation cohort, yielding a similar result. These results illustrate the potential of transcriptomic profiles to identify patient endotypes and point to relevant pathogenetic mechanisms in COVID-19.
2022-02-28 | GSE197204 | GEO
Project description:Identification of immune correlates of fatal outcomes in critically ill COVID-19 patients
| PRJNA738888 | ENA
Project description:There remains an urgent need to delinate immune cell states that contribute to mortality in critially ill COVID-19 patients. To better understand determinants of mortality, we performed high dimensional profiling of blood and respiratory samples from critially ill COVID-19 patients. Single-cell RNAseq based characterization of peripheral immune states reveal distinct expression profiles that were predictive of COVID-19 mortality. Temporal analysis revealed a that persistently elevated levels of inflammatory monocyte signatures and persistent interferon signaling preceeded concerted upregulation of inflammatory cytokines. Interrogation of lower respiratory tract saples revelaed that infected myeliod cells upregulated CXCL10, and elevated levels of CXCL10 in plasma were associated with a high risk of death. Overall, our data suggest a pivotal role for myeloid cell states in severe COVID-19 and may faciliate discovery of new diagnostics and therapeutics.
2021-12-08 | GSE180578 | GEO
Project description:Objective: COVID19 is caused by the SARS-CoV-2 virus and has been associated with severe inflammation leading to organ dysfunction and mortality. Our aim was to profile the transcriptome in leukocytes from critically ill ICU patients positive for COVID19 vs. those negative for COVID19 to better understand the COVID19 associated host response. Design: Transcriptome profiling of buffy coat cells via ribonucleic acid sequencing (RNAseq) at the time of admission to the ICU. Setting: Tertiary care ICU and academic laboratory. Subjects: All patients admitted to the ICU suspected of being infected with SARS-CoV-2, using standardized hospital screening methodologies, had blood samples collected at the time of admission to the ICU. Interventions: None. Measurement and Main Results: Age- and sex-matched ICU patients that were either COVID19+ (PCR positive, 2 genes) or COVID19- (PCR negative) were enrolled. Cohorts were well-balanced with the exception that COVID19- patients had significantly higher total white blood cell counts and circulating neutrophils and COVID19+ patients were more likely to suffer bilateral pneumonia compared to COVID19- patients. Further, the mortality rate for this cohort of COVID19+ ICU patients was 29%. Transcriptional analysis revealed that when compared to COVID19- patients, the altered transcriptional responses of leukocytes in critically ill COVID19+ ICU patients appeared to be associated with multiple interrelated outcomes, including but not limited to robust interferon (IFN)-associated transcriptional responses, a marked decrease in the transcriptional activity of genes contributing to protein synthesis and the dysregulated expression of genes that contribute to coagulation, platelet activation, Toll-like receptor activation, neurotrophin signaling, and protein SUMOylation/ubiquitination. Conclusions: COVID19+ patients on day 1 of admission to the ICU display a unique leukocyte transcriptional profile that distinguishes them from COVID19- patients. Identification of this profile provides guidance for future targeted studies exploring novel prognostic/therapeutic aspects of COVID19.
2020-10-01 | GSE154998 | GEO
Project description:Respiratory failure in COVID-19 is characterized by widespread disruption of the lung’s alveolar gas exchange interface. To elucidate determinants of alveolar lung damage, we performed epithelial and immune cell profiling in lungs from 24 COVID-19 autopsies and 43 uninfected organ donors ages 18-92 years. We found marked loss of type 2 alveolar epithelial (T2AE) cells and increased peri-alveolar lymphocyte cytotoxicity in all fatal COVID-19 cases, even at early stages before typical patterns of acute lung injury are histologically apparent. In lungs from uninfected organ donors, there is also progressive loss of T2AE with increasing age which may increase susceptibility to COVID-19 mediated lung damage in older individuals. In the fatal COVID-19 cases, macrophage infiltration differed according to the histopathological pattern of lung injury. In cases with acute lung injury, we found accumulation of CD4+ macrophages that express distinctly high levels of T-cell activation and co-stimulation genes and strongly correlate with increased extent of alveolar epithelial cell depletion and CD8 T-cell cytotoxicity. Together, our results show that T2AE deficiency may underlie age-related COVID-19 risk and initiate alveolar dysfunction shortly after infection; and we define immune cell mediators that may contribute to alveolar injury in distinct pathological stages of fatal COVID-19.
