Cut-off values of serum interleukin-6 for culture-confirmed sepsis in neonates

Abstract

Introduction: Neonatal sepsis accounts for 0.97% of all disability-adjusted life years worldwide. Interleukin-6 has been used in sepsis diagnosis, but cut-off values are missing.

Methods: Neonates admitted to the neonatal wards with measurements of serum interleukin-6 born between September 2015 and September 2019 were retrospectively analysed. Mean serum interleukin-6 values of patients who never had increased laboratory parameters of infection nor died during their stay and mean interleukin-6 values on the day of blood sampling for a later positive culture in patients with culture-confirmed sepsis were analysed for each time period.

Results: In all, 8.488 values in 1.695 neonates, including 752 very-preterm-infants and 701 very-low-birthweight infants, were analysed. The AUC for interleukin-6 was 0.84-0.91 in all neonates, 0.88-0.89 in very-preterm and 0.89-0.91 in very-low-birthweight infants. Using interleukin-6 cut-off values of 80 pg/ml on day of life 1, 40 pg/ml on day of life 2-7 and 30 pg/ml after day of life 7, a sensitivity of 75% and a specificity of 81% for culture-confirmed sepsis were achieved. In very-preterm infants, the corresponding values were 74% for sensitivity and 83% for specificity and in very-low-birthweight infants 74% and 86%, respectively.

Conclusion: Serum interleukin-6 has high accuracy for the detection of neonatal sepsis.

Impact: Serum interleukin-6 can be used with high accuracy to detect sepsis in neonates with the cut-off values of 80 pg/ml on day of life 1, 40 pg/ml on day of life 2-7 and 30 pg/ml after day of life 7. Serum interleukin-6 can be used with high accuracy to detect sepsis in neonates and very-preterm as well as very-low-birthweight infants. Interleukin-6 values display distinct cut-off values depending on the chronological age of the infant. Our article provides the first cut-off values for interleukin-6 in the first days of life in neonates.

Fig. 1. Serum interleukin-6 values of healthy neonates and on the day of culture-confirmed sepsis.

Serum interleukin-6 values of neonates who never had increased laboratory parameters of infection following Neo-KISS criteria nor died during their stay at our unit (lines) and mean serum interleukin-6 values on the day of blood sampling for a later positive culture in culture-confirmed sepsis following Neo-KISS criteria (dots). Vertical lines divide the study episodes into day of life 1, day of life 2–7 and after day of life 7 and horizontal lines represent the cut-off values during the episodes with 80 pg/ml on day of life 1, 40 pg/ml on day of life 2–7 and 30 pg/ml after day of life 7.

Fig. 2. STARD flowchart.

STARD flowchart with number of interleukin-6 values as cases in all neonates.

Fig. 3. Receiver operating characteristic curves for serum interleukin-6 and culture-confirmed sepsis.

Receiver operating characteristic curves for interleukin-6 in neonates, very-low-birthweight infants (VLBWI, birthweight <1500 g), extremely low-birthweight infants (ELBWI, birthweight <1000 g), preterm infants (PI, born before 37 weeks of gestation), very-preterm infants (VPI, born before 32 weeks of gestation) and extremely preterm infants (EPI, born before 28 weeks of gestation) for day of life 1 (a), day of life 2–7 (b) and after day of life 7 (c). The points represent the cut-off values of 80 pg/ml (a), 40 pg/ml (b) and 30 pg/ml (c).

Fig. 4. Interleukin-6 and C-reactive protein and their development over time in sepsis.

Serum interleukin-6 and C-reactive protein (CRP) in culture-confirmed sepsis on day of life 1 (a) and after day of life 7 (b).