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Paolini L, Guida F, Calvaruso A, Andreozzi L, Pierantoni L, Lanari M, Fabi M. Endothelial Dysfunction: Molecular Mechanisms and Therapeutic Strategies in Kawasaki Disease. Int J Mol Sci 2024; 25:13322. [PMID: 39769085 PMCID: PMC11676170 DOI: 10.3390/ijms252413322] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2024] [Revised: 11/30/2024] [Accepted: 12/06/2024] [Indexed: 01/11/2025] Open
Abstract
The endothelium plays a key role in regulating vascular homeostasis by responding to a large spectrum of chemical and physical stimuli. Vasculitis is a group of inflammatory conditions affecting the vascular bed, and it is known that they are strongly linked to endothelial dysfunction (ED). Kawasaki disease (KD) is one childhood systemic vasculitis, and it represents the leading cause of acquired cardiac disease in children due to coronary damage and subsequent cardiovascular (CV) morbidity and mortality. We aimed to focus on the actual knowledge of ED in the pathogenesis of KD and its practical implications on therapeutical strategies to limit cardiovascular complications. Understanding ED in KD provides insight into the underlying mechanisms and identifies potential therapeutic targets to mitigate vascular damage, ultimately improving cardiovascular outcomes in both the acute and chronic stages of the disease. However, research gaps remain, particularly in translating findings from animal models into clinical applications for cardiovascular lesions and related morbidity in KD patients.
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Affiliation(s)
- Lucia Paolini
- Specialty School of Paediatrics, Alma Mater Studiorum, University of Bologna, 40139 Bologna, Italy; (L.P.); (A.C.)
| | - Fiorentina Guida
- Pediatric Emergency Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40139 Bologna, Italy; (F.G.); (L.A.); (L.P.); (M.L.)
| | - Antonino Calvaruso
- Specialty School of Paediatrics, Alma Mater Studiorum, University of Bologna, 40139 Bologna, Italy; (L.P.); (A.C.)
| | - Laura Andreozzi
- Pediatric Emergency Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40139 Bologna, Italy; (F.G.); (L.A.); (L.P.); (M.L.)
| | - Luca Pierantoni
- Pediatric Emergency Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40139 Bologna, Italy; (F.G.); (L.A.); (L.P.); (M.L.)
| | - Marcello Lanari
- Pediatric Emergency Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40139 Bologna, Italy; (F.G.); (L.A.); (L.P.); (M.L.)
- Department of Medical and Surgical Sciences, Alma Mater Studiorum, University of Bologna, 40139 Bologna, Italy
| | - Marianna Fabi
- Pediatric Emergency Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40139 Bologna, Italy; (F.G.); (L.A.); (L.P.); (M.L.)
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Gu W, Mirsaidi-Madjdabadi S, Ramirez F, Simonson TS, Makino A. Transcriptome meta-analysis of Kawasaki disease in humans and mice. Front Pediatr 2024; 12:1423958. [PMID: 39350793 PMCID: PMC11440715 DOI: 10.3389/fped.2024.1423958] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/26/2024] [Accepted: 08/29/2024] [Indexed: 10/04/2024] Open
Abstract
Kawasaki Disease (KD) affects young children less than five years old with severe blood vessel inflammation. Despite being treatable, the causes and mechanisms remain elusive. This study conducted a meta-analysis of RNA sequencing (RNA-seq) data from human and animal models to explore KD's transcriptomic profile and evaluate animal models. We retrieved bulk and single-cell RNA-seq data from Gene Expression Omnibus, with blood and coronary artery samples from KD patients, aorta samples from KD mouse models (Lactobacillus casei cell wall extract-injected mice), and their controls. Upon consistent quality control, we applied Fisher's exact test to assess differential gene expression, followed by an enrichment analysis of overlapping genes. These studies identified 400 differentially expressed genes in blood samples of KD patients compared to controls and 413 genes in coronary artery samples. The data from KD blood and KD coronary artery samples shared only 16 differentially expressed genes. Eighty-one genes overlapped between KD human coronary arteries and KD mouse aortas, and 67 of these 81 genes were regulated in parallel in both humans and mice: 30 genes were up-regulated, and 37 were down-regulated. These included previously identified KD-upregulated genes: CD74, SFRP4, ITGA4, and IKZF1. Gene enrichment analysis revealed significant alterations in the cardiomyopathy pathway. Single-cell RNAseq showed a few significant markers, with known KD markers like S100A9, S100A8, CD74, CD14, IFITM2, and IFITM3, being overexpressed in KD cohorts. Gene profiles obtained from KD human coronary artery are more compatible with data from aorta samples of KD mice than blood samples of KD humans, validating KD animal models for identifying therapeutic targets. Although blood samples can be utilized to discover novel biomarkers, more comprehensive single-cell sequencing is required to detail gene expression in different blood cell populations. This study identifies critical genes from human and mouse tissues to help develop new treatment strategies for KD.
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Affiliation(s)
- Wanjun Gu
- Department of Medicine, University of California, San Diego, CA, United States
| | | | - Francisco Ramirez
- Department of Medicine, University of California, San Diego, CA, United States
- Center for Inflammation Science and Systems Medicine, The Herbert Wertheim University of Florida Scripps Institute for Biomedical Innovation & Technology, Jupiter, FL, United States
| | - Tatum S. Simonson
- Department of Medicine, University of California, San Diego, CA, United States
| | - Ayako Makino
- Department of Medicine, University of California, San Diego, CA, United States
- Center for Inflammation Science and Systems Medicine, The Herbert Wertheim University of Florida Scripps Institute for Biomedical Innovation & Technology, Jupiter, FL, United States
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Wang Y, Chen X, Zhang D, Chen R, Alifu A. Whole-exome sequencing reveals Kawasaki disease susceptibility genes and their association with coronary artery lesion. Front Pediatr 2024; 12:1400123. [PMID: 39318622 PMCID: PMC11420030 DOI: 10.3389/fped.2024.1400123] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/13/2024] [Accepted: 08/27/2024] [Indexed: 09/26/2024] Open
Abstract
Objective This study aimed to explore Kawasaki disease (KD) susceptibility genes and their complications like coronary artery lesions (CAL) using whole exome sequencing (WES). Methods Between April 1, 2021, and December 31, 2022, our study included 55 pediatric patients diagnosed KD at our center, alongside a cohort of healthy children who sought medical care at our institution during the same timeframe. We extracted peripheral blood DNA from all participants and employed the advanced high-throughput Illumina Next-Generation Sequencing technology for comprehensive analysis. Through bioinformatics evaluation, we identified potential susceptibility genes. Moreover, from the 55 KD patients, we selected 15 for the CAL group and 40 for the non-CAL group. We aimed to investigate whether there were significant differences in the allele frequencies of the targeted susceptibility genes between these subgroups, to explore the risk alleles associated with the development of CAL in KD. Results HLA-DRB1 rs17882084 and IL6ST rs781455079 genotypes and alleles differed significantly between KD and non-KD (P < 0.05). No differences existed for IL17RC rs143781415 and VEGFB rs776229557 (P > 0.05). No differences in HLA-DRB1 rs17882084, IL6ST rs781455079, and VEGFB rs776229557 genotypes existed between CAL and non-CAL groups (P > 0.05). However, the IL17RC rs143781415 genotype differed significantly between them (P < 0.05). Conclusions HLA-DRB1 rs17882084 and IL6ST rs781455079 genotypes may be potential KD susceptibility gene candidates. Specifically, HLA-DRB1 rs17882084 GA genotype and A allele, and IL6ST rs781455079 TC genotype and C allele may increase KD risk. Additionally, the IL17RC rs143781415 genotype may increase CAL risk in KD patients.
