Critical care
Two blood gene signatures track sepsis outcomes
Open access · cc by · source: Europe PMC
In UK ICU adults with pneumonia sepsis, leukocyte transcriptomes split into SRS1 (immunosuppressed, ~41%) and SRS2; SRS1 had roughly 2–3× higher 14-day mortality, and a 7-gene set classified the groups.
Study at a glance
- Design
- Cohort — GAinS prospective ICU transcriptomic discovery + validation
- N
- N=265 · Discovery cohort; validation n=106 further ICU patients
- Population
- UK ICU adults with community-acquired pneumonia sepsis and organ dysfunction
- Outcome
- Transcriptomic sepsis response signatures (SRS1/SRS2) and 14-day mortality
Structured fields used in claim comparison tables when every cited study has a complete layer.
Key findings
Unsupervised clustering defined two sepsis response signatures, SRS1 and SRS2. SRS1 (~41% of discovery patients) showed an immunosuppressed phenotype (endotoxin tolerance, T-cell exhaustion, HLA class II downregulation) and higher 14-day mortality (discovery HR 2.4; validation HR 2.8). A predictive set of seven genes classified SRS membership.
Methodology
In the GAinS study, authors profiled peripheral-blood leukocyte gene expression in a prospective discovery cohort of 265 UK ICU adults with community-acquired pneumonia sepsis and organ dysfunction, then validated in 106 further patients. They related transcriptomic subgroups to outcomes and mapped expression quantitative trait loci (eQTL).
Limitations
Does not prove that assigning SRS at the bedside and treating differently improves survival in a randomized trial. The discovery setting is pneumonia-driven ICU sepsis in UK adults—not every infection source or age group. Genetic eQTL findings explain expression variation; they are not prescriptions for IL-6 drugs.
How this study connects
Role on claims
Each row is a claim on a concept or method page where this paper supports, challenges, or qualifies the statement. Roles are hand-checked — not a model guess.
Blood leukocyte transcriptomes split ICU pneumonia sepsis into SRS1 vs SRS2 with different early mortality.
In prospective UK ICU adults with community-acquired pneumonia sepsis, unsupervised transcriptomics defined SRS1 (~41%) as an immunosuppressed state with higher 14-day mortality than SRS2 (discovery HR 2.4; validation HR 2.8), classifiable with a seven-gene set.
Evidence for the claim as stated.
Genetically proxied IL6R blockade associates with lower sepsis risk and severity.
Mendelian randomisation treating IL6R variants as lifelong proxies for receptor blockade found lower odds of sepsis in UK Biobank (OR 0.80) and stronger associations for critical-care sepsis phenotypes (e.g., OR 0.48), with a similar-sized protective association for severe COVID-19 where IL-6 blockade is already recommended.
Scope note — related host-response theme, but SRS classes are acute transcriptomic states — not IL6R MR instruments
Limits the claim's scope: a different population, assay, or outcome.
A three-metabolite serum panel can flag sepsis-associated AKI early in a small cohort.
After mouse kidney multi-omics discovery, a 56-patient serum cohort supported an IC3 model (inosine, creatine, 3-hydroxybutyric acid) for early SA-AKI identification (AUC 0.90).
Scope note — different readout — kidney metabolites vs blood leukocyte SRS
Limits the claim's scope: a different population, assay, or outcome.
SRS classes describe acute ICU transcriptomic states after pneumonia sepsis; IL6R MR estimates lifelong pathway effects on sepsis risk across a volunteer biobank. Both can be true without being the same assay or the same treatment decision.
Evidence for the claim as stated.
IC3 targets early recognition of SA-AKI; SRS targets host-response prognosis. Shared sepsis context does not make kidney metabolites interchangeable with blood immune subtypes.
Evidence for the claim as stated.
Open questions
Tensions this paper is part of
From concept pages' “where studies disagree.” Disagreement means the same question; scope means different assays, populations, or outcomes.
SRS classes describe acute ICU transcriptomic states after pneumonia sepsis; IL6R MR estimates lifelong pathway effects on sepsis risk across a volunteer biobank. Both can be true without being the same assay or the same treatment decision.
IC3 targets early recognition of SA-AKI; SRS targets host-response prognosis. Shared sepsis context does not make kidney metabolites interchangeable with blood immune subtypes.
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