Skip to main content
Top
Published in: Clinical and Experimental Medicine 2/2019

01-05-2019 | Aneurysm | Original Article

Interleukin-6 is prone to be a candidate biomarker for predicting incomplete and IVIG nonresponsive Kawasaki disease rather than coronary artery aneurysm

Authors: Yue Wu, Fei Fei Liu, Yao Xu, Jing Jing Wang, Sama Samadli, Yang Fang Wu, Hui Hui Liu, Wei Xia Chen, Huang Huang Luo, Dong Dong Zhang, Wei Wei, Peng Hu

Published in: Clinical and Experimental Medicine | Issue 2/2019

Login to get access

Abstract

Kawasaki disease (KD) is an acute, systemic vasculitis and occurs mainly in childhood. Interleukin-6 (IL-6) is a pleiotropic cytokine synthesized predominantly by neutrophils and monocytes/macrophages and plays an important role in systemic inflammatory disease. However, a little information is currently available on the relationship of serum IL-6 with conventional inflammatory mediators, clinical classification, IVIG response and coronary artery aneurysm (CAA). 165 Chinese children with KD were enrolled and divided into six subgroups, including complete KD, incomplete KD, IVIG-responsive KD, IVIG-nonresponsive KD, coronary artery noninvolvement KD and coronary artery involvement KD. Blood samples were collected from all subjects within 24-h pre- and 48-h post-IVIG therapy, respectively. Serum IL-6 and conventional inflammatory mediators were detected. (1) Serum IL-6 markedly increased in the acute phase of KD, whereas declined to normal after IVIG therapy; it was positively correlated with C-reactive protein and erythrocyte sedimentation rate. (2) Serum IL-6 was significantly elevated in patients with incomplete KD when compared with their complete counterparts. The area under receiver operating characteristic curve (AUC) value for serum IL-6 in prediction of incomplete KD was 0.596, and the estimated sensitivity and specificity were 77.80% and 54.40% with a cutoff of IL-6 > 13.25 pg/ml, respectively. (3) Serum IL-6 was significantly elevated in patients with IVIG-nonresponsive KD when compared with their IVIG-responsive counterparts; the AUC value for serum IL-6 in prediction of IVIG-nonresponsive KD was 0.580, and the estimated sensitivity and specificity were 60.00% and 66.30% with a cutoff of IL-6 > 26.40 pg/ml, respectively. (4) No significant differences in IL-6 were found between KD patients with and without CAA. IL-6 is prone to be a candidate biomarker for predicting incomplete and IVIG nonresponsive KD rather than CAA.
Literature
1.
go back to reference Chen JJ, Ma XJ, Liu F, et al. Epidemiologic features of Kawasaki disease in Shanghai from 2008 through 2012. Pediatr Infect Dis J. 2016;35:7–12.PubMed Chen JJ, Ma XJ, Liu F, et al. Epidemiologic features of Kawasaki disease in Shanghai from 2008 through 2012. Pediatr Infect Dis J. 2016;35:7–12.PubMed
2.
go back to reference Crindle BW, Rowley AH, Newburger JW, et al. Diagnosis, treatment, and long-term management of Kawasaki disease: a scientific statement for health professionals from the American Heart Association. Circulation. 2017;135:e927–99. Crindle BW, Rowley AH, Newburger JW, et al. Diagnosis, treatment, and long-term management of Kawasaki disease: a scientific statement for health professionals from the American Heart Association. Circulation. 2017;135:e927–99.
3.
