Interleukins in Neonatal Sepsis Diagnosis: A Comprehensive Evidence Review and Research Agenda

Abstract

Background: Neonatal sepsis remains a leading cause of neonatal mortality worldwide. Timely diagnosis is critical, yet current methods, such as blood culture, are slow (24–48 hours) and may fail to detect up to 20% of cases. To improve early diagnosis, attention has turned to inflammatory biomarkers, particularly interleukins (IL-6, IL-8, and IL-10), which rise rapidly in response to infection. IL-6 increases within hours of onset, IL-8 promotes neutrophil recruitment and demonstrates high sensitivity, and IL-10, though anti-inflammatory, is associated with disease severity. This review evaluates the diagnostic accuracy of these interleukins compared to conventional markers like C-reactive protein (CRP) and procalcitonin (PCT) in neonatal sepsis.
Methods:  This systematic review adhered to PRISMA guidelines and was registered on PROSPERO (CRD42024569564). A comprehensive search was conducted in Medline, Embase, CINAHL, PsycInfo, Scopus, and Web of Science through April 23, 2024. Eligible studies reported sensitivity, specificity, or predictive values of IL-6, IL-8, or IL-10 in diagnosing neonatal sepsis and included ≥100 neonates. Observational studies from both low- and high-income countries were considered. Reviews, case reports, interventional studies, and conference abstracts were excluded. Two reviewers independently screened studies and extracted data on study design, population characteristics, diagnostic tools, and outcomes. Study quality was assessed using the JBI checklist. Meta-analysis was conducted using STATA v18 with a random-effects model and Freeman-Tukey transformation. Heterogeneity was evaluated via Cochran’s Q and I². Subgroup and sensitivity analyses were performed, along with tests for publication bias.
Results: A total of 47 studies were included in the meta-analysis. IL-6 showed a pooled sensitivity of 0.81 (95% CI: 0.73–0.87), specificity of 0.77 (95% CI: 0.72–0.81), and AUC of 0.89. The diagnostic odds ratio (DOR) was 13.90. IL-6 levels typically rose within 2 hours of infection, preceding the rise in CRP and PCT. IL-8 demonstrated a pooled sensitivity of 0.78 (95% CI: 0.72–0.83), specificity of 0.84 (95% CI: 0.79–0.88), DOR of 21.64, and AUC of 0.89. IL-10 showed a pooled sensitivity of 0.82 (95% CI: 0.78–0.86), specificity of 0.79 (95% CI: 0.75–0.82), DOR of 17.52, and AUC of 0.88.
Compared to CRP and PCT, interleukins—especially IL-6 and IL-8—demonstrated faster kinetic responses and superior or comparable diagnostic performance. Subgroup analysis revealed IL-8 had higher accuracy in early-onset sepsis, while IL-27 was more effective for late-onset cases. In premature infants, Serum Amyloid A (SAA) and IL-6 performed notably well.
Conclusion:
This review confirms that IL-6, IL-8, and IL-10 are effective early diagnostic biomarkers for neonatal sepsis, offering superior speed and comparable or better accuracy than traditional markers. Their integration into clinical protocols may improve early detection, guide timely interventions, and optimise antibiotic stewardship. Future research should focus on standardizing biomarker thresholds and validating findings across diverse neonatal populations.