Therapeutic strategies targeting inflammation and immunity in atherosclerosis: how to proceed?
Nature reviews. Cardiology
Atherosclerosis is a chronic inflammatory disease of the arterial wall, characterized by the formation of plaques containing lipid, connective tissue and immune cells in the intima of large and medium-sized arteries. Over the past three decades, a substantial reduction in cardiovascular mortality has been achieved largely through LDL-cholesterol-lowering regimes and therapies targeting other traditional risk factors for cardiovascular disease, such as hypertension, smoking, diabetes mellitus and obesity. However, the overall benefits of targeting these risk factors have stagnated, and a huge global burden of cardiovascular disease remains. The indispensable role of immunological components in the establishment and chronicity of atherosclerosis has come to the forefront as a clinical target, with proof-of-principle studies demonstrating the benefit and challenges of targeting inflammation and the immune system in cardiovascular disease. In this Review, we provide an overview of the role of the immune system in atherosclerosis by discussing findings from preclinical research and clinical trials. We also identify important challenges that need to be addressed to advance the field and for successful clinical translation, including patient selection, identification of responders and non-responders to immunotherapies, implementation of patient immunophenotyping and potential surrogate end points for vascular inflammation. Finally, we provide strategic guidance for the translation of novel targets of immunotherapy into improvements in patient outcomes.
10.1038/s41569-021-00668-4
Increased levels of circulating fibroblast growth factor 21 in children with Kawasaki disease.
Peng Yue,Pei Qiongfei,Feng Siqi,Su Ya,Liu Ruixi,Yi Qijian,Guo Pengfei
Clinical and experimental medicine
The purpose of this study was to examine the serum levels of fibroblast growth factor 21 (FGF21) in children with acute Kawasaki disease (KD) and to investigate its relationship with coronary artery lesions (CALs). Blood samples from 58 children with KD before intravenous immunoglobulin treatment and from 28 healthy children as control group were collected. Serum FGF21 levels in all participants were measured using enzyme-linked immunosorbent assay, and clinical parameters were tested in all KD patients. Serum FGF21 levels were significantly increased in acute KD patients as compared to the control group. Serum levels of FGF21 were substantially higher in the group of KD patients with CALs (KD-CALs) than in KD patients without CALs (KD-NCALs). Positive relationships between serum levels of FGF21 and percentage of leukomonocytes (L %), C-reactive protein, activated partial thromboplastin time and D-dimer were observed in KD patients. Furthermore, serum FGF21 levels were negatively correlated with red blood cell counts, hemoglobin (Hb), percentage of neutrophils (N %) and albumin. Serum level of FGF21 is associated with inflammation and coagulation. The paradoxical increase in serum FGF21 in acute KD patients may indicate a protective compensatory response.
10.1007/s10238-019-00577-4
Serum proteins may facilitate the identification of Kawasaki disease and promote in vitro neutrophil infiltration.
Li Sung-Chou,Tsai Kuo-Wang,Huang Lien-Hung,Weng Ken-Pen,Chien Kuang-Jen,Lin Yuyu,Tu Chi-Ying,Lin Pei-Hsien
Scientific reports
Kawasaki disease (KD) usually affects the children younger than 5 years of age and subsequently causes coronary artery lesions (CALs) without timely identification and treatment. Developing a robust and fast prediction method may facilitate the timely diagnosis of KD, significantly reducing the risk of CALs in KD patients. The levels of inflammatory serum proteins dramatically vary during the onsets of many immune diseases, including in KD. However, our understanding of their pathogenic roles in KD is behind satisfaction. The purpose of this study was to evaluate candidate diagnostic serum proteins and the potential mechanism in KD using iTRAQ gel-free proteomics. We enrolled subjects and conducted iTRAQ gel-free proteomics to globally screen serum proteins followed by specific validation with ELISA. Further in vitro leukocyte trans-endothelial model was also applied to investigate the pathogenesis roles of inflammatory serum proteins. We identified six KD protein biomarkers, including Protein S100-A8 (S100A8), Protein S100-A9 (S100A9), Protein S100-A12 (S100A12), Peroxiredoxin-2 (PRDX2), Neutrophil defensin 1 (DEFA1) and Alpha-1-acid glycoprotein 1 (ORM1). They enabled us to develop a high-performance KD prediction model with an auROC value of 0.94, facilitating the timely identification of KD. Further assays concluded that recombinant S100A12 protein treatment activated neutrophil surface adhesion molecules responsible for adhesion to endothelial cells. Therefore, S100A12 promoted both freshly clinically isolated neutrophils and neutrophil-like cells to infiltrate through the endothelial layer in vitro. Finally, the antibody against S100A12 may attenuate the infiltration promoted by S100A12. Our result demonstrated that evaluating S100A8, S100A9, S100A12, PRDX2, DEFA1 and ORM1 levels may be a good diagnostic tool of KD. Further in vitro study implied that S100A12 could be a potential therapeutic target for KD.
