Am J Perinatol 2003; 20(8): 491-502
DOI: 10.1055/s-2003-45382

Copyright © 2003 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel.: +1(212) 584-4662

Diagnostic Value of Cytokines and C-reactive Protein in the First 24 Hours of Neonatal Sepsis

Gary Laborada1 , Maria Rego1 , Ajey Jain1 , Michael Guliano2 , Joseph Stavola3 , Praveen Ballabh1 , Alfred N. Krauss1 , Peter A.M. Auld1 , Mirjana Nesin1
  • 1Perinatology Center, New York Presbyterian Hospital, New York, New York
  • 2Lenox Hill Hospital, New York, New York
  • 3Division of Infectious Diseases, Weill Medical College, New York, New York
Further Information

Publication History

Publication Date:
02 January 2004 (online)


The first objective of this article was to determine the diagnostic accuracy of tumor necrosis factor-α, interleukin-6 (IL-6), and interleukin-8 (IL-8) in differentiating infected from noninfected neonates during the first 24 hours of suspected sepsis and to compare them to the currently used laboratory parameters: C-reactive protein (CRP), immature-to-total neutrophil ratio, and leukocyte and platelet count. The secondary objective was to compare the cytokine levels in subpopulations of neonates. Seventy-five premature and 30 term infants were enrolled. Blood samples for the “currently used laboratory tests” and the cytokine levels were obtained at the first suspicion of sepsis (“0-hour”) and 18 to 30 hours later (“24-hours”). Patients were classified as septic (48) or nonseptic (57). Thirty-two septic patients had positive blood cultures and 16 showed clinical signs of sepsis. Twenty septic patients had early-onset and 28 had late-onset sepsis. Sensitivity, specificity, and positive and negative predictive values (PPV and NPV) were calculated for each test. Receiver-operating characteristic curves were analyzed to determine the optimal thresholds. A combination of CRP > 10 pg/mL plus IL-6 > 18 pg/mL (sensitivity = 89%, specificity = 73%, PPV = 70%, NPV = 90%) was the best “0-hour” test, and CRP (sensitivity = 78%, specificity = 94%) was the best “24-hours” test. Lower IL-6 at 0-hour (p = 0.018) and IL-8 at 24 hours (p = 0.023) were detected among the patients infected with coagulase-negative staphylococci then with other bacteria. In conclusion, a combination of CRP + IL-6 provided additional diagnostic accuracy for differentiation between septic and nonseptic patients during the first 24 hours of suspected sepsis.


  • 1 Fowlie P W, Schmidt B. Diagnostic tests for bacterial infection from birth to 90 days: a systematic review.  Arch Dis Child Fetal Neonatal Ed . 1998;  78 F92-F98
  • 2 de Bont E J M S, Martens A, van Raan J. et al . Diagnostic value of plasma levels of tumor necrosis factor and interleukin-6 in newborns with sepsis.  Acta Paediatr . 1994;  83 696-699
  • 3 Messer J, Eyer D, Donato L, Gallati H, Matis J, Simeoni U. Evaluation of interleukin-6 and soluble receptors of tumor necrosis factor for early diagnosis of neonatal infection.  J Pediatr . 1996;  129 574-580
  • 4 Ng P C, Cheng S H, Chui K M. et al . Diagnosis of late onset sepsis with cytokines, adhesion molecule, and C-reactive protein in preterm very low birthweight infants.  Arch Dis Child Fetal Neonatal Ed . 1997;  77 F221-F227
  • 5 Kishimoto T. The biology of interleukin-6.  Blood . 1989;  74 1-10
  • 6 Buck C, Bundschu J, Gallati H, Bartman P, Pohlandt F. Interleukin 6: a sensitive parameter for early diagnosis of neonatal bacterial infection.  Pediatrics . 1994;  93 54-58
  • 7 Netea M G, Blok L W, Kulberg B J. et al . Pharmacologic inhibitors of tumor necrosis factor production exert differential effects in lethal endotoxemia and in infection with live micro-organisms in mice.  J Infect Dis . 1995;  171 393-399
  • 8 Franz A R, Steinbach G, Kron M, Pohlandt F. Reduction of unnecessary antibiotic therapy in newborn infants using interleukin-8 and C-reactive protein as markers of bacterial infections.  Pediatrics . 1999;  104 447-453
  • 9 Lehrnbecher T, Schrod T, Kraus D, Roos T, Martius J, von Stockhausen B H. Interleukin-6 and soluble interleukin-6 receptor in cord blood in the diagnosis of early onset sepsis in neonates.  Acta Paediatr . 1995;  84 806-808
  • 10 Grether J K, Nelson K B. Maternal infection and cerebral palsy in infants of normal birthweight.  JAMA . 1997;  278 207-210
  • 11 Leviton A, Paneth N, Reuss M L. et al . Maternal infection, fetal inflammatory response, and brain damage in very low birth weight infants.  Pediatr Res . 1999;  46 566-575
  • 12 Dammann O, Leviton A. Maternal intrauterine infection, cytokines, and brain damage in preterm newborn.  Pediatr Res . 1997;  42 1-8
  • 13 Romero R, Gomez R, Ghezzi F. et al . A fetal systemic inflammatory response is followed by spontaneous onset of preterm parturition.  Am J Obstet Gynecol . 1998;  179 186-193
  • 14 Opsjon S L, Wathen N C, Tingulstad S. et al . TNF-alpha, IL-1, and IL-6 in normal human pregnancy.  Am J Obstet Gynecol . 1993;  169 397-404
  • 15 Steinborn A, Kuhnert M, Halberstadt E. Immunomodulating cytokines induce term and preterm parturition.  J Perinat Med . 1996;  24 381-390
  • 16 Genç M R, Gerber S, Nesin M, Witkin S S. Polymorphism in the interleukin-1 gene complex and preterm delivery.  Am J Obstet Gynecol . 2002;  187 157-163
  • 17 Hanley J A, McNeil B J. A method for comparing the areas under the various ROC curves derived from the same cases.  Radiology . 1983;  148 839-843