2022-04-19 | GSE200988 | GEO
Project description:Plasma proteomics provide valuable and unbiased information about disease progression and therapeutic candidates. Recent proteomic studies have identified molecular changes in plasma of COVID-19 patients that implied significant dysregulation of several aspects of the inflammatory response accompanied to a general metabolic suppression. However, which of these plasma alterations are associated to disease severity remain partly characterized. A known limitation of proteomic studies of plasma samples is the large difference in the macromolecule abundance, with concentration spanning at least 10 orders of magnitude. To improve the coverage of plasma contents, we performed a deep proteomic analysis of plasma from 10 COVID-19 patients with severe/fatal pneumonia compared to 10 COVID-19 patients with pneumonia who did not require ICU admission (non-ICU). To this aim, plasma samples were first depleted of most abundant proteins and peptides obtained by trypsin digestion subjected to a high pH reversed-phase peptide fractionation before LC-MS analysis.
2023-03-11 | PXD036491 | Pride
Project description:Background: Systemic inflammation is a whole body reaction that can have an infection-positive (i.e. sepsis) or infection-negative origin. It is important to distinguish between septic and non-septic presentations early and reliably, because this has significant therapeutic implications for critically ill patients. We hypothesized that a molecular classifier based on a small number of RNAs expressed in peripheral blood could be discovered that would: 1) determine which patients with systemic inflammation had sepsis; 2) be robust across independent patient cohorts; 3) be insensitive to disease severity; and 4) provide diagnostic utility. The overall goal of this study was to identify and validate such a molecular classifier. Methods and Findings: We conducted an observational, non-interventional study of adult patients recruited from tertiary intensive care units (ICU). Biomarker discovery was conducted with an Australian cohort (n = 105) consisting of sepsis patients and post -surgical patients with infection-negative systemic inflammation. Using this cohort, a four-gene classifier consisting of a combination of CEACAM4, LAMP1, PLA2G7 and PLAC8 RNA biomarkers was identified. This classifier, designated SeptiCyte® Lab, was externally validated using RT-qPCR and receiver operating characteristic (ROC) curve analysis in five cohorts (n = 345) from the Netherlands. Cohort 1 (n=59) consisted of unambiguous septic cases and infection-negative systemic inflammation controls; SeptiCyte® Lab gave an area under curve (AUC) of 0.96 (95% CI: 0.91-1.00). ROC analysis of a more heterogeneous group of patients (Cohorts 2-5; 249 patients after excluding 37 patients with infection likelihood possible) gave an AUC of 0.89 (95% CI: 0.85-0.93). Disease severity, as measured by Sequential Organ Failure Assessment (SOFA) score or the Acute Physiology and Chronic Health Evaluation (APACHE) IV score, was not a significant confounding variable. The diagnostic utility o f SeptiCyte® Lab was evaluated by comparison to various clinical and laboratory parameters that would be available to a clinician within 24 hours of ICU admission. SeptiCyte® Lab was significantly better at differentiating sepsis from infection-negative systemic inflammation than all tested parameters, both singly and in various logistic combinations. SeptiCyte® Lab more than halved the diagnostic error rate compared to PCT in all tested cohorts or cohort combinations. Conclusions: SeptiCyte® Lab is a rapid molecular assay that may be clinically useful in the management of ICU patients with systemic inflammation. SIRS and Sepsis ICU patients, admission samples Retrospective, mutli-site sutdy using retrospective physician adjudication as a comparator
2015-10-24 | E-GEOD-74224 | biostudies-arrayexpress