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Affiliation(s)
- Yazhou Wang
- Department of Pediatric Vasculocardiology, Hainan Women and Children’s Medical Center, Haikou, China
| | - Xuepeng Chen
- Department of Pediatric Vasculocardiology, Hainan Women and Children’s Medical Center, Haikou, China
| | - Dufei Zhang
- Department of Pediatric Vasculocardiology, Hainan Women and Children’s Medical Center, Haikou, China
| | - Renwei Chen
- Department of Cardiothoracic Surgery, Hainan Women and Children’s Medical Center, Haikou, China
| | - Ailixiati Alifu
- Department of Cardiothoracic Surgery, Hainan Women and Children’s Medical Center, Haikou, China
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Rigante D, De Rosa G, Delogu AB, Rotunno G, Cianci R, Di Pangrazio C, Sodero G, Basile U, Candelli M. Hypovitaminosis D and Leukocytosis to Predict Cardiovascular Abnormalities in Children with Kawasaki Disease: Insights from a Single-Center Retrospective Observational Cohort Study. Diagnostics (Basel) 2024; 14:1228. [PMID: 38928644 PMCID: PMC11202909 DOI: 10.3390/diagnostics14121228] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2024] [Revised: 06/07/2024] [Accepted: 06/11/2024] [Indexed: 06/28/2024] Open
Abstract
Introduction: An aberrant immune response involving yet unidentified environmental and genetic factors plays a crucial role in triggering Kawasaki disease (KD). Aims: The aim of this study was to assess general and laboratory data at the onset of KD in a single-center cohort of children managed between 2003 and 2023 and retrospectively evaluate any potential relationship with the development of KD-related cardiovascular abnormalities (CVAs). Patients and methods: We took into account a total of 65 consecutive children with KD (42 males, median age: 22 months, age range: 2-88 months) followed at the Department of Life Sciences and Public Health in our University; demographic data, clinical signs, and laboratory variables at disease onset, before IVIG infusion, including C-reactive protein, hemoglobin, white blood cell (WBC) count, neutrophil count, platelet count, aminotransferases, natremia, albumin, total bilirubin, and 25-hydroxyvitamin D were evaluated. Results: Twenty-one children (32.3% of the whole cohort) were found to have echocardiographic evidence of CVAs. Univariate analysis showed that diagnosis of KD at <1 year or >5 years was associated with CVAs (p = 0.001 and p = 0.01, respectively); patients with CVAs had a longer fever duration and mostly presented atypical or incomplete presentations. Interestingly, all patients with CVAs had lower levels of vitamin D (less than 30 mg/dL, p = 0.0001) and both higher WBC and higher neutrophil counts than those without CVAs (p = 0.0001 and p = 0.01, respectively). Moreover, blood levels of albumin were significantly lower in KD patients with CVAs compared to those without (11/21, 52% versus 13/44, 30%, p = 0.02). Multiple logistic regression with correction for sex showed that serum vitamin D < 30 ng/mL, WBC count > 20.000/mm3, and age > 60 months at KD onset were the only independent factors statistically associated with CVAs. Conclusions: Hypovitaminosis D, WBC count over 20.000/mm3, and age above 5 years at KD onset emerged as independent factors statistically associated with the occurrence of CVAs.
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Affiliation(s)
- Donato Rigante
- Department of Life Sciences and Public Health, Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Rome, Italy
- Department of Pediatrics, Università Cattolica Sacro Cuore, 00168 Rome, Italy
| | - Gabriella De Rosa
- Department of Life Sciences and Public Health, Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Rome, Italy
- Department of Pediatrics, Università Cattolica Sacro Cuore, 00168 Rome, Italy
| | - Angelica Bibiana Delogu
- Department of Life Sciences and Public Health, Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Rome, Italy
- Department of Pediatrics, Università Cattolica Sacro Cuore, 00168 Rome, Italy
| | - Giulia Rotunno
- Department of Life Sciences and Public Health, Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Rome, Italy
| | - Rossella Cianci
- Department of Pediatrics, Università Cattolica Sacro Cuore, 00168 Rome, Italy
- Department of Translational Medicine and Surgery, Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Rome, Italy
| | - Claudia Di Pangrazio
- Department of Life Sciences and Public Health, Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Rome, Italy
| | - Giorgio Sodero
- Department of Life Sciences and Public Health, Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Rome, Italy
| | - Umberto Basile
- Department of Clinical Pathology, Santa Maria Goretti Hospital, 04100 Latina, Italy
| | - Marcello Candelli
- Department of Emergency Anesthesiological and Reanimation Sciences, Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Rome, Italy;
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Xiong Y, Xu J, Zhang D, Wu S, Li Z, Zhang J, Xia Z, Xia P, Xia C, Tang X, Liu X, Liu J, Yu P. MicroRNAs in Kawasaki disease: An update on diagnosis, therapy and monitoring. Front Immunol 2022; 13:1016575. [PMID: 36353615 PMCID: PMC9638168 DOI: 10.3389/fimmu.2022.1016575] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2022] [Accepted: 09/30/2022] [Indexed: 08/15/2023] Open
Abstract
Kawasaki disease (KD) is an acute autoimmune vascular disease featured with a long stage of febrile. It predominantly afflicts children under 5 years old and causes an increased risk of cardiovascular combinations. The onset and progression of KD are impacted by many aspects, including genetic susceptibility, infection, and immunity. In recent years, many studies revealed that miRNAs, a novel class of small non-coding RNAs, may play an indispensable role in the development of KD via differential expression and participation in the central pathogenesis of KD comprise of the modulation of immunity, inflammatory response and vascular dysregulation. Although specific diagnose criteria remains unclear up to date, accumulating clinical evidence indicated that miRNAs, as small molecules, could serve as potential diagnostic biomarkers and exhibit extraordinary specificity and sensitivity. Besides, miRNAs have gained attention in affecting therapies for Kawasaki disease and providing new insights into personalized treatment. Through consanguineous coordination with classical therapies, miRNAs could overcome the inevitable drug-resistance and poor prognosis problem in a novel point of view. In this review, we systematically reviewed the existing literature and summarized those findings to analyze the latest mechanism to explore the role of miRNAs in the treatment of KD from basic and clinical aspects retrospectively. Our discussion helps to better understand the pathogenesis of KD and may offer profound inspiration on KD diagnosis, treatment, and prognosis.
