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      Defining the risk of first intravenous immunoglobulin unresponsiveness in non-Asian patients with Kawasaki disease

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          Abstract

          About 10–20% of patients with Kawasaki disease (KD) are unresponsive to intravenous immunoglobulin (IVIg) and are at increased risk of coronary artery abnormalities (CAAs). Early identification is critical to initiate aggressive therapies, but available scoring systems lack sensitivity in non-Japanese populations. We investigated the accuracy of 3 Japanese scoring systems and studied factors associated with IVIg unresponsiveness in a large multiethnic French population of children with KD to build a new scoring system. Children admitted for KD between 2011–2014 in 65 centers were enrolled. Factors associated with second line-treatment; i.e. unresponsiveness to initial IVIg treatment, were analyzed by multivariate regression analysis. The performance of our score and the Kobayashi, Egami and Sano scores were compared in our population and in ethnic subgroups. Overall, 465 children were reported by 84 physicians; 425 were classified with KD (55% European Caucasian, 12% North African/Middle Eastern, 10% African/Afro-Caribbean, 3% Asian and 11% mixed). Eighty patients (23%) needed second-line treatment. Japanese scores had poor performance in our whole population (sensitivity 14–61%). On multivariate regression analysis, predictors of secondary treatment after initial IVIG were hepatomegaly, ALT level ≥30 IU/L, lymphocyte count <2400/mm 3 and time to treatment <5 days. The best sensitivity (77%) and specificity (60%) of this model was with 1 point per variable and cut-off ≥2 points. The sensitivity remained good in our 3 main ethnic subgroups (74–88%). We identified predictors of IVIg resistance and built a new score with good sensitivity and acceptable specificity in a non-Asian population.

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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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            Efficacy of immunoglobulin plus prednisolone for prevention of coronary artery abnormalities in severe Kawasaki disease (RAISE study): a randomised, open-label, blinded-endpoints trial.

            Evidence indicates that corticosteroid therapy might be beneficial for the primary treatment of severe Kawasaki disease. We assessed whether addition of prednisolone to intravenous immunoglobulin with aspirin would reduce the incidence of coronary artery abnormalities in patients with severe Kawasaki disease. We did a multicentre, prospective, randomised, open-label, blinded-endpoints trial at 74 hospitals in Japan between Sept 29, 2008, and Dec 2, 2010. Patients with severe Kawasaki disease were randomly assigned by a minimisation method to receive either intravenous immunoglobulin (2 g/kg for 24 h and aspirin 30 mg/kg per day) or intravenous immunoglobulin plus prednisolone (the same intravenous immunoglobulin regimen as the intravenous immunoglobulin group plus prednisolone 2 mg/kg per day given over 15 days after concentrations of C-reactive protein normalised). Patients and treating physicians were unmasked to group allocation. The primary endpoint was incidence of coronary artery abnormalities during the study period. Analysis was by intention to treat. This trial is registered with the University Hospital Medical Information Network clinical trials registry, number UMIN000000940. We randomly assigned 125 patients to the intravenous immunoglobulin plus prednisolone group and 123 to the intravenous immunoglobulin group. Incidence of coronary artery abnormalities was significantly lower in the intravenous immunoglobulin plus prednisolone group than in the intravenous immunoglobulin group during the study period (four patients [3%] vs 28 patients [23%]; risk difference 0·20, 95% CI 0·12-0·28, p<0·0001). Serious adverse events were similar between both groups: two patients had high total cholesterol and one neutropenia in the intravenous immunoglobulin plus prednisolone group, and one had high total cholesterol and another non-occlusive thrombus in the intravenous immunoglobulin group. Addition of prednisolone to the standard regimen of intravenous immunoglobulin improves coronary artery outcomes in patients with severe Kawasaki disease in Japan. Further study of intensified primary treatment for this disease in a mixed ethnic population is warranted. Japanese Ministry of Health, Labour and Welfare. Copyright © 2012 Elsevier Ltd. All rights reserved.
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              Prediction of resistance to intravenous immunoglobulin treatment in patients with Kawasaki disease.

