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

Funding Information: We would like to thank all the patients and their relatives as well as the treatment teams for their participation in this study. We also thank Dr. Mischa Keizer for his help in developing the MRP8/14 ELISA. We would like to thank the EUCLIDS Consortium, PERFORM Consortium, and the Genetic Determinants of Kawasaki Disease Study group (UK). Funding. This work was partially supported by the European Seventh Framework Program for Research and Technological Development (FP7) under EUCLIDS grant agreement no. 279185; from the European Union's Horizon 2020 research and innovation program under grant agreement no. 668303; by STINAFO and anonymous donor; and by Sanquin Blood Supply Product and Process Development Cellular Products Fund (PPOC 1957). Publisher Copyright: © Copyright © 2020 Zandstra, van de Geer, Tanck, van Stijn-Bringas Dimitriades, Aarts, Dietz, van Bruggen, Schweintzger, Zenz, Emonts, Zavadska, Pokorn, Usuf, Moll, Schlapbach, Carrol, Paulus, Tsolia, Fink, Yeung, Shimizu, Tremoulet, Galassini, Wright, Martinón-Torres, Herberg, Burns, Levin, Kuijpers, EUCLIDS Consortium, PERFORM Consortium and UK Kawasaki Disease Genetics Study Network. Copyright: Copyright 2020 Elsevier B.V., All rights reserved.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.publishersversionPeer reviewe

Peripheral Endothelial (Dys)Function, Arterial Stiffness and Carotid Intima-Media Thickness in Patients after Kawasaki Disease: A Systematic Review and Meta-Analyses

Kawasaki disease (KD) is a systemic pediatric vasculitis. Its main complication is the development of coronary arterial aneurysms (CAA), causing an increased risk for ischemia and myocardial infarction. It is unclear whether KD patients, apart from the presence of CAA, have an increased cardiovascular disease (CVD) risk due to the previous systemic vasculitis. The aim of this study was to systematically review and meta-analyse the literature regarding surrogate markers for CVD risk in KD patients. Medline and Embase were searched for articles comparing endothelial dysfunction (flow-mediated dilation, nitroglycerin-mediated dilation and peripheral arterial tonometry), vascular stiffness (stiffness index, pulse wave velocity) and carotid intima-media thickness (cIMT) between patients and controls. Two investigators assessed the articles for eligibility and evaluated quality. Thirty studies were included. For all outcomes, moderate to high heterogeneity between studies was found. Most studies reported a decreased flow-mediated dilation in the whole KD- and CAA-positive group compared to controls, while data on CAA-negative patients were conflicting. The stiffness index was increased in the majority of studies evaluating the whole KD- and CAA-positive group, but not in most studies on CAA-negative patients. Mean cIMT was neither significantly increased in the whole KD-group nor in the CAA-positive group nor in most studies studying CAA-negative patients. Studies measuring maximum cIMT were conflicting. Literature suggests that surrogate markers for CVD risk in KD patients are increased in CAA-positive but not in CAA-negative patients. This may indicate that CAA-positive patients should be monitored for CVD in later life. The results of this review have to be interpreted with care due to substantial heterogeneity between studies and methodological limitations, as well as the lack of long-term follow-up studie

Extracardial Vasculopathy After Kawasaki Disease: A Long-Term Follow-up Study

Kawasaki disease (KD) is a pediatric vasculitis with coronary artery aneurysm (CAA) as a major complication. Controversy exists about cardiovascular risk later in life. The aim of our study was to evaluate whether KD patients are at increased risk, as assessed by carotid intima-media thickness (cIMT). We measured cIMT over 15 years by B-mode ultrasonography in KD patients during follow-up and in unaffected controls (mostly siblings). A multilevel, repeated-measures, linear mixed-effects model was used to evaluate the association between KD and cIMT. A total of 319 patients with 528 measurements were compared with 150 controls. In KD patients, the mean cIMT was increased compared with controls (0.375 mm [95% CI 0.372-0.378 mm] versus 0.363 mm [95% CI 0.358-0.368 mm]; P <0.001). Furthermore, mean cIMT of CAA-negative patients was 0.373 mm (P <0.01 compared with controls), of patients with small-medium CAA was 0.374 mm (P <0.05 compared with controls), and of patients with giant CAA was 0.381 mm (P <0.01 compared with controls). Compared with controls, CAA-negative participants started with an increased cIMT (+0.0193±0.0053 mm, P <0.001) but showed slower progression (-0.0014±0.0006 mm/year, P=0.012). Patients with giant CAA showed a trend toward increased cIMT progression (0.0013±0.0007 mm/year, P=0.058). We observed a positive correlation between cIMT and KD severity of coronary arteritis at the acute stage. Although initially increased, the cIMT in CAA-negative patients normalized at a later age. In contrast, patients with a history of KD complicated by giant CAA showed a trend toward persistently increased cIMT. These patients may need cardiovascular counseling and follow-up beyond the hear