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Affiliation(s)
- Yiyi Xiong
- The Second Clinical Medical College of Nanchang University, The Second Affiliated Hospital of Nanchang University, Nanchang, China
| | - Jiawei Xu
- The Second Clinical Medical College of Nanchang University, The Second Affiliated Hospital of Nanchang University, Nanchang, China
| | - Deju Zhang
- Food and Nutritional Sciences, School of Biological Sciences, The University of Hong Kong, Hong Kong, Hong Kong SAR, China
| | - Shuqin Wu
- The Second Clinical Medical College of Nanchang University, The Second Affiliated Hospital of Nanchang University, Nanchang, China
| | - Zhangwang Li
- The Second Clinical Medical College of Nanchang University, The Second Affiliated Hospital of Nanchang University, Nanchang, China
| | - Jing Zhang
- Department of Anesthesiology, The Second Affiliated Hospital of Nanchang University, Nanchang, China
| | - Zhongbin Xia
- The Second Clinical Medical College of Nanchang University, The Second Affiliated Hospital of Nanchang University, Nanchang, China
| | - Panpan Xia
- Department of Anesthesiology, The Second Affiliated Hospital of Nanchang University, Nanchang, China
| | - Cai Xia
- Department of Endocrinology and Metabolism, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
| | - Xiaoyi Tang
- Department of Anesthesiology, The Second Affiliated Hospital of Nanchang University, Nanchang, China
| | - Xiao Liu
- Department of Cardiology, The Second Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Jianping Liu
- The Second Clinical Medical College of Nanchang University, The Second Affiliated Hospital of Nanchang University, Nanchang, China
- Department of Endocrinology and Metabolism, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
| | - Peng Yu
- The Second Clinical Medical College of Nanchang University, The Second Affiliated Hospital of Nanchang University, Nanchang, China
- Department of Endocrinology and Metabolism, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
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Song S, Chen L, Ning Q, Zhu D, Qiu F, Li G, Zhang H, Xiao T, Ding G, Huang M. eQTL Highlights the Potential Role of Negative Control of Innate Immunity in Kawasaki Disease. Int J Gen Med 2022; 15:837-848. [PMID: 35125885 PMCID: PMC8807868 DOI: 10.2147/ijgm.s343225] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2021] [Accepted: 01/11/2022] [Indexed: 11/23/2022] Open
Abstract
Purpose Kawasaki disease (KD) is an acute systemic vasculitis mainly found in the medium-sized arteries, especially the coronary arteries. Immune system is involved in the pathogenesis of acute KD in children, but the functional differences in the immune system between healthy children and KD patients remain unclear. Patients and Methods A total of 190 KD patients and 119 healthy controls were recruited for the next-generation sequencing of 512 targeted genes from 4 immune-related pathways. Subsequently, the peripheral blood mononuclear cells (PBMCs) were isolated. RNA sequencing of the LPS treated PBMCs from additional 20 KD patients and 20 healthy controls was used to examine the differentially expressed genes (DEGs). Then, an expression quantitative trait locus (eQTL) analysis combined with previously analyzed RNA data were used to examine the DEGs. Finally, the serum levels of 13 cytokines were detected before and after LPS treatment in 40 samples to confirm the findings from eQTL analysis. Results A total of 319 significant eQTL were found, and both eQTL analysis and RNA sequencing showed some DEGs were involved in the connective tissue disorders and inflammatory diseases. DEGs that function to negatively regulate immunity were closely related to the pathogenesis of KD. In addition, the serum levels of IL-10 (an inflammatory and immunosuppressive factor) and SCD25 (an important immunosuppressant) reduced significantly in the KD patients. Conclusion Our study shows the expression of factors responsible for the negative control of innate immunity is altered, which plays an important role in the etiology of KD.
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Affiliation(s)
- Sirui Song
- Department of Cardiology, Shanghai Children’s Hospital, Shanghai Jiao Tong University, Shanghai, People’s Republic of China
| | - Liqin Chen
- Department of Cardiology, Shanghai Children’s Hospital, Shanghai Jiao Tong University, Shanghai, People’s Republic of China
| | - Qianqian Ning
- Shanghai Center for Bioinformation Technology, Shanghai, People’s Republic of China
| | - Danying Zhu
- Department of Cardiology, Shanghai Children’s Hospital, Shanghai Jiao Tong University, Shanghai, People’s Republic of China
| | - Feng Qiu
- Shanghai Center for Bioinformation Technology, Shanghai, People’s Republic of China
| | - Guang Li
- Shanghai Center for Bioinformation Technology, Shanghai, People’s Republic of China
| | - Hong Zhang
- Department of Laboratory, Shanghai Children’s Hospital, Shanghai Jiao Tong University, Shanghai, People’s Republic of China
| | - Tingting Xiao
- Department of Cardiology, Shanghai Children’s Hospital, Shanghai Jiao Tong University, Shanghai, People’s Republic of China
| | - Guohui Ding
- International Human Phenome Institutes, Shanghai, 200235, People’s Republic of China
- Guohui Ding, International Human Phenome Institutes, Shanghai, 200235, People’s Republic of China, Email
| | - Min Huang
- Department of Cardiology, Shanghai Children’s Hospital, Shanghai Jiao Tong University, Shanghai, People’s Republic of China
- Correspondence: Min Huang, Department of Cardiology, Shanghai Children’s Hospital, Shanghai Jiao Tong University, Shanghai, People’s Republic of China, Email
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Refractory Kawasaki Disease—a Challenge for the Pediatrician. SN COMPREHENSIVE CLINICAL MEDICINE 2021; 3:855-860. [PMID: 33532696 PMCID: PMC7843002 DOI: 10.1007/s42399-021-00775-w] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Accepted: 01/20/2021] [Indexed: 10/27/2022]
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Abstract
Kawasaki disease (KD) is a medium vessel vasculitis that affects young children. Despite extensive research over the last 50 years, the etiology of KD remains an enigma. Seasonal change in wind patterns was shown to have correlation with the epidemics of KD in Japan. Occurrence of disease in epidemiological clusters, seasonal variation, and a very low risk of recurrence suggest that KD is triggered by an infectious agent. The identification of oligoclonal IgA response in the affected tissues suggests an antigen-driven inflammation. The recent identification of a viral antigen in the cytoplasm of bronchial ciliated epithelium also favors infection as the main trigger for KD. Pointers that suggest a genetic basis of KD include a high disease prevalence in North-East Asian populations, a high risk among siblings, and familial occurrence of cases. Dysregulated innate and adaptive immune responses are evident in the acute stages of KD. In addition to the coronary wall inflammation, endothelial dysfunction and impaired vascular remodeling contribute to the development of coronary artery abnormalities (CAAs) and thrombosis. Genetic aberrations in certain intracellular signaling pathways involving immune effector functions are found to be associated with increased susceptibility to KD and development of coronary artery abnormalities (CAAs). Several susceptible genes have been identified through genome-wide association studies (GWAS) and linkage studies (GWLS). The genes that are studied in KD can be classified under 4 major groups-enhanced T cell activation (ITPKC, ORAI1, STIM1), dysregulated B cell signaling (CD40, BLK, FCGR2A), decreased apoptosis (CASP3), and altered transforming growth factor beta signaling (TGFB2, TGFBR2, MMP, SMAD). The review aims to highlight the role of several genetic risk factors that are linked with the increased susceptibility to KD.
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Affiliation(s)
- Rajni Kumrah
- Pediatric Allergy Immunology Unit, Department of Pediatrics, Advanced Pediatrics Centre, Postgraduate Institute of Medical Education and Research, Chandigarh, 160012, India
| | - Pandiarajan Vignesh
- Pediatric Allergy Immunology Unit, Department of Pediatrics, Advanced Pediatrics Centre, Postgraduate Institute of Medical Education and Research, Chandigarh, 160012, India.
| | - Amit Rawat
- Pediatric Allergy Immunology Unit, Department of Pediatrics, Advanced Pediatrics Centre, Postgraduate Institute of Medical Education and Research, Chandigarh, 160012, India
| | - Surjit Singh
- Pediatric Allergy Immunology Unit, Department of Pediatrics, Advanced Pediatrics Centre, Postgraduate Institute of Medical Education and Research, Chandigarh, 160012, India
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Lan Y, Li S, Yang D, Zhou J, Wang Y, Wang J, Xu Y, Chen Z. Clinical characteristics of Kawasaki disease complicated with Mycoplasma pneumoniae pneumonia: A retrospective study. Medicine (Baltimore) 2020; 99:e19987. [PMID: 32384451 PMCID: PMC7220055 DOI: 10.1097/md.0000000000019987] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
This study aimed to investigate the inner linkage and mechanism of Mycoplasma pneumoniae (MP) infection and Kawasaki disease (KD), as well as the risk factors of outcome in this cohort of patients.A retrospective study was performed in 210 patients diagnosed with KD complicated with community acquired pneumonia (CAP) in Children's Hospital, Zhejiang University School of Medicine from January 2014 to December 2017. They were divided into two groups based on MP infection: MP infection group (n = 97) and non-MP infection group (n = 113). We compared the variables of these two groups based on medical records.The MP infection group had higher ESR than the non-MP infection group. During hospitalization, the non-MP infection group had higher levels of WBC during hospital, LDH, PCT, and lower HB when compared to the MP infection group. No differences were found in the hs-CRP level, N%, PLT, ALT, CKMB, and cytokine levels (IL-2, IL-4, IL-6, IL-10, TNF-α, and IFN-γ) between MP and non-MP infection group. Likewise, no difference was found in fever duration or hospital stays between them. Totally 19 patients in the infection group had CAA with a rate of 19.59%; and 27 (23.89%) patients had CAA in the non-MP infection group. Unfortunately, no difference was found in CAA rate between the two groups.MP infection may occur simultaneously in children with Kawasaki disease. KD patients with MP infection tended to occur in older population. MP infection may not increase the risk of CAA, which still needs further large-scaled studies to confirm. Clinicians should be alert to KD patients with high level of ESR. MP should be screened and early treatment with macrolides should be given timely.