go back to reference Daniels LB, Tjajadi MS, Walford HH, et al. Prevalence of Kawasaki disease in young adults with suspected myocardial ischemia. Circulation. 2012;125:2447–53.CrossRefPubMedPubMedCentral Daniels LB, Tjajadi MS, Walford HH, et al. Prevalence of Kawasaki disease in young adults with suspected myocardial ischemia. Circulation. 2012;125:2447–53.CrossRefPubMedPubMedCentral
4.
go back to reference Newburger JW, Takahashi M, Burns JC, et al. The treatment of Kawasaki syndrome with intravenous gamma globulin. N Engl J Med. 1986;315:341–7.CrossRefPubMed Newburger JW, Takahashi M, Burns JC, et al. The treatment of Kawasaki syndrome with intravenous gamma globulin. N Engl J Med. 1986;315:341–7.CrossRefPubMed
5.
go back to reference Xiu-Yu S, Jia-Yu H, Qiang H, Shu-Hui D. Platelet count and erythrocyte sedimentation rate are good predictors of Kawasaki disease: ROC analysis. J Clin Lab Anal. 2010;24:385–8.CrossRefPubMedPubMedCentral Xiu-Yu S, Jia-Yu H, Qiang H, Shu-Hui D. Platelet count and erythrocyte sedimentation rate are good predictors of Kawasaki disease: ROC analysis. J Clin Lab Anal. 2010;24:385–8.CrossRefPubMedPubMedCentral
7.
go back to reference Hu P, Jiang GM, Wu Y, et al. TNF-α is superior to conventional inflammatory mediators in forecasting IVIG nonresponse and coronary arteritis in Chinese children with Kawasaki disease. Clin Chim Acta. 2017;471:76–80.CrossRefPubMed Hu P, Jiang GM, Wu Y, et al. TNF-α is superior to conventional inflammatory mediators in forecasting IVIG nonresponse and coronary arteritis in Chinese children with Kawasaki disease. Clin Chim Acta. 2017;471:76–80.CrossRefPubMed
8.
go back to reference Wang Y, Wang W, Gong F, et al. Evaluation of intravenous immunoglobulin resistance and coronary artery lesions in relation to Th1/Th2 cytokine profiles in patients with Kawasaki disease. Arthritis Rheum. 2013;65:805–14.CrossRefPubMed Wang Y, Wang W, Gong F, et al. Evaluation of intravenous immunoglobulin resistance and coronary artery lesions in relation to Th1/Th2 cytokine profiles in patients with Kawasaki disease. Arthritis Rheum. 2013;65:805–14.CrossRefPubMed
10.
go back to reference Mesquida M, Molins B, Llorenç V, de la Maza MS, Adán A. Targeting interleukin-6 in autoimmune uveitis. Autoimmun Rev. 2017;16:1079–89.CrossRefPubMed Mesquida M, Molins B, Llorenç V, de la Maza MS, Adán A. Targeting interleukin-6 in autoimmune uveitis. Autoimmun Rev. 2017;16:1079–89.CrossRefPubMed
11.
go back to reference Rubbert-Roth A, Furst DE, Nebesky JM, Jin A, Berber E. A review of recent advances using Tocilizumab in the treatment of rheumatic diseases. Rheumatol Ther. 2018;5:21–42.CrossRefPubMedPubMedCentral Rubbert-Roth A, Furst DE, Nebesky JM, Jin A, Berber E. A review of recent advances using Tocilizumab in the treatment of rheumatic diseases. Rheumatol Ther. 2018;5:21–42.CrossRefPubMedPubMedCentral
12.
go back to reference Spîrchez M, Samaşca G, Iancu M, Bolba C, Miu N. Relation of interleukin-6, TNF-alpha and interleukin-1α with disease activity and severity in juvenile idiopathic arthritis patients. Clin Lab. 2012;58:253–60.PubMed Spîrchez M, Samaşca G, Iancu M, Bolba C, Miu N. Relation of interleukin-6, TNF-alpha and interleukin-1α with disease activity and severity in juvenile idiopathic arthritis patients. Clin Lab. 2012;58:253–60.PubMed
13.
