eQTLs identify regulatory networks and drivers of variation in the individual response to sepsis.

Sepsis is a clinical syndrome of life-threatening organ dysfunction caused by a dysregulated response to infection, for which disease heterogeneity is a major obstacle to developing targeted treatments. We have previously identified gene-expression-based patient subgroups (sepsis response signatures [SRS]) informative for outcome and underlying pathophysiology. Here, we aimed to investigate the role of genetic variation in determining the host transcriptomic response and to delineate regulatory networks underlying SRS.

Patient stratification using plasma cytokines and their regulators in sepsis: relationship to outcomes, treatment effect and leucocyte transcriptomic subphenotypes.

Rationale: Heterogeneity of the host response within sepsis, acute respiratory distress syndrome (ARDS) and more widely critical illness, limits discovery and targeting of immunomodulatory therapies. Clustering approaches using clinical and circulating biomarkers have defined hyper-inflammatory and hypo-inflammatory subphenotypes in ARDS associated with differential treatment response. It is unknown if similar subphenotypes exist in sepsis populations where leucocyte transcriptomic-defined subphenotypes have been reported.

A Transcriptomic Approach to Understand Patient Susceptibility to Pneumonia After Abdominal Surgery.

Objective: To describe immune pathways and gene networks altered following major abdominal surgery and to identify transcriptomic patterns associated with postoperative pneumonia.

Background: Nosocomial infections are a major healthcare challenge, developing in over 20% of patients aged 45 or over undergoing major abdominal surgery, with postoperative pneumonia associated with an almost 5-fold increase in 30-day mortality.

Methods: From a prospective consecutive cohort (n=150) undergoing major abdominal surgery, whole-blood RNA was collected preoperatively and at 3 time-points postoperatively (2-6, 24, and 48 h).

Neutrophils and emergency granulopoiesis drive immune suppression and an extreme response endotype during sepsis.

Sepsis arises from diverse and incompletely understood dysregulated host response processes following infection that leads to life-threatening organ dysfunction. Here we showed that neutrophils and emergency granulopoiesis drove a maladaptive response during sepsis. We generated a whole-blood single-cell multiomic atlas (272,993 cells, n = 39 individuals) of the sepsis immune response that identified populations of immunosuppressive mature and immature neutrophils.

An immune dysfunction score for stratification of patients with acute infection based on whole-blood gene expression.

Dysregulated host responses to infection can lead to organ dysfunction and sepsis, causing millions of global deaths each year. To alleviate this burden, improved prognostication and biomarkers of response are urgently needed. We investigated the use of whole-blood transcriptomics for stratification of patients with severe infection by integrating data from 3149 samples from patients with sepsis due to community-acquired pneumonia or fecal peritonitis admitted to intensive care and healthy individuals into a gene expression reference map.

Genetic mechanisms of critical illness in COVID-19.

Host-mediated lung inflammation is present, and drives mortality, in the critical illness caused by coronavirus disease 2019 (COVID-19). Host genetic variants associated with critical illness may identify mechanistic targets for therapeutic development. Here we report the results of the GenOMICC (Genetics Of Mortality In Critical Care) genome-wide association study in 2,244 critically ill patients with COVID-19 from 208 UK intensive care units.

Coronary revascularisation in cardiac amyloidosis.

We present a case of coronary artery bypass grafting in a 78-year-old man with triple vessel disease and concomitant cardiac amyloidosis. Postoperatively, he developed a profound low cardiac output state and multiorgan failure. He died 3 weeks following surgery.

The Effect of β-Adrenoceptor Agonists on Leucocyte-Endothelial Adhesion in a Rodent Model of Laparotomy and Endotoxemia.

The β-adrenoceptor agonist dopexamine may possess anti-inflammatory actions which could reduce organ injury during endotoxemia and laparotomy. Related effects on leucocyte-endothelial adhesion remain unclear. Thirty anesthetized Wistar rats underwent laparotomy followed by induction of endotoxemia with lipopolysaccharide and peptidoglycan ( = 24) or sham ( = 6).

Epstein-Barr virus reactivation in sepsis due to community-acquired pneumonia is associated with increased morbidity and an immunosuppressed host transcriptomic endotype.

Epstein-Barr virus (EBV) reactivation is common in sepsis patients but the extent and nature of this remains unresolved. We sought to determine the incidence and correlates of EBV-positivity in a large sepsis cohort. We also hypothesised that EBV reactivation would be increased in patients in whom relative immunosuppression was the major feature of their sepsis response.

Transcriptomic Signatures in Sepsis and a Differential Response to Steroids. From the VANISH Randomized Trial.

Rationale: There remains uncertainty about the role of corticosteroids in sepsis with clear beneficial effects on shock duration, but conflicting survival effects. Two transcriptomic sepsis response signatures (SRSs) have been identified. SRS1 is relatively immunosuppressed, whereas SRS2 is relatively immunocompetent.

Post-operative immune suppression is mediated via reversible, Interleukin-10 dependent pathways in circulating monocytes following major abdominal surgery.