              The objective of this study was to find the predictors and generate a prediction score of resistance to intravenous immunoglobulin (IVIG) in patients with Kawasaki disease (KD). Patients diagnosed as having KD were sampled when they received initial high-dose IVIG treatment (2 g/kg dose) within 9 days of illness (n = 320). These patients were divided into 2 groups: the resistance (n = 41) and the responder (n = 279). The following data were obtained and compared between resistance and responder: age, sex, illness days at initial treatment, and laboratory data. Multivariate logistic regression analysis identified age, illness days, platelet count, alanine aminotransferase (ALT), and C-reactive protein (CRP) as significant predictors for resistance to IVIG. We generated prediction score assigning 1 point for (1) infants less than 6 months old, (2) before 4 days of illness, (3) platelet count or= 8 mg/dL, as well as 2 points for (5) ALT >or= 80 IU/L. Using a cut-off point of 3 and more with this prediction score, we could identify the IVIG-resistant group with 78% sensitivity and 76% specificity. Resistance to IVIG treatment can be predicted using age, illness days, platelet count, ALT, and CRP. Randomized, multicenter clinical trials are necessary to create a new strategy to treat these high-risk patients.
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                Author and article information

                Contributors
                maryam.piram@aphp.fr
                Journal
                Sci Rep
                Sci Rep
                Scientific Reports
                Nature Publishing Group UK (London )
                2045-2322
                20 February 2020
                20 February 2020
                2020
                : 10
                : 3125
                Affiliations
                [1 ]Université Paris-Saclay, Univ. Paris-Sud, UVSQ, CESP, Inserm, 1018 Le Kremlin Bicêtre, France
                [2 ]ISNI 0000 0001 2181 7253, GRID grid.413784.d, AP-HP, CHU de Bicêtre, Pediatric Rheumatology, CEREMAIA, ; Le Kremlin Bicêtre, France
                [3 ]ISNI 0000 0001 1457 2980, GRID grid.411175.7, CHU de de Toulouse, Paediatric Rheumatology, Nephrology and Internal medicine, ; Toulouse, France
                [4 ]ISNI 0000 0001 2163 3825, GRID grid.413852.9, Hospices civils de Lyon, Cardiology, ; Lyon, France
                [5 ]ISNI 0000 0004 0593 7118, GRID grid.42399.35, CHU de Bordeaux, Dermatology, ; Bordeaux, France
                [6 ]ISNI 0000 0004 1765 2136, GRID grid.414145.1, CHIC, Paediatrics, ; Créteil, France
                [7 ]ISNI 0000 0001 2175 4109, GRID grid.50550.35, APHP, CHU Robert Debré, Paediatrics,Paediatric Internal Medicine,Rheumatology and Infectious Diseases, RAISE, ; Paris, France
                [8 ]ISNI 0000 0004 1757 2822, GRID grid.4708.b, Department of Clinical Sciences and Community Health, University of Milan, ; Milan, Italy
                [9 ]ISNI 0000 0001 2181 7253, GRID grid.413784.d, APHP, CHU de Bicêtre, Clinical Research Unit, ; Le Kremlin Bicêtre, France
                Author information
                http://orcid.org/0000-0001-6816-5272
                Article
                59972
                10.1038/s41598-020-59972-7
                7033244
                32080307
                2fdf7c68-9641-47fa-97a4-be8840cf63ed
                © The Author(s) 2020

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as 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. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 2 April 2019
                : 27 January 2020
                Funding
                Funded by: French Ministry of Health (PHRC) Societe française de Rhumatologie
                Categories
                Article
                Custom metadata
                © The Author(s) 2020

                Uncategorized
                paediatric rheumatic diseases,vasculitis syndromes
                Uncategorized
                paediatric rheumatic diseases, vasculitis syndromes

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