Use of plasma C-reactive protein, procalcitonin, neutrophils, macrophage migration inhibitory factor, soluble urokinase-type plasminogen activator receptor, and soluble triggering receptor expressed on myeloid cells-1 in combination to diagnose infections: a prospective study

Kristian Kofoed, Ove Andersen, Gitte Kronborg, Michael Tvede, Janne Petersen, Jesper Eugen-Olsen, Klaus Larsen, Kristian Kofoed, Ove Andersen, Gitte Kronborg, Michael Tvede, Janne Petersen, Jesper Eugen-Olsen, Klaus Larsen

Abstract

Introduction: Accurate and timely diagnosis of community-acquired bacterial infections in patients with systemic inflammation remains challenging both for clinician and laboratory. Combinations of markers, as opposed to single ones, may improve diagnosis and thereby survival. We therefore compared the diagnostic characteristics of novel and routinely used biomarkers of sepsis alone and in combination.

Methods: This prospective cohort study included patients with systemic inflammatory response syndrome who were suspected of having community-acquired infections. It was conducted in a medical emergency department and department of infectious diseases at a university hospital. A multiplex immunoassay measuring soluble urokinase-type plasminogen activator (suPAR) and soluble triggering receptor expressed on myeloid cells (sTREM)-1 and macrophage migration inhibitory factor (MIF) was used in parallel with standard measurements of C-reactive protein (CRP), procalcitonin (PCT), and neutrophils. Two composite markers were constructed - one including a linear combination of the three best performing markers and another including all six - and the area under the receiver operating characteristic curve (AUC) was used to compare their performance and those of the individual markers.

Results: A total of 151 patients were eligible for analysis. Of these, 96 had bacterial infections. The AUCs for detection of a bacterial cause of inflammation were 0.50 (95% confidence interval [CI] 0.40 to 0.60) for suPAR, 0.61 (95% CI 0.52 to 0.71) for sTREM-1, 0.63 (95% CI 0.53 to 0.72) for MIF, 0.72 (95% CI 0.63 to 0.79) for PCT, 0.74 (95% CI 0.66 to 0.81) for neutrophil count, 0.81 (95% CI 0.73 to 0.86) for CRP, 0.84 (95% CI 0.71 to 0.91) for the composite three-marker test, and 0.88 (95% CI 0.81 to 0.92) for the composite six-marker test. The AUC of the six-marker test was significantly greater than that of the single markers.

Conclusion: Combining information from several markers improves diagnostic accuracy in detecting bacterial versus nonbacterial causes of inflammation. Measurements of suPAR, sTREM-1 and MIF had limited value as single markers, whereas PCT and CRP exhibited acceptable diagnostic characteristics.

Trial registration: ClinicalTrials.gov NCT00389337.

Figures

Figure 1
Figure 1
Flowchart of the patients included in the study. Flowchart describing the number of patients included in the study, the reasons for subsequent exclusions, the final diagnoses of the patients, and the ability C-reactive protein (CRP), procalcitonin (PCT), and the three-marker and six-marker combined tests to correctly diagnose patients as having bacterial infection. Optimal cutoffs for bacterial infection (determined by Youdens Index) were used for all four markers. SIRS, systemic inflammatory response syndrome.
Figure 2
Figure 2
Plasma concentrations of the markers. Shown are individual admission plasma concentrations of (a) C-reactive protein (CRP), (b) procalcitonin (PCT), (c) neutrophil count, (d) soluble urokinase-type plasminogen activator receptor (suPAR), (e) soluble triggering receptor expressed on myeloid cells (sTREM)-1 and (f) macrophage migration inhibitory factor (MIF) in patients with no infection (circle), bacterial (triangle, apex up), viral (triangle, apex down), or parasitic infection (square). Bars represent the medians of the concentrations.
Figure 3
Figure 3
ROC curves comparing markers' ability to detect bacterial infections in patients with systemic inflammation. Receiver operating characteristic (ROC) curves comparing soluble urokinase-type plasminogen activator receptor (suPAR), soluble triggering receptor expressed on myeloid cells (sTREM)-1, macrophage migration inhibitory factor (MIF), neutrophil count, procalcitonin (PCT), C-reactive protein (CRP), and the combined three-marker and six-marker tests for detection of bacterial versus nonbacterial causes of systemic inflammation.

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