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Affiliation(s)
- Yinle Lan
- Department of Pulmonology, The Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, Zhejiang
| | - Shuxian Li
- Department of Pulmonology, The Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, Zhejiang
| | - Dehua Yang
- Department of Pulmonology, The Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, Zhejiang
| | - Junfen Zhou
- Department of Pulmonology, The Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, Zhejiang
- Department of Pediatrics, Wenling Maternal and Child Health Care Hospital, Wenling, Zhejiang, China
| | - Yingshuo Wang
- Department of Pulmonology, The Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, Zhejiang
| | - Jianhua Wang
- Department of Pulmonology, The Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, Zhejiang
| | - Yingchun Xu
- Department of Pulmonology, The Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, Zhejiang
| | - Zhimin Chen
- Department of Pulmonology, The Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, Zhejiang
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Kawasaki Disease following administration of 13-valent pneumococcal conjugate vaccine in young children. Sci Rep 2019; 9:14705. [PMID: 31604998 PMCID: PMC6788987 DOI: 10.1038/s41598-019-51137-5] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2019] [Accepted: 09/23/2019] [Indexed: 11/08/2022] Open
Abstract
Kawasaki disease (KD) is a systemic vasculitis mainly affecting young children and the leading cause of acquired heart disease in developed countries. We performed a self-controlled case series analysis to investigate the association between PCV13 and KD. All hospitalized KD cases <2 y old from our hospital in Singapore from 2010 to 2014 were included. Complete KD cases were classified based on the definitions of the American Heart Association. During the study period, 288 KD cases were identified. A total of 21 KD cases (12 were classified as Complete KD) had date of onset within the risk interval of day 1 to day 28 post PCV13. The age-adjusted Relative Incidence (RI) for KD following PCV13 dose 1, dose 2 and dose 3 were 1.40 (95%CI, 0.72 to 2.71), 1.23 (95% CI, 0.62 to 2.44) and 0.34 (95% CI, 0.08 to 1.40) respectively. There were seven Complete KD cases with onset during the risk interval after dose 1 of PCV13 (age-adjusted RI 2.59, 95%confidence interval (CI), 1.16 to 5.81). We did not detect a significant increased risk for overall KD among PCV13 recipients. However, a significant association between PCV13 and Complete KD was noted following receipt of the first dose of PCV13.
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Song MS. Predictors and management of intravenous immunoglobulin-resistant Kawasaki disease. KOREAN JOURNAL OF PEDIATRICS 2019; 62:119-123. [PMID: 30999718 PMCID: PMC6477551 DOI: 10.3345/kjp.2019.00150] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 02/13/2019] [Accepted: 03/13/2019] [Indexed: 02/07/2023]
Abstract
Kawasaki disease (KD) is a systemic vasculitis that mainly affects younger children. Intravenous immunoglobulin (IVIG) resistant cases are at increasing risk for coronary artery complications. The strategy on prediction of potential nonresponders and treatment of IVIG-resistant patients is now controversial. In this review the definition and predictors of IVIG-resistant KD and current evidence to guide management are discussed.
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Affiliation(s)
- Min Seob Song
- Department of Pediatrics, Inje University Haeundae Paik Hospital, Inje University College of Medicine, Busan, Korea
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Marchesi A, Tarissi de Jacobis I, Rigante D, Rimini A, Malorni W, Corsello G, Bossi G, Buonuomo S, Cardinale F, Cortis E, De Benedetti F, De Zorzi A, Duse M, Del Principe D, Dellepiane RM, D'Isanto L, El Hachem M, Esposito S, Falcini F, Giordano U, Maggio MC, Mannarino S, Marseglia G, Martino S, Marucci G, Massaro R, Pescosolido C, Pietraforte D, Pietrogrande MC, Salice P, Secinaro A, Straface E, Villani A. Kawasaki disease: guidelines of the Italian Society of Pediatrics, part I - definition, epidemiology, etiopathogenesis, clinical expression and management of the acute phase. Ital J Pediatr 2018; 44:102. [PMID: 30157897 PMCID: PMC6116535 DOI: 10.1186/s13052-018-0536-3] [Citation(s) in RCA: 67] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/23/2017] [Accepted: 05/03/2018] [Indexed: 12/18/2022] Open
Abstract
The primary purpose of these practical guidelines related to Kawasaki disease (KD) is to contribute to prompt diagnosis and appropriate treatment on the basis of different specialists' contributions in the field. A set of 40 recommendations is provided, divided in two parts: the first describes the definition of KD, its epidemiology, etiopathogenetic hints, presentation, clinical course and general management, including treatment of the acute phase, through specific 23 recommendations.Their application is aimed at improving the rate of treatment with intravenous immunoglobulin and the overall potential development of coronary artery abnormalities in KD. Guidelines, however, should not be considered a norm that limits treatment options of pediatricians and practitioners, as treatment modalities other than those recommended may be required as a result of peculiar medical circumstances, patient's condition, and disease severity or complications.
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Affiliation(s)
- Alessandra Marchesi
- Bambino Gesù Children's Hospital, Rome, Italy, Piazza S. Onofrio n. 4, 00165, Rome, Italy.
| | | | - Donato Rigante
- Fondazione Policlinico Universitario A. Gemelli, Università Cattolica Sacro Cuore, Rome, Italy
| | | | | | | | | | - Sabrina Buonuomo
- Bambino Gesù Children's Hospital, Rome, Italy, Piazza S. Onofrio n. 4, 00165, Rome, Italy
| | | | | | - Fabrizio De Benedetti
- Bambino Gesù Children's Hospital, Rome, Italy, Piazza S. Onofrio n. 4, 00165, Rome, Italy
| | - Andrea De Zorzi
- Bambino Gesù Children's Hospital, Rome, Italy, Piazza S. Onofrio n. 4, 00165, Rome, Italy
| | - Marzia Duse
- , Università degli Studi Sapienza, Rome, Italy
| | | | | | | | - Maya El Hachem
- Bambino Gesù Children's Hospital, Rome, Italy, Piazza S. Onofrio n. 4, 00165, Rome, Italy
| | | | | | - Ugo Giordano
- Bambino Gesù Children's Hospital, Rome, Italy, Piazza S. Onofrio n. 4, 00165, Rome, Italy
| | | | | | | | | | - Giulia Marucci
- Bambino Gesù Children's Hospital, Rome, Italy, Piazza S. Onofrio n. 4, 00165, Rome, Italy
| | | | | | | | | | | | - Aurelio Secinaro
- Bambino Gesù Children's Hospital, Rome, Italy, Piazza S. Onofrio n. 4, 00165, Rome, Italy
| | | | - Alberto Villani
- Bambino Gesù Children's Hospital, Rome, Italy, Piazza S. Onofrio n. 4, 00165, Rome, Italy
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13
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Melatonin: A hypothesis for Kawasaki disease treatment. Med Hypotheses 2018; 119:6-10. [PMID: 30122493 DOI: 10.1016/j.mehy.2018.07.010] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2018] [Accepted: 07/11/2018] [Indexed: 01/18/2023]
Abstract
Kawasaki disease (KD) is the most common cause of acquired heart disease with unknown etiology among children in developed countries. Acute inflammation of the vasculature, genetic susceptibility and immunopathogenesis based on a transmittable and infectious origin, are the pathologic events involved in the early inflammatory etiology and progression of this disease. However, the exact causes of KD remain unknown. Current proposed recommendations include three therapy lines; firstly, an initial standard therapy with intravenous immunoglobulin (IVIG) followed by aspirin. Secondly, in cases of high risk of coronary lesions, the adjunctive therapy with corticosteroid is commonly considered. Thirdly, in KD patients refractory to the previous therapies, tumor necrosis factor (TNF-α) antagonists are being used to modulate pro-inflammatory cytokines. In view of this status quo, our starting hypothesis is that the ubiquitous and non-toxic neurohormone melatonin could be of critical importance in developing novel adjuvant therapies against KD, as it occurs with a plethora of other diseases. Considering its pleiotropic properties, particularly its antiinflammatory and immunoregulatory capacities, melatonin should be of great therapeutic interest for helping to control the main pathologic features of KD patients. In addition, this multifunctional indole has a safe pharmacological profile, enhancing the therapeutic activity of several drugs and reducing their possible side effects. Consequently, melatonińs actions to manage KD need to be tested in further clinical studies.
