Original article
Early diagnostic markers for neonatal sepsis: Comparing C-reactive protein, interleukin-6, soluble tumour necrosis factor receptors and soluble adhesion molecules

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Abstract

We compared six inflammatory mediators (C-reactive protein (CRP), interleukin-6 (IL-6), soluble tumour necrosis factor receptors (p55 and p75) and soluble adhesion molecules (ICAM-1, E-selectin)) as early diagnostic tests for neonatal sepsis, and studied the possible benefit of combining parameters. Blood samples were obtained from 166 consecutively admitted neonates, who were suspected to suffer from infection within the first week of life. Neonates were retrospectively classified as infected (sepsis, clinical sepsis or pneumonia), possibly infected, or non-infected. Twenty-four infected neonates had higher serum levels of all six mediators (all P < 0.05), and 18 possibly infected neonates had higher levels of CRP, IL-6, ICAM-1 and E-selectin (all P < 0.05), than neonates without infection (n = 124). Receiver operator characteristic plots showed that CRP was the single best diagnostic test. Multiple logistic regression modelling, including various combinations of two to six mediators, consistently showed that IL-6, in addition to CRP, predicted sepsis. With infected and possibly infected neonates as the reference standard, a combined test of CRP ⩾ 10 mg/l and/or IL-6 ⩾ 20 pg/ml had a sensitivity of 85%, specificity of 62%, and negative likelihood ratio of 0.24. Using infected neonates as reference standard alone, and including possibly infected as controls, sensitivity increased to 96%, whereas specificity decreased to 58%; a negative test result (CRP < 10 mg/l and IL-6 < 20 pg/ml) ruled out sepsis with high certainty (likelihood ratio = 0.07). CRP performed best as a diagnostic test for neonatal sepsis. Diagnostic accuracy was further improved by combining CRP and IL-6, whereas the other parameters (p55, p75, ICAM-1 and E-selectin) added no further diagnostic information.

Introduction

Bacterial sepsis is one of the major causes of neonatal morbidity and mortality [1]. The incidence ranges from 1–10 per 1000 live births [1]. Early-onset sepsis is probably caused by bacterial exposure during intrauterine life or at delivery, and clinical manifestations may be present at delivery or develop during the first days of life [1]. It is vital to identify infected neonates as early as possible, but unreliable clinical signs and the absence of good diagnostic tests hinder an accurate early diagnosis [1]. Thus, sick neonates are frequently treated with broad-spectrum antibiotics, but true infection is only verified in a minority 1, 2.

Previously, various white blood cell counts and the acute phase reactant C-reactive protein (CRP) have been used to diagnose neonatal sepsis. The ratio between immature and total neutrophil cell count (I/T-ratio) is a sensitive, but not very specific, diagnostic method 3, 4 with substantial interobserver variability [4]. CRP is specific, but less sensitive in the early stages of neonatal sepsis [5]. However, the neonatal immune response includes increased production of other inflammatory mediators, and assessing them may improve diagnostic accuracy. Tumour necrosis factor (TNF) increases initially [6], and high levels have been reported in neonates with sepsis 7, 8, 9, but its diagnostic usefulness may be limited by very short halftime [6]. TNF binds to specific receptors (p55, p75) on target cells [10], that also exist as soluble isoforms (sTNFR) [10]. Shedding of sTNFR is stimulated by inflammatory cytokines [TNF, interleukin-1 (IL-1), IL-6] 10, 11 and elevated sTNFR levels have been observed in children with meningococcaemia [12] and in neonates with sepsis 13, 14. IL-6 increases early during infection probably stimulated by TNF [6]. High levels of IL-6 have been observed in children and in neonates with sepsis 7, 8, 13, 15, 16, 17, and measurement of IL-6 may be a sensitive diagnostic test 13, 15, 16. IL-6 and TNF induce the acute phase response that includes the increase of CRP [6] and TNF enhances the shedding of adhesion molecules from cell membranes [18]. Elevated concentrations of soluble adhesion molecules (ICAM-1 and E-selectin) have been observed during sepsis among adults [18] and in neonates 19, 20, and it has been suggested that ICAM-1 may be a sensitive parameter of neonatal infection [21].

In this study we have compared the usefulness of CRP, IL-6, p55, p75, ICAM-1 and E-selectin as early indicators of neonatal sepsis in the first week of life, and in a multivariate analysis, we have assessed whether diagnostic accuracy could benefit from using a combination of mediators.

Section snippets

Patients and methods

The study took place at the University Hospital of Trondheim, Norway, during 11 months in 1993. In all, 436 neonates were admitted during the first week of life to the Neonatal Intensive Care Unit. We included 166 consecutive neonates, who were suspected to suffer from infection due to clinical signs and symptoms. In the presence of perinatal risk factors (premature rupture of membranes, preterm labor, and maternal fever), even subtle signs could elicit a “sepsis work up.” Neonates were

Study population

Twenty-four neonates were classified as infected, yielding a prevalence of 14.5%. Among these, six had sepsis, 10 had clinical sepsis and eight had pneumonia. No neonates had septic shock. Causative organisms cultured from septic patients included Staphylococcus aureus (n = 2), coagulase-negative staphylococci (n = 2), β-hemolytic streptococci Group B (n = 1), and Hemophilus influenzae (n = 1). Eighteen neonates were classified as possibly infected. In all, 124 neonates with a negative sepsis

Discussion

Our results show that by studying several mediators simultaneously (CRP, IL-6, ICAM-1, E-selectin, p55 and p75), CRP was the single best test for early diagnosis of neonatal sepsis in the first week of life. However, using CRP and IL-6 in combination was superior to using CRP alone. This finding is consistent with the results from experimental studies, that IL-6 elicited by bacterial antigens induces CRP during the acute phase response [6]. E-selectin, ICAM-1, p55 and p75 provided diagnostic

Acknowledgements

We are grateful to P.E. Haereid and S. Aag for evaluating blood smears and medical records, R.S. Salvesen for organizing data collection, S. Rahimipoor, K. Nygaard, L. Nygaard, M. Soerensen and W. Richardsen for technical assistance and to R. Johnsen for statistical advice. Supported by The Norwegian Medical Research Council, The Norwegian National Health Association and The Neonatal Fund at the University Hospital of Trondheim.

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