Introduction: Post-operative infections occur frequently following major surgery. The magnitude of the post-operative immune response is associated with an increased risk of post-operative infections, although the mechanisms driving post-operative immune-dysfunction and the potential reversibility of this response with immune stimulants are not well understood. This study aims to describe the immediate immune response to major surgery and establish links to both post-operative infection and functional aspects of immune dysregulation.

A community approach to mortality prediction in sepsis via gene expression analysis.

Improved risk stratification and prognosis prediction in sepsis is a critical unmet need. Clinical severity scores and available assays such as blood lactate reflect global illness severity with suboptimal performance, and do not specifically reveal the underlying dysregulation of sepsis. Here, we present prognostic models for 30-day mortality generated independently by three scientific groups by using 12 discovery cohorts containing transcriptomic data collected from primarily community-onset sepsis patients.

Pharmacogenomic biomarkers do not predict response to drotrecogin alfa in patients with severe sepsis.

Purpose: To explore potential design for pharmacogenomics trials in sepsis, we investigate the interaction between pharmacogenomic biomarkers and response to drotrecogin alfa (activated) (DrotAA). This trial was designed to validate whether previously identified improved response polymorphisms (IRPs A and B) were associated with an improved response to DrotAA in severe sepsis.

Methods: Patients with severe sepsis at high risk of death, who received DrotAA or not, with DNA available were included and matched to controls adjusting for age, APACHE II or SAPS II, organ dysfunction, ventilation, medical/surgical status, infection site, and propensity score (probability that a patient would have received DrotAA given their baseline characteristics).

Microvesicle Subsets in Sepsis Due to Community Acquired Pneumonia Compared to Faecal Peritonitis.

Rationale: Microvesicles (MV) act as a nonsoluble means of intercellular communication, with effector roles in disease pathogenesis and potentially as biomarkers. Previously, we reported that neutrophil MV expressing alpha-2-macroglobulin (A2MG) are protective in experimental sepsis and associate with survival in a small cohort of patients with sepsis due to community acquired pneumonia (CAP).

Objectives: To characterize MV profiles in sepsis due to CAP or fecal peritonitis (FP) and determine their relation to outcome.

Derivation and validation of a prognostic model for postoperative risk stratification of critically ill patients with faecal peritonitis.

Background: Prognostic scores and models of illness severity are useful both clinically and for research. The aim of this study was to develop two prognostic models for the prediction of long-term (6 months) and 28-day mortality of postoperative critically ill patients with faecal peritonitis (FP).

Methods: Patients admitted to intensive care units with faecal peritonitis and recruited to the European GenOSept study were divided into a derivation and a geographical validation subset; patients subsequently recruited to the UK GAinS study were used for temporal validation.

Classification of patients with sepsis according to blood genomic endotype: a prospective cohort study.

Background: Host responses during sepsis are highly heterogeneous, which hampers the identification of patients at high risk of mortality and their selection for targeted therapies. In this study, we aimed to identify biologically relevant molecular endotypes in patients with sepsis.

Methods: This was a prospective observational cohort study that included consecutive patients admitted for sepsis to two intensive care units (ICUs) in the Netherlands between Jan 1, 2011, and July 20, 2012 (discovery and first validation cohorts) and patients admitted with sepsis due to community-acquired pneumonia to 29 ICUs in the UK (second validation cohort).

Shared and Distinct Aspects of the Sepsis Transcriptomic Response to Fecal Peritonitis and Pneumonia.

Rationale: Heterogeneity in the septic response has hindered efforts to understand pathophysiology and develop targeted therapies. Source of infection, with different causative organisms and temporal changes, might influence this heterogeneity.

Objectives: To investigate individual and temporal variations in the transcriptomic response to sepsis due to fecal peritonitis, and to compare these with the same parameters in community-acquired pneumonia.

Genetic Factors of the Disease Course after Sepsis: A Genome-Wide Study for 28Day Mortality.

Sepsis is the dysregulated host response to an infection which leads to life-threatening organ dysfunction that varies by host genomic factors. We conducted a genome-wide association study (GWAS) in 740 adult septic patients and focused on 28day mortality as outcome. Variants with suggestive evidence for an association (p≤10) were validated in two additional GWA studies (n=3470) and gene coding regions related to the variants were assessed in an independent exome sequencing study (n=74).

Genomic landscape of the individual host response and outcomes in sepsis: a prospective cohort study.

Background: Effective targeted therapy for sepsis requires an understanding of the heterogeneity in the individual host response to infection. We investigated this heterogeneity by defining interindividual variation in the transcriptome of patients with sepsis and related this to outcome and genetic diversity.

Methods: We assayed peripheral blood leucocyte global gene expression for a prospective discovery cohort of 265 adult patients admitted to UK intensive care units with sepsis due to community-acquired pneumonia and evidence of organ dysfunction.

Epigenetic regulatory pathways involving microRNAs may modulate the host immune response following major trauma.

Background: Posttraumatic nosocomial pneumonia is a common complication resulting in significant morbidity. Trauma-induced immunocompromise is associated with an enhanced susceptibility to pneumonia. In this study, we explore the hypothesis that posttranscriptional epigenetic regulation of gene expression may be an important factor in determining this immune phenotype.