10.1038/s41598-020-72695-z
Neutrophil-Derived Semaphorin 4D Induces Inflammatory Cytokine Production of Endothelial Cells via Different Plexin Receptors in Kawasaki Disease.
Huang Junhua,Wu Shouzhen,Cao Sancheng,Zhu Xieying,Zhang Shuwan
BioMed research international
Inflammation of endothelial cells (ECs) plays an important role in the pathogenesis of coronary artery lesions (CALs) in Kawasaki disease (KD). Semaphorin 4D (Sema4D) is the first semaphorin shown to have immunoregulatory functions by interacting with its receptors-plexin Bs. Recently, Sema4D has been reported to exert a proinflammatory effect on the endothelium and to be involved in cardiovascular disease. However, the role of Sema4D in KD remains unknown. This study was aimed at revealing the change of soluble Sema4D (sSema4D) in the serum of patients with KD and the effect of the sSema4D-plexin axis on the production of proinflammatory cytokines from human coronary endothelial cells (HCAECs) stimulated with sera from KD patients. Our results showed that serum sSema4D levels were specifically elevated in KD patients, especially in those with CALs, and correlated positively with disease severity and serum concentrations of interleukin- (IL-) 1, IL-6, and IL-8. The disintegrin and metalloproteinase domain 17- (AMAM17-) mediated Sema4D shedding from neutrophils contributed to the elevation of sSema4D in the serum of KD patients. Furthermore, we found that Sema4D induced IL-1 production of HCAECs via plexin B2, whereas it promoted IL-6 and IL-8 production via plexin B1. Moreover, the expression of both plexin B1 and plexin B2 was upregulated in HCAECs treated with KD sera, and silencing of the two plexin receptors suppressed the overexpression of IL-1, IL-6, and IL-8 in KD serum-treated HCAECs. Thus, our findings indicated that sSema4D released from neutrophils participates in the pathogenesis of KD-CALs by promoting inflammatory cytokine production of ECs via both plexin B1 and plexin B2, and Sema4D may be a novel predictor for KD-CALs and a candidate therapeutic target for anti-inflammatory strategies of KD.
10.1155/2020/6663291
Prediction of repeated intravenous immunoglobulin resistance in children with Kawasaki disease.
