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      Dissecting Kawasaki disease: a state-of-the-art review


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          Kawasaki disease (KD) is a pediatric vasculitis with coronary artery aneurysms (CAA) as its main complication. The diagnosis is based on the presence of persistent fever and clinical features including exanthema, lymphadenopathy, conjunctival injection, and changes to the mucosae and extremities. Although the etiology remains unknown, the current consensus is that it is likely caused by an (infectious) trigger initiating an abnormal immune response in genetically predisposed children. Treatment consists of high dose intravenous immunoglobulin (IVIG) and is directed at preventing the development of CAA. Unfortunately, 10–20% of all patients fail to respond to IVIG and these children need additional anti-inflammatory treatment. Coronary artery lesions are diagnosed by echocardiography in the acute and subacute phases. Both absolute arterial diameters and z-scores, adjusted for height and weight, are used as criteria for CAA. Close monitoring of CAA is important as ischemic symptoms or myocardial infarction due to thrombosis or stenosis can occur. These complications are most likely to arise in the largest, so-called giant CAA. Apart from the presence of CAA, it is unclear whether KD causes an increased cardiovascular risk due to the vasculitis itself.

          Conclusion: Many aspects of KD remain unknown, although there is growing knowledge on the etiology, treatment, and development and classification of CAA. Since children with previous KD are entering adulthood, long-term follow-up is increasingly important.

          What is known:

          • Kawasaki disease (KD) is a pediatric vasculitis with coronary artery damage as its main complication .

          • Although KD approaches its 50th birthday since its first description, many aspects of the disease remain poorly understood .
          What is new:

          • In recent years, multiple genetic candidate pathways involved in KD have been identified, with recently promising information about the ITPKC pathway .

          • As increasing numbers of KD patients are reaching adulthood, increasing information is available about the long-term consequences of coronary artery damage and broader cardiovascular risk .

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          Most cited references108

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          CD40 ligand on activated platelets triggers an inflammatory reaction of endothelial cells.

          CD40 ligand (CD40L, CD154), a transmembrane protein structurally related to the cytokine TNF-alpha, was originally identified on stimulated CD4+ T cells, and later on stimulated mast cells and basophils. Interaction of CD40L on T cells with CD40 on B cells is of paramount importance for the development and function of the humoral immune system. CD40 is not only constitutively present on B cells, but it is also found on monocytes, macrophages and endothelial cells, suggesting that CD40L has a broader function in vivo. We now report that platelets express CD40L within seconds of activation in vitro and in the process of thrombus formation in vivo. Like TNF-alpha and interleukin-1, CD40L on platelets induces endothelial cells to secrete chemokines and to express adhesion molecules, thereby generating signals for the recruitment and extravasation of leukocytes at the site of injury. Our results indicate that platelets are not only involved in haemostasis but that they also directly initiate an inflammatory response of the vessel wall.
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            Prediction of intravenous immunoglobulin unresponsiveness in patients with Kawasaki disease.

            In the present study, we developed models to predict unresponsiveness to intravenous immunoglobulin (IVIG) in Kawasaki disease (KD). We reviewed clinical records of 546 consecutive KD patients (development dataset) and 204 subsequent KD patients (validation dataset). All received IVIG for treatment of KD. IVIG nonresponders were defined by fever persisting beyond 24 hours or recrudescent fever associated with KD symptoms after an afebrile period. A 7-variable logistic model was constructed, including day of illness at initial treatment, age in months, percentage of white blood cells representing neutrophils, platelet count, and serum aspartate aminotransferase, sodium, and C-reactive protein, which generated an area under the receiver-operating-characteristics curve of 0.84 and 0.90 for the development and validation datasets, respectively. Using both datasets, the 7 variables were used to generate a simple scoring model that gave an area under the receiver-operating-characteristics curve of 0.85. For a cutoff of 0.15 or more in the logistic regression model and 4 points or more in the simple scoring model, sensitivity and specificity were 86% and 67% in the logistic model and 86% and 68% in the simple scoring model. The kappa statistic is 0.67, indicating good agreement between the logistic and simple scoring models. Our predictive models showed high sensitivity and specificity in identifying IVIG nonresponders among KD patients.
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              A single intravenous infusion of gamma globulin as compared with four infusions in the treatment of acute Kawasaki syndrome.

