Evaluation of interleukin-6 and soluble receptors of tumor necrosis factor for early diagnosis of neonatal infection

Objective: To evaluate plasma levels of interleukin-6 (IL-6) and soluble tumor necrosis factor receptors (sTNF-R) 55 and 75 in neonates as a contribution to the early diagnosis of infection. Study design: We prospectively measured IL-6 and sTNF-R 55 and sTNF-R 75 plasma levels in 157 newborn infants admitted to our regional neonatal center in a 3-month period and in cord blood of 131 newborn infants delivered in our obstetrics unit. C-reactive protein was sequentially determined after admission. Newborn infants were classified into four groups: group 0, not infected; group 1, possibly infected; group 2a, infected (culture positive), and group 2b, probably infected (culture negative). We looked for the optimal cutoff point of these parameters, using the receiver operating characteristics (ROC) curve. Results: IL-6 levels were significantly higher in group 2 (n = 11; median level, 250 pg/ml; range, 0 to 81,000), group 2b (n = 25; median level, 750 pg/ml; range, 0 to 180,000), and group 1 (n = 35; median level, 160 pg/ml; range, 0 to 10,000), in comparison with group 0 (n = 217; median level, 0 pg/ml; range, 0 to 3400). A cutoff value of 100 pg/ml or greater obtained by the ROC method gives a sensitivity of 83.3% and a specificity of 90.3%. For inborn infants (n = 220) sampled at birth, sensitivity is 100% and specificity 92.3%. This high sensitivity persists until the twelfth hour of life. The sTNF-R 55 levels are significantly higher in group 2a (median, 12.0 ng/ml; range, 3.2 to 24.4), in group 2b (median, 7.0 ng/ml; range, 3.0 to 25.2), and in group 1 (median, 7.0 ng/ml; range, 2.5 to 18.9) than in group 0 (median, 3.9 ng/ml; range, 1.5 to 15.0), and with a cutoff value of 6 ng/ml, sensitivity is 75% and specificity 69%. The sTNF-R 75 levels are significantly higher in group 2a (median, 17.0 ng/ml; range, 7.2 to 48.8), in group 2b (median, 11.2 ng/ml; range, (2.0 to 31.3), and in group 1 (median, 10.6 ng/ml; range, 2.0 to 33.0); than in group 0 (median, 7.0 ng/ml; range, 1 to 23.0). With a cutoff value of 9 ng/ml, sensitivity is 80% and specificity 67%. Sensitivity of C-reactive protein is low initially but improves with time. Combining IL-6 with C-reactive protein provides the possibility of identifying the majority of infected infants in the postnatal period. Conclusion: A plasma IL-6 level of 100 pg/ml or greater, obtained before the twelfth hour of life, appears to be an ideal marker for detecting early-onset neonatal infection with a high degree of sensitivity and specificity. After the twelfth hour, the combined determination of IL-6 and C-reactive protein may be equally useful. The sTNF-R levels appear to be less useful in the early diagnosis of infection because of their smaller magnitude of variation.