Giant aneurysms: A gender-specific complication of Kawasaki disease?

Kawasaki disease (KD) is a pediatric vasculitis of unknown origin. Its main complication is the development of coronary artery aneurysms (CAA) with giant CAA at the end of the spectrum. In this cohort study, we evaluated the association between patient characteristics and the development of giant CAA based on z-scores. Multivariable, multinomial logistic regression analysis was used to identify variables associated with giant CAA. A total of 301 KD patients, comprising 216 patients without enlargement, 45 with small-sized, 19 with medium-sized, and 21 with giant CAA with all echocardiographies at our center were retrospectively included. Remarkably, 95% of patients with giant CAA were boys. In addition to 'no/late intravenous immunoglobulin (IVIG) treatment', 'male gender' (OR 16.23, 95% CI 1.88-140.13), 'age <1 year' (OR 7.49, 95% CI 2.29-24.46), and 'IVIG re-treatment (9.79, 95% CI 2.79-34.37)' were significantly associated with an increased risk of giant CAA, with patients without enlargement as reference. Compared to patients with medium-sized CAA, 'IVIG re-treatment' was significantly associated with giant CAA. The majority of giant CAA continued to increase in size during the first 40 days. We identified risk factors associated with an increased risk of giant CAA. The difference in variables between the giant CAA group and the other CAA subgroups suggests a separation between patients with the treatment-resistant giant CAA and the other IVIG-responsive patients, in which gender may be factored as a most relevant genetic trait. The increase in size during the first 2 months indicates the need for repeated echocardiograph

Forest plots of difference in flow-mediated dilation between patients and controls.

<p><b>(A)</b> Forest plot: flow-mediated dilation of Kawasaki patients and controls, in order of ‘time since KD’. (<b>B)</b> Forest plot: flow-mediated dilation of CAA-positive patients and controls, in order of ‘time since KD’.</p

Flow diagram of selected studies.

<p>Flow diagram of selected studies.</p

Quality of studies.

<p>Quality of studies.</p

Forest plots of difference in stiffness index between patients and controls.

<p><b>(A)</b> Forest plot: stiffness index of Kawasaki patients and controls, in order of ‘time since KD’. <b>(B)</b> Forest plot: stiffness index of CAA-positive patients and controls, in order of ‘time since KD’.</p

Carotid Intima-Media Thickness in Patients With a History of Kawasaki Disease

Kawasaki disease (KD) is an acute pediatric vasculitis with coronary artery aneurysms (CAA) as its main complication. Concerns have been raised regarding the possibility of a predisposition of KD to premature cardiovascular disease (CVD) risk later in life. Our aim was to assess carotid intima-media thickness (cIMT), as a surrogate marker of CVD risk, in patients with a history of KD compared with unaffected controls. B-mode ultrasound cIMT measurements were performed in 168 patients with a history of KD, and 82 controls; 7 patients were excluded because of incomplete cIMT assessments. Mean cIMT (±SD) was increased in patients with KD compared with controls (0.378±0.030 mm vs. 0.360±0.027 mm, respectively; P adjusted <0.0001). If the cIMTs of CAA-negative patients and controls were plotted against age, increased cIMT was only apparent at young age. In patients with CAA, increased cIMT was observed over the entire age range. Our findings show that arterial wall thickening is more apparent in patients with a history of KD as compared with controls. In CAA-negative patients, cIMT is indistinguishable from controls at older age, whereas an increased cIMT is observed at any age in patients with CAA, suggesting a more general and severe effect of KD on the arterial wal