BMC pediatrics
BACKGROUND:Repeated intravenous immunoglobulin (IVIG) resistance prediction is one of the pivotal topics in Kawasaki disease (KD). Those non-responders of repeated IVIG treatment might be improved by an early-intensified therapy to reduce coronary artery lesion and medical costs. This study investigated predictors of resistance to repeated IVIG treatment in KD. METHODS:A total of 94 children with IVIG-resistant KD treated at our hospital between January 2016 and August 2020 were retrospectively analyzed. According to the therapeutic effect of a second dose IVIG treatment, the children were divided into repeated IVIG-responsive group and repeated IVIG-resistant group, and the clinical and laboratory data were compared. Predictors of repeated IVIG resistance and the optimal cut-off value were determined by multiple logistic regression analysis and receiver operating characteristic (ROC) curve analysis. RESULTS:The Pre-IVIG laboratory data showed the percentage of neutrophils (N%) and levels of serum procalcitonin (PCT), N-terminal pro-brain natriuretic peptide (NT-proBNP) were significantly higher in repeated IVIG-resistant group compared with repeated IVIG-responsive group, while levels of serum sodium and albumin (ALB) were significantly lower (P < 0.05). The post-IVIG laboratory values of N% and C-reactive protein (CRP) were significantly higher in the repeated IVIG-resistant group compared with repeated IVIG-responsive group, while hemoglobin and ALB were lower (P < 0.05). Pre-IVIG PCT and post-IVIG CRP exhibited AUC of 0.751 and 0.778 respectively in predicting repeated IVIG resistance in KD. Pre-IVIG PCT > 1.81ng/ml (OR 4.1, 95 % CI 1.4 ~ 12.0, P < 0.05) and post-IVIG CRP > 45 mg/L (OR 4.6, 95 % CI 1.3 ~ 16.2, P < 0.05) were independent predictors of repeated IVIG resistance in KD. CONCLUSIONS:Our study illustrates the serum PCT level before initial IVIG treatment and CRP after initial IVIG could be used to predict repeated IVIG resistance in KD.
10.1186/s12887-021-02876-w
Neutrophil-to-lymphocyte ratio and scoring system for predicting coronary artery lesions of Kawasaki disease.
Chang Ling-Sai,Lin Yi-Ju,Yan Jia-Huei,Guo Mindy Ming-Huey,Lo Mao-Hung,Kuo Ho-Chang
BMC pediatrics
BACKGROUND:Kawasaki disease (KD) causes coronary artery lesions (CAL) and is the leading cause of acquired heart disease in children. The aim of this study is to evaluate the risk factors and set-up a scoring system for predicting CAL of KD. METHODS:We retrospectively reviewed a total of 478 patients diagnosed with KD. We compared age, gender, laboratory data, and treatment response in two groups and developed a scoring system for predicting CAL. RESULTS:During the study period, 365 of these patients had complete medical records of coronary surveys by echocardiography. Anemia, hypoalbuminemia, C reactive protein (CRP), alanine aminotransferase, neutrophil count, and neutrophil/lymphocyte ratio (NLR) showed significant differences with CAL formation. We determined the cut-off value using a receiver-operating-characteristic (ROC) curve, and following multivariate logistic regression analysis, four independent risk factors demonstrated a significant difference with CAL formation, including CRP > 103 mg/L, NLR > 3.5, male gender, and intravenous immunoglobulin (IVIG) resistance. We established a score system based on the above evaluation, for which a ROC curve was performed, and a total score of ≥ 2 points showed a sensitivity of 60.8% and a specificity of 70.6%, with an area under the ROC curve of 0.696. CONCLUSIONS:Identifying children at risk is important in order to prevent CAL from developing. Four independent risk factors that can predict CAL formation were CRP > 103 mg/L, NLR > 3.5, male gender, and IVIG resistance. This first report incorporated NLR into score systems to predict CAL reinforces previously well-known risk factors for the CAL formation among KD patients.
10.1186/s12887-020-02285-5
Distinguishing between typical Kawasaki disease and multisystem inflammatory syndrome in children (MIS-C) associated with SARS-CoV-2.
Yeo Wee Song,Ng Qin Xiang
Medical hypotheses
In recent months, there are increasing reports of a Kawasaki disease-like syndrome in children infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), termed 'Paediatric Multisystem Inflammatory Syndrome temporally associated with SARS-CoV-2 (PIMS-TS)' in the UK. Debate is ongoing regarding the nature of these pro-inflammatory syndromes. We herein propose that the platelet count may, at least in part, be able to help us differentiate between the two aforementioned syndromes. In a recent report, compared to a historical 'classical' Kawasaki disease (KD) cohort, patients with PIMS-TS had significantly lower platelet counts (188 vs 383 g/L, p < 0.0001). A possible explanation for this is their difference in underlying immunopathogenesis. In KD, the fundamental pathogenesis is thought to be immune complex-mediated, hence, the use of intravenous immunoglobulin (IVIg) which competes with the immunoglobulin Fc receptors (FcRs) on inflammatory cells, preventing the activation of these cells and thereby ameliorating the inflammatory response. If left untreated, these immune complexes activates the inflammatory cells (including monocytes and neutrophils), which also results in recruitment of platelets, resulting in the thrombocytosis we commonly see in KD. These immune complexes may also bind to platelets directly via FcRs on platelet membranes. In contrast, in viral-associated hyperinflammatory syndromes (e.g. PIMS-TS or MIS-C), there are mediators being secreted in the process of eradication of the virus (mainly to stimulate CD8+ cells to kill viral infected cells), which would inadvertently suppress bone marrow function and activate platelets, culminating in thrombocytopenia.
