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      A novel score system of blood tests for differentiating Kawasaki disease from febrile children

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          Abstract

          Background

          Kawasaki disease is the most common cause of acquired heart disease among febrile children under the age of 5 years old. It is also a clinically diagnosed disease. In this study, we developed and assessed a novel score system using objective parameters to differentiate Kawasaki disease from febrile children.

          Methods

          We analyzed 6,310 febrile children and 485 Kawasaki disease subjects in this study. We collected biological parameters of a routine blood test, including complete blood count with differential, C-reactive protein, aspartate aminotransferase, and alanine aminotransferase. Receiver operating characteristic curve, logistic regression, and Youden’s index were all used to develop the prediction model. Two other independent cohorts from different hospitals were used for verification.

          Results

          We obtained eight independent predictors (platelets, eosinophil, alanine aminotransferase, C-reactive protein, hemoglobin, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration, and monocyte) and found the top three scores to be eosinophil >1.5% (score: 7), alanine aminotransferase >30 U/L (score: 6), and C-reactive protein>25 mg/L (score: 6). A score of 14 represents the best sensitivity value plus specificity prediction rate for Kawasaki disease. The sensitivity, specificity, and accuracy for our cohort were 0.824, 0.839, and 0.838, respectively. The verification test of two independent cohorts of Kawasaki disease patients (N = 103 and 170) from two different institutes had a sensitivity of 0.780 (213/273).

          Conclusion

          Our findings demonstrate a novel score system with good discriminatory ability for differentiating between children with Kawasaki disease and other febrile children, as well as highlight the importance of eosinophil in Kawasaki disease. Using this novel score system can help first-line physicians diagnose and then treat Kawasaki disease early.

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          Most cited references43

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          Diagnosis, Treatment, and Long-Term Management of Kawasaki Disease: A Scientific Statement for Health Professionals From the American Heart Association

          Kawasaki disease is an acute vasculitis of childhood that leads to coronary artery aneurysms in ≈25% of untreated cases. It has been reported worldwide and is the leading cause of acquired heart disease in children in developed countries.
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            Diagnosis, Treatment, and Long-Term Management of Kawasaki Disease: A Statement for Health Professionals From the Committee on Rheumatic Fever, Endocarditis and Kawasaki Disease, Council on Cardiovascular Disease in the Young, American Heart Association

            Kawasaki disease is an acute self-limited vasculitis of childhood that is characterized by fever, bilateral nonexudative conjunctivitis, erythema of the lips and oral mucosa, changes in the extremities, rash, and cervical lymphadenopathy. Coronary artery aneurysms or ectasia develop in approximately 15% to 25% of untreated children and may lead to ischemic heart disease or sudden death. A multidisciplinary committee of experts was convened to revise the American Heart Association recommendations for diagnosis, treatment, and long-term management of Kawasaki disease. The writing group proposes a new algorithm to aid clinicians in deciding which children with fever for > or =5 days and < or =4 classic criteria should undergo echocardiography, receive intravenous gamma globulin (IVIG) treatment, or both for Kawasaki disease. The writing group reviews the available data regarding the initial treatment for children with acute Kawasaki disease, as well for those who have persistent or recrudescent fever despite initial therapy with IVIG, including IVIG retreatment and treatment with corticosteroids, tumor necrosis factor-alpha antagonists, and abciximab. Long-term management of patients with Kawasaki disease is tailored to the degree of coronary involvement; recommendations regarding antiplatelet and anticoagulant therapy, physical activity, follow-up assessment, and the appropriate diagnostic procedures to evaluate cardiac disease are classified according to risk strata. Recommendations for the initial evaluation, treatment in the acute phase, and long-term management of patients with Kawasaki disease are intended to assist physicians in understanding the range of acceptable approaches for caring for patients with Kawasaki disease. The ultimate decisions for case management must be made by physicians in light of the particular conditions presented by individual patients.
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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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                Author and article information

                Contributors
                Role: Formal analysisRole: InvestigationRole: MethodologyRole: ValidationRole: Writing – original draft
                Role: Data curationRole: InvestigationRole: MethodologyRole: SoftwareRole: Validation
                Role: MethodologyRole: ResourcesRole: Validation
                Role: MethodologyRole: ResourcesRole: Validation
                Role: Data curationRole: Formal analysisRole: Investigation
                Role: ConceptualizationRole: Data curationRole: Formal analysisRole: InvestigationRole: Project administrationRole: Writing – original draft
                Role: ConceptualizationRole: Funding acquisitionRole: ResourcesRole: SupervisionRole: Writing – review & editing
                Role: Editor
                Journal
                PLoS One
                PLoS One
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                22 January 2021
                2021
                : 16
                : 1
                : e0244721
                Affiliations
                [1 ] Department of Pediatrics, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
                [2 ] Department of Statistics, National Cheng Kung University, Tainan, Taiwan
                [3 ] Department of Pediatrics, Baoan Women's and Children's Hospital, Jinan University, Shenzhen, China
                [4 ] Department of Pediatrics, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan
                [5 ] Faculty of Medicine, National Yang-Ming University, Taipei, Taiwan
                [6 ] Department of Respiratory Therapy, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan
                [7 ] Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine, Kaohsiung Chang Gung Memorial Hospital, and Chang Gung University College of Medicine, Kaohsiung, Taiwan
                [8 ] Kawasaki Disease Center, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan
                Oregon State University, UNITED STATES
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Author information
                https://orcid.org/0000-0001-5267-9594
                https://orcid.org/0000-0002-7883-377X
                Article
                PONE-D-20-24219
                10.1371/journal.pone.0244721
                7822339
                33481812
                7e684a2a-d83e-4689-9022-fb5bbecb2a9a
                © 2021 Tsai et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 6 August 2020
                : 2 December 2020
                Page count
                Figures: 2, Tables: 5, Pages: 13
                Funding
                Funded by: funder-id http://dx.doi.org/10.13039/501100004663, Ministry of Science and Technology, Taiwan;
                Award ID: MOST 108-2314-B-182 -037 -MY3
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/501100004663, Ministry of Science and Technology, Taiwan;
                Award ID: MOST 103-2410-H-264-004
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/100012553, Chang Gung Memorial Hospital;
                Award ID: 8E0212
                Award Recipient :
                This study received funding from the following grants: MOST 108-2314-B-182 -037 -MY3 and MOST 103-2410-H-264-004 from the Ministry of Science and Technology of Taiwan and 8E0212 from Chang Gung Memorial Hospital, Taiwan. Although these institutes provided financial support, they had no influence on the way in which we collected, analyzed, or interpreted the data or wrote this manuscript.
                Categories
                Research Article
                Biology and Life Sciences
                Cell Biology
                Cellular Types
                Animal Cells
                Blood Cells
                White Blood Cells
                Eosinophils
                Biology and Life Sciences
                Cell Biology
                Cellular Types
                Animal Cells
                Immune Cells
                White Blood Cells
                Eosinophils
                Biology and Life Sciences
                Immunology
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                Eosinophils
                Medicine and Health Sciences
                Immunology
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                Medicine and Health Sciences
                Clinical Medicine
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                Autoimmune Diseases
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