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14
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Cai K, Wang F, Gui YH. [Research advances in the pathogenesis of familial Kawasaki disease]. ZHONGGUO DANG DAI ER KE ZA ZHI = CHINESE JOURNAL OF CONTEMPORARY PEDIATRICS 2018; 20:594-597. [PMID: 30022765 PMCID: PMC7389202 DOI: 10.7499/j.issn.1008-8830.2018.07.016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Subscribe] [Scholar Register] [Received: 04/10/2018] [Accepted: 05/14/2018] [Indexed: 06/08/2023]
Abstract
Kawasaki disease has become the leading cause of acquired heart disease in children in North America and Japan. The incidence rate of Kawasaki disease varies significantly across regions and races. The first-degree relatives of patients with Kawasaki disease have a significantly higher risk of this disease than the general population. This article reviews the onset of familial Kawasaki disease and possible pathogenesis.
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Affiliation(s)
- Ke Cai
- Department of Cardiology, Children's Hospital of Fudan University, Shanghai 201102, China.
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15
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Lack of association between miR-218 rs11134527 A>G and Kawasaki disease susceptibility. Biosci Rep 2018; 38:BSR20180367. [PMID: 29717030 PMCID: PMC6048205 DOI: 10.1042/bsr20180367] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2018] [Revised: 04/19/2018] [Accepted: 04/30/2018] [Indexed: 12/22/2022] Open
Abstract
Kawasaki disease (KD) is a type of disease that includes the development of a fever that lasts at least 5 days and involves the clinical manifestation of multicellular vasculitis. KD has become one of the most common pediatric cardiovascular diseases. Previous studies have reported that miR-218 rs11134527 A>G is associated with susceptibility to various cancer risks. However, there is a lack of evidence regarding the relationship between this polymorphism and KD risk. The present study explored the correlation between the miR-218 rs11134527 A>G polymorphism and the risk of KD. We recruited 532 patients with KD and 623 controls to genotype the miR-218 rs11134527 A>G polymorphism with a TaqMan allelic discrimination assay. Our results illustrated that the miR-218 rs11134527 A>G polymorphism was not associated with KD risk. In an analysis stratified by age, sex, and coronary artery lesions, we found only that the risk of KD was significantly decreased for children older than 5 years (GG vs. AA/AG: adjusted OR = 0.26, 95% CI = 0.07–0.94, P=0.041). The present study demonstrated that the miR-218 rs1113452 A>G polymorphism may have an age-related relationship with KD susceptibility that has not previously been revealed.
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16
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Bijnens J, Missiaen L, Bultynck G, Parys JB. A critical appraisal of the role of intracellular Ca 2+-signaling pathways in Kawasaki disease. Cell Calcium 2018; 71:95-103. [PMID: 29604968 DOI: 10.1016/j.ceca.2018.01.002] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2018] [Accepted: 01/20/2018] [Indexed: 12/31/2022]
Abstract
Kawasaki disease is a multi-systemic vasculitis that generally occurs in children and that can lead to coronary artery lesions. Recent studies showed that Kawasaki disease has an important genetic component. In this review, we discuss the single-nucleotide polymorphisms in the genes encoding proteins with a role in intracellular Ca2+ signaling: inositol 1,4,5-trisphosphate 3-kinase C, caspase-3, the store-operated Ca2+-entry channel ORAI1, the type-3 inositol 1,4,5-trisphosphate receptor, the Na+/Ca2+ exchanger 1, and phospholipase Cß4 and Cß1. An increase of the free cytosolic Ca2+ concentration is proposed to be a major factor in susceptibility to Kawasaki disease and disease outcome, but only for polymorphisms in the genes encoding the inositol 1,4,5-trisphosphate 3-kinase C and the Na+/Ca2+ exchanger 1, the free cytosolic Ca2+ concentration was actually measured and shown to be increased. Excessive cytosolic Ca2+ signaling can result in hyperactive calcineurin in T cells with an overstimulated nuclear factor of activated T cells pathway, in hypersecretion of interleukin-1ß and tumor necrosis factor-α by monocytes/macrophages, in increased urotensin-2 signaling, and in an overactivation of vascular endothelial cells.
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Affiliation(s)
- Jeroen Bijnens
- KU Leuven, Laboratory of Molecular and Cellular Signaling, Department of Cellular and Molecular Medicine, B-3000 Leuven, Belgium
| | - Ludwig Missiaen
- KU Leuven, Laboratory of Molecular and Cellular Signaling, Department of Cellular and Molecular Medicine, B-3000 Leuven, Belgium
| | - Geert Bultynck
- KU Leuven, Laboratory of Molecular and Cellular Signaling, Department of Cellular and Molecular Medicine, B-3000 Leuven, Belgium
| | - Jan B Parys
- KU Leuven, Laboratory of Molecular and Cellular Signaling, Department of Cellular and Molecular Medicine, B-3000 Leuven, Belgium.
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17
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Liu W, Liu C, Zhang L, Xie X, Gu X, Sang C, Xu M, Xu W, Jia H. Molecular basis of coronary artery dilation and aneurysms in patients with Kawasaki disease based on differential protein expression. Mol Med Rep 2017; 17:2402-2414. [PMID: 29207079 PMCID: PMC5783486 DOI: 10.3892/mmr.2017.8111] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2017] [Accepted: 10/10/2017] [Indexed: 12/29/2022] Open
Abstract
Kawasaki disease (KD) is an acquired cardiac disease with a high incidence that affects children. KD has various complications, including coronary artery dilation (CAD) and coronary artery aneurysms (CAA). The identification of differentially expressed proteins and the underlying mechanisms may be the key to understanding differences between these KD complications. In the present study, isobaric tags for relative and absolute quantitation were used to identify variations in serum proteins between KD patients with CAD and CAA. In total, 87 (37 upregulated and 50 downregulated) and 65 (33 upregulated and 32 downregulated) significantly differentially-expressed proteins were identified in comparisons between control samples (healthy individuals) and those obtained from patients with KD and with CAD or CAA. Investigation into the underlying biological process revealed that variations between the two complications were associated with the wound healing response, as well as lipoprotein- and cholesterol-associated processes. Important proteins involved in the formation of the wound healing signaling network were identified via enriched biological processes and pathway analysis using ClueGo and ReactomeFIViz software. In the present study, 5 significantly differentially-expressed proteins, including mannose binding lectin 2 (MBL2), complement factor H (CFH), kininogen 1 (KNG1), serpin family C member 1 (SERPINC1) and fibronectin 1 (FN1), were selected and confirmed by western blotting. Analysis indicated that these proteins were associated to immunity, inflammation and metabolism, serving a key role within each module, which has never been reported previously. The present study proposed that MBL2, CFH, KNG1, SERPINC1 and FN1 may be a potentially excellent indicator group for distinguishing the two major KD complications, CAD and CAA.