10.1016/j.mehy.2020.110263
Five immune-gene-signatures participate in the development and pathogenesis of Kawasaki disease.
Nie Han,Wang Shizhi,Wu Quanli,Xue Danni,Zhou Weimin
Immunity, inflammation and disease
OBJECTIVE:To screen for immune genes that play a major role in Kawasaki disease and to investigate the pathogenesis of Kawasaki disease through bioinformatics analysis. METHODS:Kawasaki disease-related datasets GSE18606, GSE68004, and GSE73461 were downloaded from the Gene Expression Omnibus database. Three microarrays were integrated and standardized to include 173 Kawasaki disease samples and 101 normal samples. The samples were analyzed using CIBERSORT to obtain the infiltration of 22 immune cells and analyze the differential immune cells in the samples and correlations. The distribution of the samples was analyzed using principal component analysis (PCA). Immune-related genes were downloaded, extracted from the screened samples and analyzed for differential analysis (different expression genes [DEG]) and weighted gene co-expression network analysis (WGCNA). We constructed coexpression networks, and used the cytohobbe tool in Cytoscape to analyze the coexpression networks and select the immune genes that played a key role in them. RESULTS:Immune cell infiltration analysis showed that B cells naive, T cells CD8, natural killer (NK) cells activated, and so forth were highly expressed in normal samples. T cells CD4 memory activated, monocytes, neutrophils, and so forth were highly expressed in Kawasaki disease samples. PCA results showed a significant difference in the distribution of normal and Kawasaki disease samples. From the screened samples, 97 upregulated and 103 downregulated immune-related genes were extracted. WGCNA analysis of DEG yielded 10 gene modules, of which the three most relevant to Kawasaki disease were red, yellow, and gray modules. They were associated with cytokine regulation, T-cell activation, presentation of T-cell receptor signaling pathways, and NK cell-mediated cytotoxicity. CXCL8, CCL5, CCR7, CXCR3, and CCR1 were identified as key genes by constructing a coexpression network. CONCLUSION:Our study shows that we can distinguish normal samples from Kawasaki disease samples based on the infiltration of immune cells, and that CXCL8, CCL5, CCR7, CXCR3, and CCR1 may play important roles in the development of Kawasaki disease.
10.1002/iid3.373
Changes in Peripheral Blood Neutrophils, Lymphocytes and IL-10 in Children with Kawasaki Disease from Different Age Groups Undergoing Intravenous Immunoglobulin: A Retrospective Study.