go back to reference Lai JM, Wu FQ, Zhou ZX, et al. Tocilizumab for refractory systemic juvenile idiopathic arthritis. Zhonghua Er Ke Za Zhi. 2017;55:830–4.PubMed Lai JM, Wu FQ, Zhou ZX, et al. Tocilizumab for refractory systemic juvenile idiopathic arthritis. Zhonghua Er Ke Za Zhi. 2017;55:830–4.PubMed
14.
go back to reference Suganami Y, Kawashima H, Hasegawa D, Sato S, Hoshika A. Clinical application of rapid assay of serum interleukin-6 in Kawasaki disease. Pediatr Int. 2008;50:264–6.CrossRefPubMed Suganami Y, Kawashima H, Hasegawa D, Sato S, Hoshika A. Clinical application of rapid assay of serum interleukin-6 in Kawasaki disease. Pediatr Int. 2008;50:264–6.CrossRefPubMed
15.
go back to reference Cai XY, Lu Y, Tang C, et al. Effect of interleukin-6 promoter DNA methylation on the pathogenesis of systemic lupus erythematosus. Zhonghua Yi Xue Za Zhi. 2017;97:1491–5.PubMed Cai XY, Lu Y, Tang C, et al. Effect of interleukin-6 promoter DNA methylation on the pathogenesis of systemic lupus erythematosus. Zhonghua Yi Xue Za Zhi. 2017;97:1491–5.PubMed
16.
go back to reference Yasuda H, Ikeda T, Hamaguchi Y, Furukawa F. Clinically amyopathic dermatomyositis with rapidly progressive interstitial pneumonia: the relation between the disease activity and the serum interleukin-6 level. J Dermatol. 2017;44:1164–7.CrossRefPubMed Yasuda H, Ikeda T, Hamaguchi Y, Furukawa F. Clinically amyopathic dermatomyositis with rapidly progressive interstitial pneumonia: the relation between the disease activity and the serum interleukin-6 level. J Dermatol. 2017;44:1164–7.CrossRefPubMed
17.
go back to reference Palizgir MT, Akhtari M, Mahmoudi M, Mostafaei S, Rezaiemanesh A, Shahram F. Curcumin reduces the expression of interleukin 1β and the production of interleukin 6 and tumor necrosis factor alpha by M1 macrophages from patients with Behcet’s disease. Immunopharmacol Immunotoxicol. 2018;40:297–302.CrossRefPubMed Palizgir MT, Akhtari M, Mahmoudi M, Mostafaei S, Rezaiemanesh A, Shahram F. Curcumin reduces the expression of interleukin 1β and the production of interleukin 6 and tumor necrosis factor alpha by M1 macrophages from patients with Behcet’s disease. Immunopharmacol Immunotoxicol. 2018;40:297–302.CrossRefPubMed
18.
go back to reference Ye Q, Shao WX, Shang SQ, Zhang T, Hu J, Zhang CC. A comprehensive assessment of the value of laboratory indices in diagnosing Kawasaki disease. Arthritis Rheumatol. 2015;67:1943–50.CrossRefPubMed Ye Q, Shao WX, Shang SQ, Zhang T, Hu J, Zhang CC. A comprehensive assessment of the value of laboratory indices in diagnosing Kawasaki disease. Arthritis Rheumatol. 2015;67:1943–50.CrossRefPubMed
20.
go back to reference Higa M, Oka M, Fujihara Y, Masuda K, Yoneda Y, Kishimoto T. Regulation of inflammatory responses by dynamic subcellular localization of RNA-binding protein Arid5a. Proc Natl Acad Sci USA. 2018;115:E1214–20.CrossRefPubMedPubMedCentral Higa M, Oka M, Fujihara Y, Masuda K, Yoneda Y, Kishimoto T. Regulation of inflammatory responses by dynamic subcellular localization of RNA-binding protein Arid5a. Proc Natl Acad Sci USA. 2018;115:E1214–20.CrossRefPubMedPubMedCentral
21.
go back to reference Masuda K, Ripley B, Nishimura R, et al. Arid5a controls IL-6 mRNA stability, which contributes to elevation of IL-6 level in vivo. Proc Natl Acad Sci USA. 2013;110:9409–14.CrossRefPubMedPubMedCentral Masuda K, Ripley B, Nishimura R, et al. Arid5a controls IL-6 mRNA stability, which contributes to elevation of IL-6 level in vivo. Proc Natl Acad Sci USA. 2013;110:9409–14.CrossRefPubMedPubMedCentral
