Serum biomarkers differentiating Kawasaki disease from febrile infections: A pilot case-control study

Abstract

Although some serum biomarkers are elevated in both Kawasaki disease (KD) and infections, these conditions have not been compared by individual or combined biomarkers. The aim of this study, undertaken between January 2016 and May 2018 in a large teaching hospital, was to compare the serum concentration of cytokines, metalloproteinases (MMP) and heat shock protein (HSP) between cases defined as children with Kawasaki disease (KD) and those with febrile infections (controls). Serum concentrations of tumour necrosis factor-alpha (TNF-alpha), interleukins (IL 1beta, 6, and 8), heat shock proteins (HSP 60 and 70) and matrix metalloproteinase (MMP 9) were measured on admission in 17 children under six years of age with a temperature >38.5 °C for ≥five days, and compared between the two groups. The median age was 25 months and the median duration of fever eight days. Seven children were diagnosed with KD and ten had a febrile infection. Only the serum concentrations of IL-6 and TNF-alpha were significantly higher in the former than in the latter group (P = 0.01 and 0.04 respectively). To differentiate between the two groups with the best sensitivity and specificity, the optimal cut-off value for IL-6 was 12.6 pg/mL, and for TNF-alpha 47.9 pg/mL. Their combined increase, however, outperformed their individual concentrations. The characteristic diagnostic "signature" of the combined elevation of IL-6 and TNF-alpha serum levels has the potential, in febrile children, to differentiate early KD from febrile infections, allowing the institution of appropriate therapy.

Keywords: Cytokine; Heat shock protein; Interleukin; Matrix metalloproteinase; Tumour necrosis factor-alpha.

Fig. 1

Receiver operating characteristics (ROC) and area under the curve (AUC) of serum IL-6 and TNF levels to differentiate between children with Kawasaki disease (n = 7) and those with febrile infections (n = 10). The optimal cut-off value For IL-6 was 12.6 pg/mL and for TNF-alpha 47.9 pg/mL IL-6: interleukin 6; TNF: tumour necrosis factor.

Fig. 2

Spider (or radar) chart of base-10 logarithmic serum biomarkers concentrations in children with Kawasaki disease (n = 7) compared to those with febrile infections (n = 10). It compares the performance of each biomarker between both groups by displaying its individual concentration on its own axis. The lines connecting the values on each axis form a polygon area which represent the magnitude of the biomarkers profile in each group and the overall differences are displayed by the size and shape of the polygons. For each biomarker, the magnitude of its value in each of the two polygon areas indicates the degree of its contribution to the panel performance. The concentrations are shown on a logarithmic scale because of the large number of biomarkers spanning a wide range of values, with many orders of magnitude, and to avoid skewness towards large values; IL: interleukin; TNF: tumour necrosis factor; MMP: matrix metalloproteinase; HSP: heat shock protein.