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Multiomic chromatin accessibility and gene expression in peripheral blood predicts future decompensation in hospitalized adults with COVID-19

ABSTRACT: To elucidate host response elements that define impending decompensation during SARS-CoV-2 infection, we enrolled subjects hospitalized with COVID-19 who were matched for disease severity and comorbidities at the time of admission and initial sampling. We then performed combined single-cell RNA sequencing (scRNA-seq) and single cell Assay for Transposase-Accessible Chromatin using sequencing (scATAC-seq) on peripheral blood mononuclear cells (PBMCs) from the time of admission and compared subjects who improved from their initial low-level oxygen requirement (no change from initial WHO Ordinal category 4/5) to those who later clinically decompensated and required invasive mechanical ventilation or died (WHO Ordinal score 7/8). Chromatin accessibility and transcriptomic immune profiles were markedly altered at admission in patients who will go on to develop critical illness. The greatest immunologic signals were seen in CD4+ T cells, inflammatory T cells, dendritic cells, and NK cell subsets, where an aggregate multiomic signature score calculated at admission offered strong prediction of future clinical deterioration (area under the receiver operating characteristic curve (auROC) 0.91). Epigenetic and transcriptional changes in PBMCs reveal unique, early, and conserved aspects of the immune response before typical clinical signals of decompensation are apparent and thus provide novel biomarkers that can predict future disease severity.

ORGANISM(S): Homo sapiens

PROVIDER: GSE215915 | GEO | 2023/10/17

REPOSITORIES: GEO

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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 SeptiCyteÂ® 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; SeptiCyteÂ® 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 SeptiCyteÂ® Lab was evaluated by comparison to various clinical and laboratory parameters that would be available to a clinician within 24 hours of ICU admission. SeptiCyteÂ® Lab was significantly better at differentiating sepsis from infection-negative systemic inflammation than all tested parameters, both singly and in various logistic combinations. SeptiCyteÂ® Lab more than halved the diagnostic error rate compared to PCT in all tested cohorts or cohort combinations. Conclusions: SeptiCyteÂ® 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

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Multiomic chromatin accessibility and gene expression in peripheral blood predicts future decompensation in hospitalized adults with COVID-19

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