Identification of a transcriptome profile associated with improvement of organ function in septic shock patients after early supportive therapy

Abstract

BackgroundSeptic shock is the most severe complication of sepsis and this syndrome is associated with high mortality. Treatment of septic shock remains largely supportive of hemodynamics and tissue perfusion. Early changes in organ function assessed by the Sequential Organ Function Assessment (SOFA) score are highly predictive of the outcome. However, the individual patient’s response to supportive therapy is very heterogeneous, and the mechanisms underlying this variable response remain elusive. The aim of the study was to investigate the transcriptome of whole blood in septic shock patients with different responses to early supportive hemodynamic therapy assessed by changes in SOFA scores within the first 48 h from intensive care unit (ICU) admission.MethodsWe performed whole blood RNA sequencing in 31 patients: 17 classified as responders (R) and 14 as non-responders (NR). Gene expression was investigated at ICU admission (time point 1, or T1), comparing R with NR [padj < 0.01; Benjamini–Hochberg (BH)] and over time from T1 to T2 (48 h later) in R and NR independently (paired analysis, padj < 0.01; BH). Then the differences in gene expression trends over time were evaluated (Mann–Whitney, P <0.01). To identify enriched biological processes, we performed an over-representation analysis based on a right-sided hypergeometric test with Bonferroni step-down as multiple testing correction (padj < 0.05).ResultsAt ICU admission, we did not identify differentially expressed genes (DEGs) between the two groups. In the transition from T1 to T2, the activation of genes involved in T cell–mediated immunity, granulocyte and natural killer (NK) cell functions, and pathogen lipid clearance was noted in the R group. Genes involved in acute inflammation were downregulated in both groups.ConclusionsWithin the limits of a small sample size, our results could suggest that early activation of genes of the adaptive immune response is associated with an improvement in organ function.Electronic supplementary materialThe online version of this article (10.1186/s13054-018-2242-3) contains supplementary material, which is available to authorized users.

Using RNA-Seq to Investigate Immune-Metabolism Features in Immunocompromised Patients With Sepsis

“…Moreover, we also used CIBERSORT to estimate cellular types and found the relative abundance of monocyte in enrolled patients, and this finding was in line with the increasing data to show the crucial role of monocyte in the pathogenesis of sepsis (Supplemental Figure 1) (7,31). Notably, the transcriptome was similar on day-1 among immunocompromised and immunocompetent patients (Figure 1A), and the findings highlight the crucial need of using paired day-1 and day-8 samples to address the dynamic transcriptome in patients with septic with high heterogeneity as shown in this study and the previous study (6). Furthermore, we employed functional pathway analysis to demonstrate the essential role of T cell immunity-relevant pathways among immunocompromised patients with sepsis.…”

“…Immunoparalysis, characterised by not only immunologic but also by metabolic dysregulation after sepsis, has been increasingly recognised and attributed to be one of the key biological bases of prolonged impact on long-term mortality in patients with sepsis (4,5). Recent advances in sequencing technology, such as RNA-Sequencing (RNA-Seq), immune repertoire sequencing, and single-cell RNA-Seq (sc-RNA-Seq), allow for addressing immunological and metabolic features in patients with sepsis and coronavirus disease 2019 (COVID-19) infection (6)(7)(8). Several studies have used MicroArray and RNA-Seq to identify the transcriptomic signature, so-called subendotype, in patients with sepsis, and the currently identified sepsis-associated subendotypes included early improvement of organ dysfunction after sepsis and the responsiveness of steroids in patients with a septic shock (6,9,10).…”

“…Recent advances in sequencing technology, such as RNA-Sequencing (RNA-Seq), immune repertoire sequencing, and single-cell RNA-Seq (sc-RNA-Seq), allow for addressing immunological and metabolic features in patients with sepsis and coronavirus disease 2019 (COVID-19) infection (6)(7)(8). Several studies have used MicroArray and RNA-Seq to identify the transcriptomic signature, so-called subendotype, in patients with sepsis, and the currently identified sepsis-associated subendotypes included early improvement of organ dysfunction after sepsis and the responsiveness of steroids in patients with a septic shock (6,9,10). Additionally, analytic tools, namely, MiXCR, have been recently developed to investigate the diversity of T cell receptor (TCR) using bulk RNA-Seq data (11,12).…”

Staging and Personalized Intervention for Infection and Sepsis

“…Another study in patients with sepsis also reports the identification of a transcriptome profile associated with improvement of organ function after early supportive therapy. Unfortunately, however, the study could not yet distinguish a profile based on gene expression immediately upon ICU admission [31].…”

Application of an Exploratory Knowledge-Discovery Pipeline Based on Machine Learning to Multi-Scale OMICS Data to Characterise Myocardial Injury in a Cohort of Patients with Septic Shock: An Observational Study

“…The characterisation of patients at the molecular level is a promising approach to identify pathophysiological mechanisms and specific targets for new therapeutic interventions in critically-ill patients with a particular condition [8]. For example, we have previously shown that changes in the metabolome (lipidome in particular) and transcriptome may play a relevant role in early recovery of organ dysfunction in patients with septic shock [9,10].…”