Zhang Chun,Zhang Xuan,Shen Jia,Lu Xiaotong,Zhang Jian,Chen Sun
Mediators of inflammation
Immunoglobulin intravenous (IVIG) is widely used in mucocutaneous lymph node syndrome, known as Kawasaki disease (KD). However, the patients' inflammatory response during usage remains unclear. In the present study, the association between inflammatory response and lymphocyte count in children with KD from different ages was evaluated before and after IVIG. The medical records of 50 children with KD were retrospectively reviewed and divided into five groups according to age. As compared with the data from healthy children, the relative neutrophil count of all children with KD was increased, and that of lymphocytes was decreased. The neutrophil/lymphocyte ratio (NLR) was different among all groups and was higher in children aged ≥4 years, as compared with other groups. Following IVIG, the relative neutrophil and lymphocyte counts of all children with KD returned to normal levels. The altered levels of neutrophils and lymphocytes were found to be linearly correlated. The correlation coefficient in the five groups was 0.99, 0.87, 0.91, 0.97 and 0.99, from young to old, respectively ( < 0.01). The age of children with KD was positively correlated with older age ( = 0.91, = 0.03). In patients aged ≥4 years, the absolute CD19 B cell count prior to IVIG increased, and that increase was linearly correlated with the decrease in interleukin-10 (IL-10) following IVIG ( = 0.71, < 0.05). The older the child's age, the better the regulatory effect of IVIG on the KD child's immune response and the recovery of immune equilibrium it achieved. In KD patients aged ≥4 years, the abnormally proliferating CD19 B cells may be involved in the secretion of IL-10 to balance the humoral immunity. In such patients, the combination of the absolute CD19 B cell count prior to IVIG and the decreased levels of IL-10 following IVIG may play a crucial role in evaluating the effect of IVIG in the inflammation.
10.1155/2020/5213451
Immune response to intravenous immunoglobulin in patients with Kawasaki disease and MIS-C.
Zhu Yanfang P,Shamie Isaac,Lee Jamie C,Nowell Cameron J,Peng Weiqi,Angulo Shiela,Le Linh Nn,Liu Yushan,Miao Huilai,Xiong Hainan,Pena Cathleen J,Moreno Elizabeth,Griffis Eric,Labou Stephanie G,Franco Alessandra,Broderick Lori,Hoffman Hal M,Shimizu Chisato,Lewis Nathan E,Kanegaye John T,Tremoulet Adriana H,Burns Jane C,Croker Ben A,
The Journal of clinical investigation
BACKGROUNDMultisystem inflammatory syndrome in children (MIS-C) is a rare but potentially severe illness that follows exposure to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Kawasaki disease (KD) shares several clinical features with MIS-C, which prompted the use of intravenous immunoglobulin (IVIG), a mainstay therapy for KD. Both diseases share a robust activation of the innate immune system, including the IL-1 signaling pathway, and IL-1 blockade has been used for the treatment of both MIS-C and KD. The mechanism of action of IVIG in these 2 diseases and the cellular source of IL-1β have not been defined.METHODSThe effects of IVIG on peripheral blood leukocyte populations from patients with MIS-C and KD were examined using flow cytometry and mass cytometry (CyTOF) and live-cell imaging.RESULTSCirculating neutrophils were highly activated in patients with KD and MIS-C and were a major source of IL-1β. Following IVIG treatment, activated IL-1β+ neutrophils were reduced in the circulation. In vitro, IVIG was a potent activator of neutrophil cell death via PI3K and NADPH oxidase, but independently of caspase activation.CONCLUSIONSActivated neutrophils expressing IL-1β can be targeted by IVIG, supporting its use in both KD and MIS-C to ameliorate inflammation.FUNDINGPatient Centered Outcomes Research Institute; NIH; American Asthma Foundation; American Heart Association; Novo Nordisk Foundation; NIGMS; American Academy of Allergy, Asthma and Immunology Foundation.
10.1172/JCI147076
KCa3.1 Inhibition of Macrophages Suppresses Inflammatory Response Leading to Endothelial Damage in a Cell Model of Kawasaki Disease.
