The Th17/IL-17 Axis and Systemic Inflammatory Biomarkers in Sepsis-Associated Encephalopathy and Delirium: A Systematic Review and Meta-Analysis
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OBJECTIVE
Sepsis-associated encephalopathy (SAE) and sepsis-associated delirium (SAD) lack confirmatory laboratory tests or biomarkers. We evaluated whether the Th17/interleukin (IL)-17 axis or neuroglial-injury biomarkers reflect acute brain dysfunction beyond systemic inflammation and whether biomarker profiles differ between these phenotypes.
DATA SOURCES
EMBASE, MEDLINE/PubMed, and the Cochrane Library from inception to August 1, 2026, supplemented by backward and forward citation searching, following PRISMA 2020.
STUDY SELECTION
Observational studies of adults with sepsis classified by SAE or SAD status and reporting circulating biomarker concentrations by neurological group or biomarker-outcome associations. Eighteen studies (2,388 participants; 1,863 with sepsis) were included.
DATA EXTRACTION
Two reviewers independently extracted study, phenotype, assay, and outcome data. Risk of bias was assessed with the Newcastle-Ottawa Scale and certainty with GRADE.
DATA SYNTHESIS
Random-effects models pooled standardized mean differences (SMDs) separately against non-septic and septic controls and odds ratios (ORs) for biomarker-outcome associations. IL-6 was the only mediator elevated in both comparative frameworks and associated with outcomes (non-septic controls: SMD, 0.54 [0.25–0.82]; septic controls: SMD, 1.05 [0.51–1.59]; OR, 1.85 [1.50–2.29]). S100B, neuron-specific enolase, IL-10, tumor necrosis factor-α, and interferon-γ were elevated versus septic controls, whereas IL-17 was modestly elevated only versus non-septic controls (SMD, 0.37 [0.01–0.73]). The IL-6 septic-control effect was concentrated in SAE (p<0.0001) and remained robust in leave-one-out and risk-of-bias sensitivity analyses. Certainty was low to very low, and all 14 computable prediction intervals included the null.
CONCLUSIONS
IL-6 emerges as the leading circulating candidate biomarker of sepsis-associated brain dysfunction, while S100B and NSE capture neuroglial injury beyond sepsis. Current evidence does not establish a discriminating role for the Th17 axis. Future studies require standardized neurological phenotyping and appropriately matched septic controls to establish diagnostic value.
KEY POINTS
Question
Do the Th17/IL-17 axis or alternative inflammatory and neuroglial-injury biomarkers identify sepsis-associated encephalopathy or delirium beyond the inflammatory signal of sepsis itself?
Findings
In this systematic review and meta-analysis of 18 observational studies and 2388 participants, IL-6 was the only biomarker significantly elevated both against non-septic and against septic controls and significantly associated with the sepsis-associated neurological outcome; IL-17 was modestly elevated only against non-septic controls, and every computable prediction interval included the null.
Meaning
IL-6, with the neuroglial-injury markers S100B and NSE, is the most promising basis for multimarker models; standardized phenotyping and septic-controlled designs are the next step.
Summary
In 18 studies (2388 patients), IL-6 alone was raised against non-septic and septic controls and linked to sepsis-associated encephalopathy and delirium. IL-17 rose only versus non-septic controls and could not be pooled against septic ones. No marker works stand-alone.
