Elsevier

Cytokine

Volume 36, Issues 5–6, December 2006, Pages 283-290
Cytokine

Neutrophil CD64 expression and serum IL-8: Sensitive early markers of severity and outcome in sepsis

https://doi.org/10.1016/j.cyto.2007.02.007Get rights and content

Abstract

The aim of the present study was to investigate which biomarker/s reliably assess severity and mortality early in the sepsis process. In 47 critically-ill patients within the 24 h of septic onset, Interleukins (IL)-8, -1β, -6, -10, and -12p70, tumor necrosis factor-α (TNF-α), procalcitonin (PCT) and C-reactive protein (CRP) were measured in serum. Additionally, CD64 expression was measured in neutrophils. In early sepsis, neutrophil CD64 expression and IL-8 levels are the only biomarkers that increased with sepsis severity, differentiating disease stages: sepsis, severe sepsis and septic shock (p < 0.001). The biomarkers that best evaluate the severity of sepsis (via APACHE II) were CD64, IL-8 and IL-6 (p < 0.01), and the severity of organ failure (via SOFA) were CD64 and IL-8 (p < 0.01). CD64 expression and IL-8 levels were associated with mortality within 28-days (OR = 1.3, p = 0.01 for CD64 and OR = 1.26, p = 0.024 for IL-8 by logistic regression analysis) and ROC curve analysis showed high sensitivity and specificity for predicting sepsis stages and the 28 day mortality. We conclude that there is an early increase of neutrophil CD64 expression and IL-8 levels during sepsis. Based on this single measurement it is possible to reliably assess the stage, detect the severity and predict the 28-day mortality of sepsis.

Introduction

Sepsis is a generalized inflammatory syndrome, resulting from dysregulated immune responses of the host to injury or infection [1]. Staging of sepsis, according to the American College of Chest Physicians/Society of Critical Care Medicine (ACCP/SCCM), categorizes the sepsis spectrum into I) systemic inflammatory response syndrome (SIRS), II) sepsis, III) severe sepsis, and IV) septic shock. Severity and degree of organ dysfunction during sepsis are expressed by the Acute Physiology and Chronic Health Evaluation (APACHE) II [2] and the Sequential Organ Failure Assessment (SOFA) scores [3] respectively. However, in assessing staging and severity for therapeutic decision-making, the use of biomarkers has been advocated. Clearly, measurement of such biomarkers must be rapid and cost-effective to be useful in the management of septic patients. Different molecules have been proposed as severity and/or outcome markers for sepsis, including acute phase proteins (protein C, procalcitonin), coagulation factors (fibrin degrading products, antitrombin III), membrane cell markers (HLA-DR, E-selectin), soluble receptors (sTNFRI, sTNF-RII) and cytokines (TNF, IL-6, IL-8, IL-10). Nevertheless, only a few markers have ultimately been applied successfully in clinical studies such as C-reactive protein (CRP) and procalcitonin (PCT).

A recent meta-analysis [4] of 12 studies that assessed the usefulness of acute phase proteins in the diagnosis of bacterial infection in hospitalized patients, showed that the procalcitonin (PCT) levels were more sensitive (88 vs. 75%) and also more specific (81 vs. 67%) than CRP levels, to distinguish bacterial from non-bacterial inflammation. However, in the few studies evaluating the prognostic value of these markers, it was found that the discriminant power of PCT and CRP for prognosis was poor [5].

Cytokines are key mediators in sepsis and increased plasma and serum levels of those mediators are associated with the intensity of the inflammatory response. However, the usefulness of individual cytokines as prognostic markers is controversial. Cytokines levels were assessed in many studies in order to evaluate their diagnostic value. Classically, IL-6 is referred to as a cytokine with important prognostic value in sepsis. Among a wide array of cytokines assessed so far, it was found that persistently elevated IL-6 values are associated with both multiple organ failure [6] and high mortality [7]. However, in a study on two groups of septic patients treated with two different antibiotic therapies, the mortality rate was independent of the IL-6 levels [8]. Acute phase protein markers and cytokines seem therefore to be weak predictors of severity and/or outcome, when measured in early sepsis. The need for a more accurate biomarker is still of great importance.

Neutrophil activation is crucial in the pathogenesis of sepsis. CD64 is not an adequately studied marker such as neutrophil CD14 [9] or HLA-DR [10]. Furthermore, it disposes the higher affinity between Fc receptors [11] and hence would be expected to have a high discriminating ability for the recognition of sepsis process. The expression of neutrophil CD64 has been investigated at different stages of sepsis but not over the whole sepsis spectrum. In fact, neutrophil CD64 expression was found to be increased in SIRS compared to healthy controls and to non-SIRS intensive care subjects, while septic patients had a higher expression than SIRS individuals [12]. Transient up-regulation of neutrophil and monocyte CD64 levels has been observed in patients with septic shock [13], [14]. Though the impact of an early decline or a persistent elevation of CD64 levels, on the mortality has been investigated in septic shock patients, firm conclusions have not as yet been drawn [14]. The power of CD64 expression to distinguish stages, severity and mortality from a single initial measurement in a population of whole sepsis spectrum has not been so far evaluated. However, in neonatal sepsis neutrophil CD64 showed a high sensitivity and negative predictive value at 0 and 24 h after the onset that was by far superior to lymphocytes antigens CD25 and CD45RO [15].

In the present study we have assessed if a single measurement of CD64 and/or IL-8 performed within the first 24 h of sepsis onset in a population of different sepsis severity is a reliable predictor of the severity and/or mortality.

Section snippets

Subjects

Forty-seven consecutive patients (35 men, 19–72 years; 12 women, 17–82 years), admitted in a General Intensive Care Unit (ICU) during a one-year period, participated in the study. Twelve healthy volunteers served as controls. The study protocol was approved by our Institutional Ethics Committee. Informed written consent was obtained from the patient or next to kin.

The patients entered the study on the day of the onset of sepsis, satisfying the staging criteria of the ACCP/SCCM [16] according to

Results

In 80% of patients blood was drawn between 16 and 24 h from onset of sepsis. In the rest between 10 and 16 h. Significant differences among the stages of sepsis were found in CD64, PCT, CRP, IL-8, IL-6, IL-10 (p < 0.005 by the Kruskal-Wallis test). Pair-wise comparisons (Mann–Whitney test with Bonferroni correction) showed that significant differences among different septic stages and the control group were observed only in CD64 and IL-8 (Fig. 1). CD64 increased with deteriorating septic stages

Discussion

In the present study it was shown that neutrophil CD64 and IL-8 measurements, determined early in the sepsis process i.e., within the first 24-hours, are superior to other biomarkers in detecting sepsis severity and mortality.

The lack of specificity of CRP as to the bacterial or viral etiology of an infectious process has led to the use of PCT measurements as a more specific indicator of bacterial infection [21], [22]. In a previous study [23] it has been suggested that increasing plasma levels

Acknowledgments

The authors are grateful to Prof. J. Milic-Emili for his editorial assistance and useful criticism as well as L. Haziroglou, B.Sc., for language review.

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    1

    These two authors contributed equally.

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