22.
go back to reference Lin CY, Lin CC, Hwang B, Chiang B. Serial changes of serum interleukin-6, interleukin-8, and tumor necrosis factor alpha among patients with Kawasaki disease. J Pediatr. 1992;121:924–6.CrossRefPubMed Lin CY, Lin CC, Hwang B, Chiang B. Serial changes of serum interleukin-6, interleukin-8, and tumor necrosis factor alpha among patients with Kawasaki disease. J Pediatr. 1992;121:924–6.CrossRefPubMed
23.
go back to reference Peng Q, Wu Q, Chen CH, Hong H, Zhang LY. Value of serum soluble interleukin-2R, interleukin-6 and C-reactive protein in the early diagnosis of Kawasaki disease. Zhongguo Dang Dai Er Ke Za Zhi. 2006;8:208–10.PubMed Peng Q, Wu Q, Chen CH, Hong H, Zhang LY. Value of serum soluble interleukin-2R, interleukin-6 and C-reactive protein in the early diagnosis of Kawasaki disease. Zhongguo Dang Dai Er Ke Za Zhi. 2006;8:208–10.PubMed
24.
go back to reference Beringer A, Thiam N, Molle J, Bartosch B, Miossec P. Synergistic effect of interleukin-17 and tumour necrosis factor-α on inflammatory response in hepatocytes through interleukin-6-dependent and independent pathways. Clin Exp Immunol. 2018;193:221–33.CrossRefPubMedPubMedCentral Beringer A, Thiam N, Molle J, Bartosch B, Miossec P. Synergistic effect of interleukin-17 and tumour necrosis factor-α on inflammatory response in hepatocytes through interleukin-6-dependent and independent pathways. Clin Exp Immunol. 2018;193:221–33.CrossRefPubMedPubMedCentral
25.
go back to reference Kopf M, Baumann H, Freer G, et al. Impaired immune and acute-phase responses in interleukin-6-deficient mice. Nature. 1994;368:339–42.CrossRefPubMed Kopf M, Baumann H, Freer G, et al. Impaired immune and acute-phase responses in interleukin-6-deficient mice. Nature. 1994;368:339–42.CrossRefPubMed
26.
go back to reference Ha KS, Jang G, Lee J, et al. Incomplete clinical manifestation as a risk factor for coronary artery abnormalities in Kawasaki disease: a meta-analysis. Eur J Pediatr. 2013;172:343–9.CrossRefPubMed Ha KS, Jang G, Lee J, et al. Incomplete clinical manifestation as a risk factor for coronary artery abnormalities in Kawasaki disease: a meta-analysis. Eur J Pediatr. 2013;172:343–9.CrossRefPubMed
27.
go back to reference Liu HC, Lo CW, Hwang B, Lee PC. Clinical manifestations vary with different age spectrums in infants with Kawasaki disease. Sci World J. 2012;2012:210382. Liu HC, Lo CW, Hwang B, Lee PC. Clinical manifestations vary with different age spectrums in infants with Kawasaki disease. Sci World J. 2012;2012:210382.
28.
go back to reference Bai L, Feng T, Yang L, et al. Retrospective analysis of risk factors associated with Kawasaki disease in China. Oncotarget. 2017;8:54357–63.PubMedPubMedCentral Bai L, Feng T, Yang L, et al. Retrospective analysis of risk factors associated with Kawasaki disease in China. Oncotarget. 2017;8:54357–63.PubMedPubMedCentral
29.
go back to reference Peng C, Luo YJ, Xing QL, Xiao MC. Clinical features of children with incomplete Kawasaki disease. Zhongguo Dang Dai Er Ke Za Zhi. 2016;18:1111–4.PubMed Peng C, Luo YJ, Xing QL, Xiao MC. Clinical features of children with incomplete Kawasaki disease. Zhongguo Dang Dai Er Ke Za Zhi. 2016;18:1111–4.PubMed
30.