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Affiliation(s)
- Wanting Liu
- Key Laboratory of Functional Protein Research of Guangdong Higher Education Institutes, Institute of Life and Health Engineering, College of Life Science and Technology, Jinan University, Guangzhou, Guangdong 510632, P.R. China
| | - Chaowu Liu
- Institute of Mass Spectrometer and Atmospheric Environment, Jinan University, Guangzhou, Guangdong 510632, P.R. China
| | - Li Zhang
- Department of Pediatric Cardiology, Guangzhou Women and Children's Medical Center, Guangzhou, Guangdong 510120, P.R. China
| | - Xiaofei Xie
- Department of Pediatric Cardiology, Guangzhou Women and Children's Medical Center, Guangzhou, Guangdong 510120, P.R. China
| | - Xiaoqiong Gu
- Department of Pediatric Cardiology, Guangzhou Women and Children's Medical Center, Guangzhou, Guangdong 510120, P.R. China
| | - Chuanlan Sang
- Laboratory Animal Center, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510405, P.R. China
| | - Mingguo Xu
- Department of Pediatric Cardiology, Shenzhen Children's Hospital, Shenzhen, Guangdong 518038, P.R. China
| | - Weijun Xu
- Information Center, Shenzhen Children's Hospital, Shenzhen, Guangdong 518038, P.R. China
| | - Hongling Jia
- Key Laboratory of Functional Protein Research of Guangdong Higher Education Institutes, Institute of Life and Health Engineering, College of Life Science and Technology, Jinan University, Guangzhou, Guangdong 510632, P.R. China
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18
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Chen Y, Ding YY, Ren Y, Cao L, Xu QQ, Sun L, Xu MG, Lv HT. Identification of differentially expressed microRNAs in acute Kawasaki disease. Mol Med Rep 2017; 17:932-938. [PMID: 29115644 PMCID: PMC5780174 DOI: 10.3892/mmr.2017.8016] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2017] [Accepted: 09/27/2017] [Indexed: 12/13/2022] Open
Abstract
The present study used microarray analysis to screen the plasma expression of microRNAs (miRNAs) in patients with acute Kawasaki disease (KD) and aimed to explore the pathogenesis of KD. Plasma was collected from children with acute KD (n=6) and from healthy control children (n=6). Total RNA was extracted and differential miRNA expression between the two groups was determined. Differentially expressed miRNAs were validated using reverse transcription-quantitative polymerase chain reaction (RT-qPCR) in an independent cohort (n=8). Target genes of the differentially expressed miRNAs were predicted and analyzed for gene ontology term enrichment and Kyoto Encyclopedia of Genes and Genomes pathways. miRNA microarray analysis revealed that seven miRNAs (miRs) were significantly upregulated (hsa-let-7b-5p, hsa-miR-223-3p, hsa-miR-4485, hsa-miR-4644, hsa-miR-4800-5p, hsa-miR-6510-5p and hsa-miR-765) and three were significantly downregulated (hsa-miR-33b-3p, hsa-miR-4443 and hsa-miR-4515) in acute KD compared with the healthy controls. hsa-miR-223-3p expression levels detected by RT-qPCR were consistent with the microarray results. A total of 62 target genes of hsa-miR-223-3p were predicted. In total, 10 differentially expressed miRNAs were identified in acute KD, of which hsa-miR-223-3p was verified by RT-qPCR.
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Affiliation(s)
- Ye Chen
- Cardiology Department, Children's Hospital of Soochow University, Suzhou, Jiangsu 215025, P.R. China
| | - Yue-Yue Ding
- Cardiology Department, Children's Hospital of Soochow University, Suzhou, Jiangsu 215025, P.R. China
| | - Yan Ren
- Radiology Department, Fudan University Affiliated Huashan Hospital, Shanghai 200040, P.R. China
| | - Lei Cao
- Cardiology Department, Children's Hospital of Soochow University, Suzhou, Jiangsu 215025, P.R. China
| | - Qiu-Qin Xu
- Cardiology Department, Children's Hospital of Soochow University, Suzhou, Jiangsu 215025, P.R. China
| | - Ling Sun
- Cardiology Department, Children's Hospital of Soochow University, Suzhou, Jiangsu 215025, P.R. China
| | - Ming-Guo Xu
- Cardiovascular Center, Shenzhen Children's Hospital, Shenzhen, Guangdong 518038, P.R. China
| | - Hai-Tao Lv
- Cardiology Department, Children's Hospital of Soochow University, Suzhou, Jiangsu 215025, P.R. China
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Quercetin Inhibits Inflammasome Activation by Interfering with ASC Oligomerization and Prevents Interleukin-1 Mediated Mouse Vasculitis. Sci Rep 2017; 7:41539. [PMID: 28148962 PMCID: PMC5288648 DOI: 10.1038/srep41539] [Citation(s) in RCA: 74] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2016] [Accepted: 12/22/2016] [Indexed: 12/19/2022] Open
Abstract
Interleukin-1β (IL-1β) is a highly inflammatory cytokine that significantly contributes to both acute and chronic inflammatory diseases. The secretion of IL-1β requires a unique protease, caspase-1, which is activated by various protein platforms called inflammasomes. Data suggests a key role for mitochondrial reactive oxygen species for inflammasome activation. Flavonoids constitute a group of naturally occurring polyphenolic molecules with many biological activities, including antioxidant effects. In this study, we investigated the effect of three flavonoids, quercetin (QUC), naringenin, and silymarim on inflammasome activation. We found that QUC inhibits IL-1β secretion by both the NLRP3 and AIM2 inflammasome in a dose dependent manner, but not the NLRC4 inflammasome. QUC inhibition of the inflammasome was still observed in Atg16l1 knockout macrophages, indicating that QUC’s effect was autophagy independent. Since QUC inhibited both NLRP3 and AIM2 inflammasomes but not NLRC4, we assessed ASC speck formation. QUC reduced ASC speck formation and ASC oligomerization compared with controls. Additionally, QUC inhibited IL-1β in Cryopyrin-Associated Periodic Syndromes (CAPS) macrophages, where NLRP3 inflammasome is constitutively activated. In conclusion, QUC inhibits both the NLRP3 and AIM2 inflammasome by preventing ASC oligomerization and may be a potential therapeutic candidate for Kawasaki disease vasculitis and other IL-1 mediated inflammatory diseases.
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Del Principe D, Pietraforte D, Gambardella L, Marchesi A, Tarissi de Jacobis I, Villani A, Malorni W, Straface E. Pathogenetic determinants in Kawasaki disease: the haematological point of view. J Cell Mol Med 2017; 21:632-639. [PMID: 28063205 PMCID: PMC5345614 DOI: 10.1111/jcmm.12992] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2016] [Accepted: 08/18/2016] [Indexed: 12/12/2022] Open
Abstract
Kawasaki disease is a multisystemic vasculitis that can result in coronary artery lesions. It predominantly affects young children and is characterized by prolonged fever, diffuse mucosal inflammation, indurative oedema of the hands and feet, a polymorphous skin rash and non‐suppurative lymphadenopathy. Coronary artery involvement is the most important complication of Kawasaki disease and may cause significant coronary stenosis resulting in ischemic heart disease. The introduction of intravenous immunoglobulin decreases the incidence of coronary artery lesions to less than 5%. The etiopathogenesis of this disease remains unclear. Several lines of evidence suggest that an interplay between a microbial infection and a genetic predisposition could take place in the development of the disease. In this review, we summarize the state of the art of pathogenetic mechanisms of Kawasaki disease underscoring the relevance of haematological features as a novel field of investigation.
