Biomarkers for the Discrimination of Acute Kawasaki Disease From Infections in Childhood

Abstract

Background: Kawasaki disease (KD) is a vasculitis of early childhood mimicking several infectious diseases. Differentiation between KD and infectious diseases is essential as KD's most important complication-the development of coronary artery aneurysms (CAA)-can be largely avoided by timely treatment with intravenous immunoglobulins (IVIG). Currently, KD diagnosis is only based on clinical criteria. The aim of this study was to evaluate whether routine C-reactive protein (CRP) and additional inflammatory parameters myeloid-related protein 8/14 (MRP8/14 or S100A8/9) and human neutrophil-derived elastase (HNE) could distinguish KD from infectious diseases. Methods and Results: The cross-sectional study included KD patients and children with proven infections as well as febrile controls. Patients were recruited between July 2006 and December 2018 in Europe and USA. MRP8/14, CRP, and HNE were assessed for their discriminatory ability by multiple logistic regression analysis with backward selection and receiver operator characteristic (ROC) curves. In the discovery cohort, the combination of MRP8/14+CRP discriminated KD patients (n = 48) from patients with infection (n = 105), with area under the ROC curve (AUC) of 0.88. The HNE values did not improve discrimination. The first validation cohort confirmed the predictive value of MRP8/14+CRP to discriminate acute KD patients (n = 26) from those with infections (n = 150), with an AUC of 0.78. The second validation cohort of acute KD patients (n = 25) and febrile controls (n = 50) showed an AUC of 0.72, which improved to 0.84 when HNE was included. Conclusion: When used in combination, the plasma markers MRP8/14, CRP, and HNE may assist in the discrimination of KD from both proven and suspected infection.

Keywords: bacterial infection; biomarker; coronary aneurysm; infectious disease; kawasaki disease; vasculitis; viral infection.

Figure 1

Myeloid-related protein 8/14 (MRP8/14) (A), C-reactive protein (CRP) (B), and neutrophil-derived elastase (HNE) (C) levels in the discovery cohort. Patients with acute Kawasaki disease are compared to patients with infections and, more specifically, patients with either bacterial or viral infections. Each dot is a unique patient. Dotted line represents the 75% concentration in the healthy controls: 400 ng/ml MRP8/14, 2.7 mg/l CRP, and 37.3 ng/ml HNE. Median levels + interquartile ranges are listed below the figure. Differences were calculated with the Kruskal–Wallis test, followed by Dunn's multiple comparisons test. **p < 0.005, ****p < 0.001; ns, not significant.

Figure 2

Receiver operator characteristic (ROC) curves of the discovery cohort (A), first validation cohort (B), and the second validation cohort (C) of MRP8/14 and CRP together for discrimination between acute Kawasaki disease and infections. The corresponding areas under the ROC curve (AUCs) are listed within the panels.

Figure 3

Receiver operator characteristic (ROC) curves of MRP8/14, CRP, and HNE combined in the meta-analysis. The corresponding area under the ROC curve (AUC) is listed within the panel.

Figure 4

Differences in the MRP8/14 levels in acute Kawasaki disease (KD) and convalescent in 25 paired samples from the discovery cohort (A) and 50 paired samples from the second validation cohort (B). In the discovery cohort, one sample above 30,000 ng/ml MRP8/14 was excluded in this graph. Analyzed by a Wilcoxon matched-pairs test. ***p < 0.0001.