title: CXCL10/IP-10 is a biomarker and mediator for Kawasaki disease.
abstract: BACKGROUND
  Kawasaki disease (KD), an acute febrile vasculitis, is the most common cause of acquired heart disease in childhood; however, diagnosing KD can be difficult.
  
  
  OBJECTIVE
  To identify unique proteomic biomarkers that can be used to facilitate earlier diagnosis of KD.
  
  
  RESULTS
  We enrolled 214 children with fever and clinical features suggestive of KD. Of those, only 100 were diagnosed with KD. 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 KD. 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 KD.
  
  
  CONCLUSIONS
  IP-10 may be used as a biomarker to facilitate KD diagnosis, and it may provide clues about the pathogenesis of KD.
authors.affiliation: 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.).
authors.forename: Tai-Ming
authors.initials: TM
authors.lastname: Ko
authors.affiliation: 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.).
authors.forename: Ho-Chang
authors.initials: HC
authors.lastname: Kuo
authors.affiliation: 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.).
authors.forename: Jeng-Sheng
authors.initials: JS
authors.lastname: Chang
authors.affiliation: 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.).
authors.forename: Shih-Ping
authors.initials: SP
authors.lastname: Chen
authors.affiliation: 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.).
authors.forename: Yi-Min
authors.initials: YM
authors.lastname: Liu
authors.affiliation: 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.).
authors.forename: Hui-Wen
authors.initials: HW
authors.lastname: Chen
authors.affiliation: 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.).
authors.forename: Fuu-Jen
authors.initials: FJ
authors.lastname: Tsai
authors.affiliation: 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.).
authors.forename: Yi-Ching
authors.initials: YC
authors.lastname: Lee
authors.affiliation: 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.).
authors.forename: Chien-Hsiun
authors.initials: CH
authors.lastname: Chen
authors.affiliation: 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.). jywu@ibms.sinica.edu.tw chen0010@ibms.sinica.edu.tw.
authors.forename: Jer-Yuarn
authors.initials: JY
authors.lastname: Wu
authors.affiliation: 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.). jywu@ibms.sinica.edu.tw chen0010@ibms.sinica.edu.tw.
authors.forename: Yuan-Tsong
authors.initials: YT
authors.lastname: Chen
mesh_terms: D015415:Biomarkers / Q000097:blood; D015815:Cell Adhesion Molecules / Q000097:blood; D054357:Chemokine CXCL10 / Q000097:blood* / Q000502:physiology; D018925:Chemokines / Q000097:blood; D002648:Child; D002675:Child, Preschool; D016207:Cytokines / Q000097:blood; D005260:Female; D005334:Fever / Q000209:etiology; D006801:Humans; D016756:Immunoglobulins, Intravenous / Q000627:therapeutic use; D007223:Infant; D007231:Infant, Newborn; D007249:Inflammation; D008297:Male; D009080:Mucocutaneous Lymph Node Syndrome / Q000097:blood* / Q000175:diagnosis / Q000503:physiopathology / Q000628:therapy; D012372:ROC Curve; D054367:Receptors, CXCR3 / Q000378:metabolism; D016037:Single-Blind Method; D013601:T-Lymphocytes / Q000378:metabolism
chemical_list: D015415:Biomarkers; C114753:CXCL10 protein, human; C515187:CXCR3 protein, human; D015815:Cell Adhesion Molecules; D054357:Chemokine CXCL10; D018925:Chemokines; D016207:Cytokines; D016756:Immunoglobulins, Intravenous; D054367:Receptors, CXCR3
keywords: IP-10; biomarkers; diagnosis; mucocutaneous lymph node syndrome; vasculitis