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CXCL10/IP-10 is a biomarker and mediator for Kawasaki disease

Significance Statement

Kawasaki disease (KD) is the most common cause of acquired heart disease in young children. To date, diagnosing Kawasaki disease is still difficult because of its varied clinical manifestations and lack of specific laboratory tests. Here we found that the IP-10 levels had extremely high area under the curve values through receiver operator characteristic (ROC) analysis from discovery and replication studies, which suggested that IP-10 can be used as a biomarker for differential diagnosis of Kawasaki disease, thus allowing Kawasaki disease patients to receive timely treatment. Moreover, IP-10 levels can be used for diagnosis of Kawasaki disease in the very early stage (getting fever less than 4 days) and monitoring the efficacy of intravenous immunoglobulin (IVIG) treatment. Based on the blinded validation study, this invention (IP-10 as a Kawasaki disease biomarker) has been proved to have a high potential to apply in clinic because of reproducible discrimination and extremely high sensitivity and specificity. Compared to the previously reported biomarkers in the blood, IP-10 appears to be the most significant biomarker that can be used as a predictor for Kawasaki disease diagnosis. In addition, this invention also provides an important clue to develop novel targets or therapeutic avenue for KD.

Microsoft PowerPoint - GMD Figure-2015_04_29-m

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Journal Reference

Ko TM, Kuo HC, Chang JS, Chen SP, Liu YM, Chen HW, Tsai FJ, Lee YC, ChenCH, Wu JY, Chen YT. Circ Res. 2015;116(5):876-83.

Affiliations
From the Institute of Biomedical Sciences (T.-M.K., S.-P.C., Y.-M.L., H.-W.C., C.-H.C., J.-Y.W., Y.-T.C.) and Institute of Cellular and Organismic Biology (Y.-C.L.), Academia Sinica, Taipei, Taiwan; Department of Pediatrics and Kawasaki Disease Center, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan (H.-C.K.); Chang Gung University College of Medicine, Taoyuan, Taiwan (H.-C.K.); Department of Pediatric Cardiology, Children’s Hospital of China Medical University, Taichung, Taiwan (J.-S.C.); School of Medicine (J.-S.C.), School of Chinese Medicine (F.-J.T.), and Department of Medical Genetics (F.-J.T., C.-H.C., J.-Y.W.), China Medical University Hospital, Taichung, Taiwan; Department of Health and Nutrition Biotechnology, Asia University, Taichung, Taiwan (F.-J.T.); and Department of Pediatrics, Duke University Medical Center, Durham, NC (Y.-T.C.).

Abstract
RATIONALE:
Kawasaki disease (KD), an acute febrile vasculitis, is the most common cause of acquired heart disease in childhood; however, diagnosing Kawasaki disease can be difficult.

OBJECTIVE:
To identify unique proteomic biomarkers that can be used to facilitate earlier diagnosis of Kawasaki disease.

METHODS AND RESULTS:
We enrolled 214 children with fever and clinical features suggestive of Kawasaki disease. Of those, only 100 were diagnosed with Kawasaki disease. Their plasma samples were globally analyzed for cytokines, chemokines, and cell adhesion molecules using an unbiased, large-scale, quantitative protein array. This study was conducted in 3 stages: discovery, replication, and blinded validation. During the discovery phase (n [KD]=37; n [control]=20), the expression of interleukin-17F, sCD40L, E-selectin, CCL23 (myeloid progenitor inhibitory factor 1), and CXCL10 (IFN-γ-inducible protein 10 [IP-10]) were upregulated during the acute phase in patients with KD when compared with that in the controls. A notable increase was observed in the IP-10 levels (KD, 3037 ± 226.7 pg/mL; control, 672 ± 130.4 pg/mL; P=4.1 × 10(-11)). Receiver-operating characteristic analysis of the combined discovery and replication data (n [KD]=77; n [control]=77) showed that the IP-10 level had high area under the curve values (0.94 [95% confidence interval, 0.9055-0.9778]; sensitivity, 100%; and specificity, 77%). With 1318 pg/mL as the optimal cutoff, the blinded validation study confirmed that the IP-10 levels were a good predictor of Kawasaki disease. With intravenous immunoglobulin treatment, the IP-10 levels returned to normal. The downstream receptor of IP-10, CXCR3, was activated in the T cells of patients with acute Kawasaki disease.

CONCLUSIONS:
IP-10 may be used as a biomarker to facilitate Kawasaki disease diagnosis, and it may provide clues about the pathogenesis of Kawasaki disease.

© 2015 American Heart Association, Inc.

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