Daily Sepsis Research Analysis

Sepsis is a life-threatening condition driven by a maladaptive host response to infection. To establish a standardized blood transcriptomic subtype model, we aggregated blood transcriptomics data from two major sepsis cohorts: the Molecular Diagnosis and Risk Stratification of Sepsis (MARS) project (n = 678 sampled on intensive care unit admission; ClinicalTrials.gov registration no. NCT01905033 ) and the Genomic Advances in Sepsis (GAinS) study (n = 444 sampled on intensive care unit admission and n = 817 follow-up samples; ClinicalTrials.gov registration no. NCT00131196 ). We demonstrate a strong interconnection across three separate classification methods, resulting in the proposed groupings of three consensus transcriptomic subtypes (CTSs). The distinguishing characteristics of CTS1 included gene activation of typical inflammatory pathways, more pronounced endothelial activation and an overall immature neutrophil theme. CTS2 was characterized by gene activation of a heme metabolism pathway, fibrinolytic disturbances and platelet and eosinophil signatures. CTS3 was associated with genes involved in the activation of allograft rejection, interferon signaling and anticoagulation functions, together with lymphocyte and nonclassical monocyte features. Evaluating CTS classification in independent patient cohorts, specifically the vasopressin vs noradrenaline as initial therapy in septic shock (VANISH) randomized controlled trial (n = 176; ISRCTN registration no. ISRCTN20769191 ) and patients hospitalized with suspected sepsis at a district hospital in Uganda (n = 128), ascertained the robustness of our approach. Notably, post hoc analysis of a pseudo-randomized cohort, along with a reanalysis of the VANISH trial data, unmasked a harmful signal in CTS2-assigned patients treated with corticosteroids. The CTS classification method aligns diverse sepsis transcriptomic subgroupings into a robust, reproducible framework, thereby enabling biological interpretation and potentially assisting aspects of clinical trial design to advance precision medicine in sepsis.

Critical care syndromes such as sepsis, acute respiratory distress syndrome (ARDS) and trauma continue to have unacceptably high morbidity and mortality, with progress limited by the inherent heterogeneity within syndromic illnesses. Although numerous immune endotypes have been proposed for sepsis and critical care, the similarities and differences between these endotypes remain unclear, hindering clinical translation. The SUBSPACE consortium is an international consortium that aims to advance precision medicine in critical care through the sharing of transcriptomic data. Here, evaluating the overlap of existing immune endotypes in sepsis across >7,074 samples from 37 independent cohorts, we developed cell-type-specific gene expression signatures to quantify dysregulation within immune compartments. Myeloid and lymphoid dysregulation were associated with disease severity and mortality across all cohorts. Importantly, this dysregulation was also observed in patients with ARDS, trauma and burns, suggesting a conserved mechanism across various critical illness syndromes. Moreover, analysis of randomized controlled trial data revealed that myeloid and lymphoid dysregulation are associated with differential mortality in patients treated with anakinra in the SAVE-MORE trial (n = 452) and corticosteroids in the VICTAS (n = 89) and VANISH (n = 117) trials, underscoring their prognostic and therapeutic implications. In conclusion, our proposed immunology-based framework for quantifying cellular compartment dysregulation offers a potentially valuable tool for understanding immune dysregulation in critical illness with prognostic and therapeutic significance.

Lack of reliable diagnostics for the presence, type and severity of infection in patients presenting to emergency departments with non-specific symptoms poses considerable challenges. We developed TriVerity, which uses isothermal amplification of 29 mRNAs and machine learning algorithms on the Myrna instrument to determine likelihoods of bacterial infection, viral infection and need for critical care interventions within 7 days. To validate TriVerity, the SEPSIS-SHIELD study enrolled 1,222 patients with clinically adjudicated infection status and need for critical care intervention within 7 days as endpoints. The TriVerity Bacterial and Viral scores had higher accuracy than C-reactive protein, procalcitonin or white blood cell count for the diagnosis of bacterial infection with area under the receiver operating characteristic (AUROC) of 0.83, and viral infection (AUROC = 0.91). The TriVerity Severity score had an AUROC of 0.78 for predicting illness severity and allowed reclassification of risk for critical care interventions compared to clinical assessment (quick Sequential Organ Failure Assessment) alone. Each of the three scores had rule-in specificity >92% and rule-out sensitivity >95%. Comparison of antibiotics administration at presentation with post-follow-up adjudication found that TriVerity could potentially reduce false positives and false negatives for inappropriate antibiotics use by 60-70%. Further clinical testing in an interventional setting is needed to prove actionability and clinical benefit of TriVerity.