              Treatment of acute Kawasaki syndrome with a four-day course of intravenous gamma globulin, together with aspirin, has been demonstrated to be safe and effective in preventing coronary-artery lesions and reducing systemic inflammation. We hypothesized that therapy with a single, very high dose of gamma globulin would be at least as effective as the standard regimen. We conducted a multicenter, randomized, controlled trial involving 549 children with acute Kawasaki syndrome. The children were assigned to receive gamma globulin either as a single infusion of 2 g per kilogram of body weight over 10 hours or as daily infusions of 400 mg per kilogram for four consecutive days. Both treatment groups received aspirin (100 mg per kilogram per day through the 14th day of illness, then 3 to 5 mg per kilogram per day). The relative prevalence of coronary abnormalities, adjusted for age and sex, among patients treated with the four-day regimen, as compared with those treated with the single-infusion regimen, was 1.94 (95 percent confidence limits, 1.01 and 3.71) two weeks after enrollment and 1.84 (95 percent confidence limits, 0.89 and 3.82) seven weeks after enrollment. Children treated with the single-infusion regimen had lower mean temperatures while hospitalized (day 2, P less than 0.001; day 3, P = 0.004), as well as a shorter mean duration of fever (P = 0.028). Furthermore, in the single-infusion group the laboratory indexes of acute inflammation moved more rapidly toward normal, including the adjusted serum albumin level (P = 0.004), alpha 1-antitrypsin level (P = 0.007), and C-reactive protein level (P = 0.017). Lower IgG levels on day 4 were associated with a higher prevalence of coronary lesions (P = 0.005) and with a greater degree of systemic inflammation. The two groups had a similar incidence of adverse effects (including new or worsening congestive heart failure in nine children), which occurred in 2.7 percent of the children overall. All the adverse effects were transient. In children with acute Kawasaki disease, a single large dose of intravenous gamma globulin is more effective than the conventional regimen of four smaller daily doses and is equally safe.

                Author and article information

                0031-205662968 , s.m.dietz@amc.nl
                Eur J Pediatr
                Eur. J. Pediatr
                European Journal of Pediatrics
                Springer Berlin Heidelberg (Berlin/Heidelberg )
                27 June 2017
                27 June 2017
                : 176
                : 8
                : 995-1009
                [1 ]ISNI 0000000404654431, GRID grid.5650.6, Department of Pediatric Hematology, Immunology and Infectious Diseases, Emma Childrens Hospital, , Academic Medical Centre (AMC), ; Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands
                [2 ]ISNI 0000 0000 9442 535X, GRID grid.1058.c, , Murdoch Childrens Research Institute, ; Parkville, VIC Australia
                [3 ]ISNI 0000 0001 2179 088X, GRID grid.1008.9, Department of Pediatrics, , Melbourne University, ; Parkville, VIC Australia
                [4 ]ISNI 0000 0004 1936 7857, GRID grid.1002.3, Department of Pediatrics, , Monash University, ; Clayton, VIC Australia
                [5 ]ISNI 0000 0001 2113 8111, GRID grid.7445.2, Pediatric Infectious Diseases Group, Division of Medicine, , Imperial College London, ; London, UK
                [6 ]ISNI 0000000404654431, GRID grid.5650.6, Department of Pediatric Cardiology, Emma Childrens Hospital, , Academic Medical Centre (AMC), ; Amsterdam, The Netherlands
                [7 ]ISNI 0000000404654431, GRID grid.5650.6, Department of Clinical Epidemiology, Bioinformatics and Biostatistics, , AMC, ; Amsterdam, The Netherlands
                Author notes

                Communicated by Peter de Winter

                © The Author(s) 2017

                Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

                : 24 February 2017
                : 11 May 2017
                : 15 May 2017
                Funded by: Stichting Stinafo
                Funded by: Schumacher Kramer stichting
                Custom metadata
                © Springer-Verlag GmbH Germany 2017

                kawasaki disease,coronary artery aneurysms,intravenous immunoglobulins,genetics
                kawasaki disease, coronary artery aneurysms, intravenous immunoglobulins, genetics


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