go back to reference Kobayashi T, Inoue Y, Takeuchi K, et al. Prediction of intravenous immunoglobulin unresponsiveness in patients with Kawasaki disease. Circulation. 2006;113:2606–12.CrossRefPubMed Kobayashi T, Inoue Y, Takeuchi K, et al. Prediction of intravenous immunoglobulin unresponsiveness in patients with Kawasaki disease. Circulation. 2006;113:2606–12.CrossRefPubMed
31.
go back to reference Baek JY, Song MS. Meta-analysis of factors predicting resistance to intravenous immunoglobulin treatment in patients with Kawasaki disease. Korean J Pediatr. 2016;59:80–90.CrossRefPubMedPubMedCentral Baek JY, Song MS. Meta-analysis of factors predicting resistance to intravenous immunoglobulin treatment in patients with Kawasaki disease. Korean J Pediatr. 2016;59:80–90.CrossRefPubMedPubMedCentral
32.
go back to reference Kim MK, Song MS, Kim GB. Factors predicting resistance to intravenous immunoglobulin treatment and coronary artery lesion in patients with Kawasaki disease: analysis of the Korean Nationwide Multicenter Survey from 2012 to 2014. Korean Circ J. 2018;48:71–9.CrossRefPubMed Kim MK, Song MS, Kim GB. Factors predicting resistance to intravenous immunoglobulin treatment and coronary artery lesion in patients with Kawasaki disease: analysis of the Korean Nationwide Multicenter Survey from 2012 to 2014. Korean Circ J. 2018;48:71–9.CrossRefPubMed
33.
go back to reference Xie T, Wang Y, Fu S, et al. Predictors for intravenous immunoglobulin resistance and coronary artery lesions in Kawasaki disease. Pediatr Rheumatol Online J. 2017;15:17.CrossRefPubMedPubMedCentral Xie T, Wang Y, Fu S, et al. Predictors for intravenous immunoglobulin resistance and coronary artery lesions in Kawasaki disease. Pediatr Rheumatol Online J. 2017;15:17.CrossRefPubMedPubMedCentral
34.
go back to reference Gupta M, Noel GJ, Schaefer M, Friedman D, Bussel J, Johann-Liang R. Cytokine modulation with immune gamma-globulin in peripheral blood of normal children and its implications in Kawasaki disease treatment. J Clin Immunol. 2001;21:193–9.CrossRefPubMed Gupta M, Noel GJ, Schaefer M, Friedman D, Bussel J, Johann-Liang R. Cytokine modulation with immune gamma-globulin in peripheral blood of normal children and its implications in Kawasaki disease treatment. J Clin Immunol. 2001;21:193–9.CrossRefPubMed
35.
go back to reference Ikeda K, Mizoro Y, Ameku T, et al. Transcriptional analysis of intravenous immunoglobulin resistance in Kawasaki disease using an induced pluripotent stem cell disease model. Circ J. 2016;81:110–8.CrossRefPubMed Ikeda K, Mizoro Y, Ameku T, et al. Transcriptional analysis of intravenous immunoglobulin resistance in Kawasaki disease using an induced pluripotent stem cell disease model. Circ J. 2016;81:110–8.CrossRefPubMed
36.
go back to reference Maric LS, Knezovic I, Papic N, et al. Risk factors for coronary artery abnormalities in children with Kawasaki disease: a 10-year experience. Rheumatol Int. 2015;35:1053–8.CrossRefPubMed Maric LS, Knezovic I, Papic N, et al. Risk factors for coronary artery abnormalities in children with Kawasaki disease: a 10-year experience. Rheumatol Int. 2015;35:1053–8.CrossRefPubMed
37.
go back to reference Si F, Wu Y, Gao F, et al. Relationship between IL-27 and coronary arterial lesions in children with Kawasaki disease. Clin Exp Med. 2017;17:451–7.CrossRefPubMed Si F, Wu Y, Gao F, et al. Relationship between IL-27 and coronary arterial lesions in children with Kawasaki disease. Clin Exp Med. 2017;17:451–7.CrossRefPubMed