Zheng Fenglei,Tao Yijing,Liu Jingjing,Geng Zhimin,Wang Ying,Wang Yujia,Fu Songling,Wang Wei,Xie Chunhong,Zhang Yiying,Gong Fangqi
Journal of inflammation research
Purpose:Macrophages-mediated inflammation is linked with endothelial damage of Kawasaki disease (KD). KCa3.1, a calcium-activated potassium channel, modulates inflammation of macrophages. However, little is known about the role of KCa3.1 in inflammation by macrophages involved in KD. Hence, this study is aimed to explore the potential role of KCa3.1 in regulating inflammatory response by macrophages and subsequent vascular injury in an in vitro model of KD. Methods:RAW264.7 cells were stimulated with cell wall extract (LCWE) with or without TRAM-34 or PDTC or AG490. Subsequently, mouse coronary artery endothelial cells (MCAECs) were incubated with RAW264.7 cells-conditioned medium to mimic local inflammatory lesions in KD. CCKi8 assay was used to evaluate cell viability. The mRNA levels of inflammatory mediators were detected by qRT-PCR. Expressions of KCa3.1, MCAECs injury-associated molecules, proteins involved in signal pathways of nuclear factor-κB (NF-κB), signal transducers and activators of transcription (STAT) 3 and p38 were evaluated by Western blot. Results:Our study showed that LCWE increased KCa3.1 protein level in RAW264.7 macrophages and KCa3.1 inhibition by TRAM-34 notably suppressed the expression of pro-inflammatory molecules in LCWE-treated macrophages via blocking the activation of NF-κB and STAT3 pathways. Besides, the inflammation and damage of MCAECs were attenuated in the TRAM-34-treated group compared with the KD model group. This vascular protective role was dependent on the down-regulation of NF-κB and STAT3 signal pathways, which was confirmed by using inhibitors of NF-κB and STAT3. Conclusion:This study demonstrates that KCa3.1 blockade of macrophages suppresses inflammatory reaction leading to mouse coronary artery endothelial cell injury in a cell model of KD by hampering the activation of NF-κB and STAT3 signaling pathway. These findings imply that KCa3.1 may be a potential therapeutic target for KD.
10.2147/JIR.S297131
IL-1 Signaling Is Critically Required in Stromal Cells in Kawasaki Disease Vasculitis Mouse Model: Role of Both IL-1α and IL-1β.
Lee Youngho,Wakita Daiko,Dagvadorj Jargalsaikhan,Shimada Kenichi,Chen Shuang,Huang Ganghua,Lehman Thomas J A,Fishbein Michael C,Hoffman Hal M,Crother Timothy R,Arditi Moshe
Arteriosclerosis, thrombosis, and vascular biology
OBJECTIVE:Kawasaki disease (KD) is the most common cause of acute vasculitis and acquired cardiac disease among US children. We have previously shown that both TLR2/MyD88 and interleukin (IL)-1β signaling are required for the Lactobacillus casei cell wall extract-induced KD vasculitis mouse model. The objectives of this study were to investigate the cellular origins of IL-1 production, the role of CD11c(+) dendritic cells and macrophages, and the relative contribution of hematopoietic and stromal cells for IL-1 responsive cells, as well the MyD88 signaling, in Lactobacillus casei cell wall extract-induced KD mouse model of vasculitis. APPROACH AND RESULTS:Using mouse knockout models and antibody depletion, we found that both IL-1α and IL-1β were required for Lactobacillus casei cell wall extract-induced KD. Both dendritic cells and macrophages were necessary, and we found that MyD88 signaling was required in both hematopoietic and stromal cells. However, IL-1 response and signaling were critically required in nonendothelial stromal cells, but not in hematopoietic cells. CONCLUSIONS:Our results suggest that IL-1α and IL-1β, as well as CD11c(+) dendritic cells and macrophages, are essential for the development of KD vasculitis and coronary arteritis in this mouse model. Bone marrow chimera experiments suggest that MyD88 signaling is important in both hematopoietic and stromal cells, whereas IL-1 signaling and response are required only in stromal cells, but not in endothelial cells. Determining the role of IL-1α and IL-1β and of specific cell types in the KD vasculitis mouse model may have important implications for the design of more targeted therapies and understanding of the molecular mechanisms of KD immunopathologies.
10.1161/ATVBAHA.115.306475
Non-receptor type, proline-rich protein tyrosine kinase 2 (Pyk2) is a possible therapeutic target for Kawasaki disease.
Suzuki Chinatsu,Nakamura Akihiro,Miura Noriko,Fukai Kuniyoshi,Ohno Naohito,Yahata Tomoyo,Okamoto-Hamaoka Akiko,Fujii Maiko,Yoshioka Ayako,Kuchitsu Yuki,Ikeda Kazuyuki,Hamaoka Kenji
Clinical immunology (Orlando, Fla.)