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Affiliation(s)
- Domenico Del Principe
- Department of Therapeutic Research and Medicine Evaluation, Section of Cell Aging and Gender Medicine, Istituto Superiore di Sanità, Rome, Italy
| | - Donatella Pietraforte
- Department of Neurosciences, Section of Cell Aging and Gender Medicine, Istituto Superiore di Sanità, Rome, Italy
| | - Lucrezia Gambardella
- Department of Therapeutic Research and Medicine Evaluation, Section of Cell Aging and Gender Medicine, Istituto Superiore di Sanità, Rome, Italy
| | - Alessandra Marchesi
- General Pediatric and Infectious Disease Unit, Internal Care Department, Bambino Gesù Children's Hospital, Rome, Italy
| | - Isabella Tarissi de Jacobis
- General Pediatric and Infectious Disease Unit, Internal Care Department, Bambino Gesù Children's Hospital, Rome, Italy
| | - Alberto Villani
- General Pediatric and Infectious Disease Unit, Internal Care Department, Bambino Gesù Children's Hospital, Rome, Italy
| | - Walter Malorni
- Department of Therapeutic Research and Medicine Evaluation, Section of Cell Aging and Gender Medicine, Istituto Superiore di Sanità, Rome, Italy
| | - Elisabetta Straface
- Department of Therapeutic Research and Medicine Evaluation, Section of Cell Aging and Gender Medicine, Istituto Superiore di Sanità, Rome, Italy
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21
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Dissecting Kawasaki disease: a state-of-the-art review. Eur J Pediatr 2017; 176:995-1009. [PMID: 28656474 PMCID: PMC5511310 DOI: 10.1007/s00431-017-2937-5] [Citation(s) in RCA: 108] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/24/2017] [Revised: 05/11/2017] [Accepted: 05/15/2017] [Indexed: 12/12/2022]
Abstract
UNLABELLED 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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22
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Agarwal S, Agrawal DK. Kawasaki disease: etiopathogenesis and novel treatment strategies. Expert Rev Clin Immunol 2016; 13:247-258. [PMID: 27590181 DOI: 10.1080/1744666x.2017.1232165] [Citation(s) in RCA: 117] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
INTRODUCTION Kawasaki disease is an acute febrile systemic vasculitis that predominantly occurs in children below five years of age. Its etiopathogenesis is still not clear, but it is thought to be a complex interplay of genetic factors, infections and immunity. Areas covered: This review article discusses in detail Kawasaki disease, with particular emphasis on the recent updates on its pathogenesis and upcoming alternate treatment options. Though self-limiting in many cases, it can lead to severe complications like coronary artery aneurysms and thrombo-embolic occlusions, and hence requires early diagnosis and urgent attention to avoid them. Intravenous immunoglobulin (IVIG) with or without aspirin has remained the sole treatment option for these cases, but 10-15% cases develop resistance to this treatment. Expert commentary: There is a need to develop additional treatment strategies for children with Kawasaki disease. Targeting different steps of pathogenesis could provide us with alternate therapeutic options.
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Affiliation(s)
- Shreya Agarwal
- a Department of Clinical & Translational Science , Creighton University School of Medicine , Omaha , NE , USA
| | - Devendra K Agrawal
- a Department of Clinical & Translational Science , Creighton University School of Medicine , Omaha , NE , USA
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23
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Assari R, Aghighi Y, Ziaee V, Sadr M, Rahmani F, Rezaei A, Sadr Z, Moradinejad MH, Raeeskarami SR, Rezaei N. Pro-inflammatory cytokine single nucleotide polymorphisms in Kawasaki disease. Int J Rheum Dis 2016; 21:1120-1126. [PMID: 27455075 DOI: 10.1111/1756-185x.12911] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
AIM Kawasaki disease (KD) is a systemic vasculitis of children associated with cardiovascular sequelae. Proinflammatory cytokines play a major role in KD pathogenesis. However, their role is both influenced and modified by regulatory T-cells. IL-1 gene cluster, IL-6 and TNF-α polymorphisms have shown significant associations with some vasculitides. Herein we investigated their role in KD. METHODS Fifty-five patients with KD who were randomly selected from referrals to the main pediatric hospital were enrolled in this case-control study. Single nucleotide polymorphisms (SNPs) of the following genes were assessed in patients and 140 healthy subjects as control group: IL-1α at -889 (rs1800587), IL-1β at -511 (rs16944), IL-1β at +3962 (rs1143634), IL-1R at Pst-I 1970 (rs2234650), IL-1RN/A at Mspa-I 11100 (rs315952), TNF-α at -308 (rs1800629), TNF-α at -238, IL-6 at -174 (rs1800795) and IL-6 at +565. RESULTS Twenty-one percent of the control group had A allele at TNF-α -238 while only 8% of KD patients had A allele at this position (P = 0.003, OR [95%CI] = 0.32 [0.14-0.71]). Consistently, TNF-α genotype GG at -238 had significant association with KD (OR [95% CI] = 4.31 [1.79-10.73]). Most controls carried the CG genotype at IL-6 -174 (n = 93 [66.9%]) while GG genotype was the most common genotype (n = 27 [49%]) among patients. Carriers of the GG haplotype at TNF-α (-308, -238) were significantly more prevalent among the KD group. No association was found between IL-1 gene cluster, allelic or haplotypic variants and KD. CONCLUSION TNF-α GG genotype at -238 and GG haplotype at positions -308 and -238 were associated with KD in an Iranian population.
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Affiliation(s)
- Raheleh Assari
- Pediatric Rheumatology Research Group, Rheumatology Research Center, Tehran University of Medical Sciences, Tehran, Iran.,Department of Pediatrics, Pediatrics Center of Excellence, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Yahya Aghighi
- Department of Pediatrics, Imam Khomeini Hospital, Tehran University of Medical Sciences, Tehran, Iran
| | - Vahid Ziaee
- Pediatric Rheumatology Research Group, Rheumatology Research Center, Tehran University of Medical Sciences, Tehran, Iran.,Department of Pediatrics, Pediatrics Center of Excellence, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Maryam Sadr
- Department of Immunology, Molecular Immunology Research Center, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Farzaneh Rahmani
- Research Center for Immunodeficiencies, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Arezou Rezaei
- Research Center for Immunodeficiencies, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Zeinab Sadr
- Department of Immunology, Molecular Immunology Research Center, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Mohammad Hassan Moradinejad
- Department of Pediatrics, Pediatrics Center of Excellence, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Seyed Reza Raeeskarami
- Department of Pediatrics, Vali-e-Asr Hospital, Tehran University of Medical Sciences, Tehran, Iran
| | - Nima Rezaei
- Research Center for Immunodeficiencies, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran.,Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.,Network of Immunity in Infection, Malignancy, and Autoimmunity (NIIMA), Universal Scientific Education and Research Network (USERN), Tehran, Iran
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Boudiaf H, Achir M. The Clinical Profile of Kawasaki Disease in Algerian Children: A Single Institution Experience. J Trop Pediatr 2016; 62:139-43. [PMID: 26655639 PMCID: PMC4886121 DOI: 10.1093/tropej/fmv090] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
UNLABELLED Kawasaki disease (KD) in an acute vasculitis of unknown etiology. The epidemiological data available for Algerian patients remains insufficient. OBJECTIVE To describe the demographic, clinical features of children with KD and to identify the risk factors for developing coronary artery lesions (CAL). METHODS This retrospective study included children admitted with KD at the pediatric hospital in Algiers from January 2005 to December 2014. RESULTS One hundred thirty-three patients (82 boys and 51 girls) with a mean age of 31 months were identified. The most common sign was fever, rash, oral changes and conjunctivitis. The cardiac complications were CAL (22.5%), pericarditis (2%) and myocarditis (1.5%). The independent variable for prediction of CAL was duration of fever >10 days, male gender and platelet count >450,000/mm3 CONCLUSION: The incidence of cardiovascular complications is high. Knowledge of KD among Algerian pediatricians should be enhanced to guarantee appropriate treatment of this disease.