38.
go back to reference Lee GL, Wu JY, Tsai CS, et al. TLR4-activated MAPK-IL-6 axis regulates vascular smooth muscle cell function. Int J Mol Sci. 2016;17:E1394.CrossRefPubMed Lee GL, Wu JY, Tsai CS, et al. TLR4-activated MAPK-IL-6 axis regulates vascular smooth muscle cell function. Int J Mol Sci. 2016;17:E1394.CrossRefPubMed
39.
go back to reference Mitani Y, Sawada H, Hayakawa H, et al. Elevated levels of high-sensitivity C-reactive protein and serum amyloid-A late after Kawasaki disease: association between inflammation and late coronary sequelae in Kawasaki disease. Circulation. 2005;111:38–43.CrossRefPubMed Mitani Y, Sawada H, Hayakawa H, et al. Elevated levels of high-sensitivity C-reactive protein and serum amyloid-A late after Kawasaki disease: association between inflammation and late coronary sequelae in Kawasaki disease. Circulation. 2005;111:38–43.CrossRefPubMed
40.
go back to reference Nozawa T, Imagawa T, Ito S. Coronary-artery aneurysm in tocilizumab-treated children with Kawasaki’s disease. N Engl J Med. 2017;377:1894–6.CrossRefPubMed Nozawa T, Imagawa T, Ito S. Coronary-artery aneurysm in tocilizumab-treated children with Kawasaki’s disease. N Engl J Med. 2017;377:1894–6.CrossRefPubMed
Metadata
Title
Interleukin-6 is prone to be a candidate biomarker for predicting incomplete and IVIG nonresponsive Kawasaki disease rather than coronary artery aneurysm
Authors
Yue Wu
Fei Fei Liu
Yao Xu
Jing Jing Wang
Sama Samadli
Yang Fang Wu
Hui Hui Liu
Wei Xia Chen
Huang Huang Luo
Dong Dong Zhang
Wei Wei
Peng Hu
Publication date
01-05-2019
Publisher
Springer International Publishing
Published in
Clinical and Experimental Medicine / Issue 2/2019
Print ISSN: 1591-8890
Electronic ISSN: 1591-9528
DOI
https://doi.org/10.1007/s10238-018-00544-5

Other articles of this Issue 2/2019

Clinical and Experimental Medicine 2/2019 Go to the issue
Live Webinar | 27-06-2024 | 18:00 (CEST)

Keynote webinar | Spotlight on medication adherence

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

WHO estimates that half of all patients worldwide are non-adherent to their prescribed medication. The consequences of poor adherence can be catastrophic, on both the individual and population level.

Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.

Prof. Kevin Dolgin
Prof. Florian Limbourg
Prof. Anoop Chauhan
Developed by: Springer Medicine
Obesity Clinical Trial Summary

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine

Highlights from the ACC 2024 Congress

Year in Review: Pediatric cardiology

Watch Dr. Anne Marie Valente present the last year's highlights in pediatric and congenital heart disease in the official ACC.24 Year in Review session.

Year in Review: Pulmonary vascular disease

The last year's highlights in pulmonary vascular disease are presented by Dr. Jane Leopold in this official video from ACC.24.

Year in Review: Valvular heart disease

Watch Prof. William Zoghbi present the last year's highlights in valvular heart disease from the official ACC.24 Year in Review session.

Year in Review: Heart failure and cardiomyopathies

Watch this official video from ACC.24. Dr. Biykem Bozkurt discusses last year's major advances in heart failure and cardiomyopathies.