Kawasaki disease (KD) is a paediatric vasculitis whose pathogenesis remains unclear. Based on experimental studies using a mouse model for KD, we report here that proline-rich protein tyrosine kinase 2 (Pyk2) plays a critical role in the onset of KD-like murine vasculitis. The mouse model for KD was prepared by administrating a Candida albicans water-soluble fraction (CAWS). Unlike CAWS-treated WT mice, CAWS-treated Pyk2-Knockout (Pyk2-KO) mice did not develop apparent vasculitis. A sustained increase in MIG/CXCL9 and IP-10/CXCL10, both of which have potent angiostatic activity, was observed in CAWS-treated Pyk2-KO mice. CAWS-induced activation of STAT3, which negatively regulates the expression of these chemokines, was also attenuated in macrophages derived from Pyk2-KO mice. The present study suggests that defects in Pyk2 suppress KD-like experimental vasculitis, presumably through CXCL9- and CXCL10-dependent interference with neo-angiogenesis. Since Pyk2-KO mice show no life-threatening phenotype, Pyk2 may be a promising therapeutic molecular target for KD.
10.1016/j.clim.2017.01.013
Anemia in Kawasaki Disease: Hepcidin as a Potential Biomarker.
Huang Ying-Hsien,Kuo Ho-Chang
International journal of molecular sciences
Kawasaki disease (KD) is an autoimmune-like disease and acute childhood vasculitis syndrome that affects various systems but has unknown etiology. In addition to the standard diagnostic criteria, anemia is among the most common clinical features of KD patients and is thought to have a more prolonged duration of active inflammation. In 2001, the discovery of a liver-derived peptide hormone known as hepcidin began revolutionizing our understanding of anemia's relation to a number of inflammatory diseases, including KD. This review focuses on hepcidin-induced iron deficiency's relation to transient hyposideremia, anemia, and disease outcomes in KD patients, and goes on to suggest possible routes of further study.
10.3390/ijms18040820
TNF-α is superior to conventional inflammatory mediators in forecasting IVIG nonresponse and coronary arteritis in Chinese children with Kawasaki disease.
Hu Peng,Jiang Guang Mei,Wu Yue,Huang Bao Yu,Liu Si Yan,Zhang Dong Dong,Xu Yao,Wu Yang Fang,Xia Xun,Wei Wei,Hu Bo
Clinica chimica acta; international journal of clinical chemistry
BACKGROUND:Tumor necrosis factor (TNF) -α is of inflammatory cytokines produced chiefly by activated monocyte/macrophages, and has been implicated in the pathogenesis of Kawasaki disease (KD). We elucidated the relationship of plasma TNF-α with conventional inflammatory mediators, clinical classification, intravenous immunoglobulin (IVIG) response and coronary arteritis in the course of KD. METHODS:Seventy Chinese children with KD were enrolled and divided into 6 subgroups, including complete KD, incomplete KD, IVIG-responsive KD, IVIG-nonresponsive KD, coronary artery (CA) -noninvolvement KD and CA-involvement KD. Blood samples were collected from all subjects at 24h pre- and 48h post-IVIG therapy, respectively. TNF-α, white blood cells counts (WBC), absolute neutrophil counts (ANC), C-reactive protein (CRP), erythrocyte sedimentation rate (ESR) and procalcitonin (PCT) were detected. RESULTS:Plasma TNF-α markedly increased in the acute phase of KD and was positively correlated with CRP and PCT, whereas remained high after IVIG therapy. TNF-α as well as conventional inflammatory mediators could not be used to differentiate the clinical classification of KD, but they may prove beneficial to heighten or reduce the suspicion of incomplete KD. Plasma TNF-α was significantly higher in both IVIG-nonresponsive patients and coronary arteritis patients, but no significant differences were observed in all the other inflammatory mediators. Moreover, plasma TNF-α was positively correlated with the internal diameter of CA. CONCLUSIONS:TNF-α is superior to conventional inflammatory mediators in forecasting IVIG nonresponse and coronary arteritis in Chinese children with KD.
