Elsevier

The Lancet

Volume 352, Issue 9136, 17 October 1998, Pages 1271-1277
The Lancet

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

https://doi.org/10.1016/S0140-6736(98)08148-3Get rights and content

Summary

Background

Neonatal sepsis is a common and lifethreatening 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.

Introduction

Neonatal sepsis has an incidence of one to ten cases per 1000 livebirths and a high mortality rate of 15–50%.1 In very-low-birthweight infants, the incidence of sepsis is much higher: about 3% for early and 9% for late bacterial sepsis.2 Since outcome and prognosis depend on early and efficient antibiotic therapy, there is a need for sensitive and specific indicators of sepsis at the earliest stage of disease. The first clinical signs of neonatal sepsis are non-specific and laboratory indicators, such as complete blood-cell count, ratio of immature to total neutrophils,3 and C-reactive protein (CRP), do not have high sensitivity,4, 5 especially if measured early in the course of sepsis.6, 7 Isolation of causative organisms from microbiological cultures takes up to 72 h and does not identify most infected infants.8

The examination of soluble immunological mediators released minutes to hours after invasion of pathogens could dramatically improve early diagnosis of sepsis. Concentrations of the cytokines interleukin-1 receptor antagonist (IL-1ra), interleukin-6 (IL-6), and the circulating intercellular adhesion molecule-1 (cICAM-1) are raised in human sepsis.

IL-1ra is the natural receptor antagonist of the proinflammatory cytokine, IL-1β9 it reaches peak concentrations 2–4 h after experimental administration of endotoxin or IL-1β and remains raised for more than 24 h.10 Pilot studies show increased plasma concentrations of IL-1ra in adults with septic shock.11 IL-1ra concentrations are also increased in newborn babies of different gestational ages with sepsis12 or severe neonatal diseases.13

IL-6 is an important mediator of the early systemic host response to infection;14 it reaches peak concentrations rapidly after the onset of bacteriaemia, several hours before the upregulation of CRP by IL-6 begins.15 Previous studies assessed IL-6 concentrations as a marker of neonatal sepsis and reported an overall sensitivity of 80–83% and a specificity of 78–90% at the time of clinical diagnosis.16, 17, 18, 19

ICAM-1 is upregulated during inflammation and is found in the circulation in a soluble form, cICAM-1.20, 21 Two studies reported that serum and plasma concentrations of cICAM-1 were useful for early diagnosis of sepsis in 11 and 25 infants of different gestational ages with culture-positive sepsis.22, 23

Despite evidence that these inflammatory markers are upregulated at the earliest stages of experimental endotoxaemia, there is no information about the time course and prognostic power of these mediators before diagnosis of sepsis. Our aim was to examine whether IL-1ra, IL-6, and cICAM-1 could reliably predict the occurrence of sepsis at an earlier stage than the conventional marker CRP and before clinical diagnosis.

Section snippets

Study population

In a prospective multicentre study, we enrolled very-low-birthweight (<1500 g) infants admitted to six neonatal intensive-care units between December, 1994, and June, 1996. We obtained plasma samples from the infants, irrespective of presence or absence of sepsis, to measure concentrations of IL-1ra, IL-6, cICAM-1, and CRP. The specimens were collected during routine sampling for biochemical or haematological tests that were not prompted by the study. We obtained the parents' informed consent

Results

Of 336 eligible very-low-birthweight infants, 182 were enrolled in the study. 154 infants were not enrolled because no study personnel were present on admission to the intensive-care unit. 57 of the 182 infants were excluded because of transfer to non-participating hospitals, insufficient blood sampling, incomplete documentation, or because the parents refused to give consent. Thus, there were 125 infants with a complete clinical dataset: 21 in the proven-sepsis group, 20 in the no-infection

Discussion

We found that plasma concentrations of IL-1ra and IL-6 increased 2 days before clinical diagnosis of sepsis in very-low-birthweight infants. Through the use of the cytokine markers IL-1ra and IL-6, two out of three cases of sepsis could have been diagnosed 1–2 days earlier than they actually were. Furthermore, in nine of ten infants, IL-1ra and IL-6 confirmed the occurrence of sepsis on the day it was suspected. CRP concentrations increased later in the course of sepsis. CRP and cICAM-1 were

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