Interleukin-1 receptor antagonist and interleukin-6 for early diagnosis of neonatal sepsis 2 days before clinical manifestation

Lancet. 1998 Oct 17;352(9136):1271-7. doi: 10.1016/S0140-6736(98)08148-3.


Background: Neonatal sepsis is a common and life-threatening disorder, particularly among preterm infants. Early initiation of antibiotic therapy is frequently delayed because the first clinical signs of sepsis are non-specific and there are no reliable early laboratory indicators. We investigated the time course of expression and the prognostic power of the early inflammatory mediators interleukin-1 receptor antagonist (IL-1ra), interleukin-6 (IL-6), and circulating intercellular adhesion molecule-1 (cICAM-1) before clinical diagnosis of sepsis.

Methods: In a prospective multicentre study, we monitored 182 very-low-birthweight infants in six intensive-care units for occurrence of sepsis. During routine or clinically indicated blood sampling, an additional sample was collected for measurement of IL-1ra, IL-6, cICAM-1, and C-reactive protein (CRP). Infants were grouped into those with proven sepsis, no infection, or unclassified. The mean study duration was 34 days. Whenever sepsis occurred, a study period of 10 days was defined: day 0 was the day of clinical diagnosis of sepsis; days -4 to -1 were the 4 days before diagnosis; days +1 to +5 were the 5 days after. We compared the concentrations of the immune mediators during the 10-day study period with group-specific baseline values from before day -4.

Findings: 101 infants were included in the analysis: 21 with proven sepsis, 20 with no infection, and 60 unclassified. We excluded 57 because of incomplete datasets and 24 who had early-onset sepsis. IL-1ra and IL-6 increased significantly 2 days before diagnosis of sepsis; maximum median increases within the study period were 15-fold for IL-1ra and 12-fold for IL-6. The diagnostic sensitivities of IL-1ra, IL-6, and CRP concentrations on day 0 of diagnosis were 93%, 86%, and 43%, respectively; corresponding values on day -1 were 64%, 57%, and 18%. The specificities of IL-1ra, IL-6, and CRP concentrations were 92%, 83%, and 93%. cICAM-1 had a specificity of only 64%.

Interpretation: IL-1ra and IL-6 are superior to cICAM-1 and CRP as predictors of sepsis 1 or more days before clinical diagnosis. Ad-hoc measurement of these cytokines could allow earlier initiation of antibiotic therapy with corresponding improvement in outcome in very-low-birthweight infants with sepsis.

Publication types

  • Clinical Trial
  • Multicenter Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Austria
  • Biomarkers / blood
  • C-Reactive Protein / metabolism*
  • Diagnosis, Differential
  • Female
  • Germany
  • Humans
  • Infant, Newborn
  • Infant, Very Low Birth Weight
  • Intercellular Adhesion Molecule-1 / blood*
  • Interleukin 1 Receptor Antagonist Protein
  • Interleukin-6 / blood*
  • Male
  • Prospective Studies
  • Sensitivity and Specificity
  • Sepsis / blood
  • Sepsis / diagnosis*
  • Sialoglycoproteins / blood*
  • Slovakia
  • Time Factors


  • Biomarkers
  • IL1RN protein, human
  • Interleukin 1 Receptor Antagonist Protein
  • Interleukin-6
  • Sialoglycoproteins
  • Intercellular Adhesion Molecule-1
  • C-Reactive Protein