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Affiliation(s)
- Houda Boudiaf
- Department of Pediatrics, Birtraria Hospital, Pasteur Avenue 16606, Algiers, Algeria, and University of Medical Sciences, Algiers, Algeria
| | - Moussa Achir
- Department of Pediatrics, Birtraria Hospital, Pasteur Avenue 16606, Algiers, Algeria, and,University of Medical Sciences, Algiers, Algeria
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Kibata T, Suzuki Y, Hasegawa S, Matsushige T, Kusuda T, Hoshide M, Takahashi K, Okada S, Wakiguchi H, Moriwake T, Uchida M, Ohbuchi N, Iwai T, Hasegawa M, Ichihara K, Yashiro M, Makino N, Nakamura Y, Ohga S. Coronary artery lesions and the increasing incidence of Kawasaki disease resistant to initial immunoglobulin. Int J Cardiol 2016; 214:209-15. [PMID: 27070994 DOI: 10.1016/j.ijcard.2016.03.017] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/29/2016] [Accepted: 03/12/2016] [Indexed: 12/25/2022]
Abstract
BACKGROUNDS Kawasaki disease (KD) is a systemic vasculitis of childhood involving coronary arteries. Treatment for intractable cases at a higher risk of cardiac sequelae remains controversial. METHODS Clinical outcomes of KD patients diagnosed in Yamaguchi prefecture, Japan between 2003 and 2014 were analyzed using the medical records from all 14 hospitals covering the prefecture. The study included 1487 patients (male:female, 873:614; median age at diagnosis, 24months). RESULTS The proportion of initial intravenous immunoglobulin (IVIG)-resistant patients increased from 7% to 23% during this decade, although no patients died. Twenty-four patients developed coronary artery lesions (CALs) over one month after the KD onset. The incidence of CAL in patients who received corticosteroid during the disease course (10/37; 27.0%) was higher than that in those who did not (14/1450; 0.97%, p=2.0×10(-35)). Nine patients who responded to initial IVIG plus corticosteroids had no CAL. Conversely, IVIG-resistant patients with alternate corticosteroid therapy more frequently developed CAL than those without it (10/28; 35.7% vs. 5/194; 2.6%, p=8.9×10(-10)). Multivariate analyses indicated corticosteroid therapy (p<0.0001), hyperbilirubinemia (p=0.0010), and a longer number of days before treatment (p=0.0005) as risk factors associated with CAL over a month after onset. The odds ratio of corticosteroid use increased from 18.3 to 43.5 if the cases were limited to initial IVIG non-responders and corticosteroid free-IVIG responders. CONCLUSIONS IVIG-failure has recently increased. The incidence of CAL increased in intractable cases with prolonged corticosteroid use. Corticosteroid may not be alternate choice for IVIG-failure to reduce the risk of cardiac sequelae.
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Affiliation(s)
- Tetsuhiro Kibata
- Department of Pediatrics, Yamaguchi University Graduate School of Medicine, Ube, Japan
| | - Yasuo Suzuki
- Department of Pediatrics, Yamaguchi University Graduate School of Medicine, Ube, Japan
| | - Shunji Hasegawa
- Department of Pediatrics, Yamaguchi University Graduate School of Medicine, Ube, Japan.
| | - Takeshi Matsushige
- Department of Pediatrics, Yamaguchi University Graduate School of Medicine, Ube, Japan
| | - Takeshi Kusuda
- Department of Pediatrics, Yamaguchi University Graduate School of Medicine, Ube, Japan
| | - Madoka Hoshide
- Department of Pediatrics, Yamaguchi University Graduate School of Medicine, Ube, Japan
| | - Kazumasa Takahashi
- Department of Pediatrics, Yamaguchi University Graduate School of Medicine, Ube, Japan
| | - Seigo Okada
- Department of Pediatrics, Yamaguchi University Graduate School of Medicine, Ube, Japan
| | - Hiroyuki Wakiguchi
- Department of Pediatrics, Yamaguchi University Graduate School of Medicine, Ube, Japan
| | - Tadashi Moriwake
- Division of Pediatrics, National Hospital Organization Iwakuni Clinical Center, Iwakuni, Japan
| | - Masashi Uchida
- Division of Pediatrics, JCHO Tokuyama Central Hospital, Shunan, Japan
| | - Noriko Ohbuchi
- Division of Pediatrics, Yamaguchi Red Cross Hospital, Yamaguchi, Japan
| | - Takashi Iwai
- Division of Pediatrics, Yamaguchi-ken Saiseikai Shimonoseki General Hospital, Shimonoseki, Japan
| | | | - Kiyoshi Ichihara
- Department of Laboratory Sciences, Faculty of Health Sciences, Yamaguchi University Graduate School of Medicine, Ube, Japan
| | - Mayumi Yashiro
- Department of Public Health, Jichi Medical University, Shimotsuke, Japan
| | - Nobuko Makino
- Department of Public Health, Jichi Medical University, Shimotsuke, Japan
| | - Yosikazu Nakamura
- Department of Public Health, Jichi Medical University, Shimotsuke, Japan
| | - Shouichi Ohga
- Department of Pediatrics, Yamaguchi University Graduate School of Medicine, Ube, Japan
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Abstract
PURPOSE OF REVIEW The aim of this review is to define childhood vasculitis and to highlight new causative factors and treatment modalities under the guidance of recently published studies. RECENT FINDINGS Childhood vasculitis is difficult to diagnose because of the wide variation in the symptoms and signs. New nomenclature and classification criteria were proposed for the diagnosis of pediatric vasculitis. Recently, progress has been made toward understanding the genetic susceptibility to pediatric vasculitis as it was in other diseases. Various radiological techniques provide great opportunities in establishing the diagnosis of pediatric vasculitis. Mild central nervous system disease can accompany Henoch-Schonlein purpura and can go unnoticed. Antineutrophilic cytoplasmic antibody-associated vasculitis is rare in children. Increased severity of the disease, subglottic stenosis, and renal disease are described more frequently among children. Biological therapies are used with success in children as in adults. Future studies, whose aims are to evaluate treatment responses, prognosis and to design guidelines for activity, and damage index of vasculitis for children are required. SUMMARY Henoch-Schonlein purpura and Kawasaki disease are the most frequent vasculitides of children. Experience from adult studies for treatment and prognosis are usually used because of low incidence of other vasculitides in children. Multicenter studies of pediatric vasculitis should be conducted to detail treatment responses and prognosis in children.
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Affiliation(s)
- Kenan Barut
- Department of Pediatric Rheumatology, Cerrahpasa Medical School, Istanbul University, Istanbul, Turkey
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Yu JJ. Use of corticosteroids during acute phase of Kawasaki disease. World J Clin Pediatr 2015; 4:135-142. [PMID: 26566486 PMCID: PMC4637804 DOI: 10.5409/wjcp.v4.i4.135] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/02/2015] [Revised: 08/28/2015] [Accepted: 10/19/2015] [Indexed: 02/06/2023] Open
Abstract
In spite of initial intravenous immunoglobulin (IVIG) treatment, a significant number of patients are unresponsive to it and are at a higher risk for coronary artery lesions. Corticosteroids have been used as a secondary drug or used in combination with IVIG. Three options of using corticosteroids for the treatment of patients during the acute phase of Kawasaki disease, have been considered. The first is their use exclusively for patients unresponsive to IVIG treatment. The second is their use in combination with IVIG as the routine first line therapy for all patients. The last is the use in the combination as the first line therapy for selected patients at a high risk being unresponsive to initial IVIG. However, it is uncertain that the corticosteroids as the second line treatment are better than the additional IVIG in patients unresponsive to initial IVIG. The combination of corticosteroids and IVIG as the routine first line therapy also have not enough evidences. The last option of using corticosteroids - the combination of corticosteroids and IVIG in patients at high risk of unresponsiveness, is a properly reasonable treatment strategy. However, there have been no globally standardized predictive models for the unresponsiveness to initial IVIG treatment. Therefore, future investigations to determine the best predictive model are necessary.
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