Thirty-five years of evolving inflammatory paradigms in sepsis (1991-2025): a comprehensive mapping of immune dysregulation research, anti-inflammatory targets, and translational barriers.

BACKGROUND

Sepsis represents a life-threatening dysregulation of the host inflammatory response, progressing from innate immune hyperactivation and pro-inflammatory cytokine release to a secondary immunosuppressive phase. Although the diagnostic framework has evolved from systemic inflammatory response syndrome (SIRS)-based criteria to the organ dysfunction-centric Sepsis-3 definition, the longitudinal evolution of inflammatory research paradigms, emerging anti-inflammatory targets, and barriers limiting clinical translation has not been systematically characterized.

METHODS

Peer-reviewed publications (n=106,884; 1991-2025) were retrieved from PubMed and the Web of Science Core Collection. A temporally stratified computational framework analyzed publication dynamics, keyword co-occurrence, citation bursts, and thematic evolution across sequential diagnostic epochs. Co-cited references were graded by Oxford Centre for Evidence-Based Medicine (OCEBM) criteria to evaluate evidence maturation and translational readiness.

RESULTS

Annual publications grew from 974 (1991) to 8,492 (2025; R 2 = 0.9841). The United States led in publication volume (32,406), while the Netherlands (77.58 citations/publication) and France (76.99) recorded the highest citation impact. The co-citation evidence base transitioned from expert consensus (Level 5) toward randomized controlled trials (RCTs) (Level 1) and prospective cohorts (Level 2). Keyword burst and thematic evolution analyses identified three sequential inflammatory research phases: early dominance of pro-inflammatory mediators (lipopolysaccharide, TNF-α), an intermediate shift toward immunosuppression and organ dysfunction, and a contemporary frontier centered on NLRP3 inflammasome signaling, regulated cell death (RCD) pathways, and gut-lung axis modulation. Emerging computational approaches, including AI-driven predictive models, demonstrated increasing research momentum; however, limited external validation, infrastructure requirements, and interpretability challenges remain barriers to clinical translation.

CONCLUSIONS

This comprehensive mapping reveals a fundamental transition in global sepsis research, from broad cytokine suppression toward precision immunomodulation of specific immune dysregulation mechanisms, while highlighting persistent challenges in translating emerging discoveries into clinical practice. Future research should prioritize mechanistically targeted interventions and equitable implementation of anti-inflammatory strategies across diverse healthcare settings.