10.1016/j.cca.2017.05.019
Allograft Inflammatory Factor-1 Links T-Cell Activation, Interferon Response, and Macrophage Activation in Chronic Kawasaki Disease Arteritis.
Journal of the Pediatric Infectious Diseases Society
BACKGROUND:Kawasaki disease (KD) is widely viewed as an acute arteritis. However, our pathologic studies show that chronic coronary arteritis can persist long after disease onset and is closely linked with arterial stenosis. Transcriptome profiling of acute KD arteritis tissues revealed upregulation of T lymphocyte, type I interferon, and allograft inflammatory factor-1 (AIF1) genes. We determined whether these immune responses persist in chronic KD arteritis, and we investigated the role of AIF1 in these responses. METHODS:Gene expression in chronic KD and childhood control arteries was determined by real-time reverse-transcriptase polymerase chain reaction, and arterial protein expression was determined by immunohistochemistry and immunofluorescence. Allograft inflammatory factor-1 small-interfering ribonucleic acid macrophage treatment was performed to investigate the role of AIF1 in macrophage and T lymphocyte activation. RESULTS:Allograft inflammatory factor-1 protein was highly expressed in stenotic KD arteries and colocalized with the macrophage marker CD68. T lymphocyte and interferon pathway genes were significantly upregulated in chronic KD coronary artery tissues. Alpha interferon-induced macrophage expression of CD80 and major histocompatibility complex class II was dependent on AIF1, and macrophage expression of AIF1 was required for antigen-specific T lymphocyte activation. CONCLUSIONS:Allograft inflammatory factor-1, originally identified in posttransplant arterial stenosis, is markedly upregulated in KD stenotic arterial tissues. T lymphocyte and type I interferon responses persist in chronic KD arteritis. Allograft inflammatory factor-1 may play multiple roles linking type I interferon response, macrophage activation, and antigen-specific T lymphocyte activation. These results suggest the likely importance of lymphocyte-myeloid cell cross-talk in the pathogenesis of KD arteritis and can inform selection of new immunotherapies for clinical trials in high-risk KD children.
10.1093/jpids/pix025
Histopathological aspects of cardiovascular lesions in Kawasaki disease.
Takahashi Kei,Oharaseki Toshiaki,Yokouchi Yuki
International journal of rheumatic diseases
Kawasaki disease (KD) is the commonest vasculitic syndrome. It affects medium-sized arteries, principally the coronary arteries. Histologically, coronary arteritis begins at 6 to 8 days after the onset of KD and the inflammation rapidly involves all layers of the artery. This results in severe damage to the structural components of the artery leading to arterial dilation. The inflammatory infiltrate in KD arteritis is characterized predominantly by infiltration of monocytes and macrophages. Activated neutrophils, monocytes and macrophages are believed to be involved in the initial stage of coronary arteritis. Inflammatory cell infiltration may continue for up to 25 days of disease following which the inflammatory cells gradually decline in number. Inflammatory lesions in the arteries are relatively synchronous as they evolve from an acute to the chronic stage. If a giant aneurysm remains or vessel recanalization occurs after thrombotic occlusion of an aneurysm, the remodeling of vascular structures may continue for a much longer time.
10.1111/1756-185X.13207
Macrophages and cytotoxic T cells infiltrate the destructed mitral tissue in Kawasaki disease.
Sugitani Yuichiro,Furuno Kenji,Sueishi Katsuo,Hara Toshiro
BMJ case reports
Kawasaki disease (KD) is an acute febrile systemic vasculitic syndrome especially affecting medium-sized arteries, including the coronary artery. Inflammation may involve all organs, and valvulitis is one of the cardiovascular complications that occurs in the acute phase of KD. However, details regarding the mechanism are unclear. An infant developed KD and severe mitral regurgitation with deformity and prolapse of the mitral tissue and underwent mitral valvotomy 1 year later. Histopathological study was conducted, and infiltrating cells consisted of mainly macrophages and cytotoxic T cells were found in resected mitral valve tissue. In addition, inflammation remained a long time after KD had developed.
10.1136/bcr-2017-223584
A critical appraisal of the role of intracellular Ca-signaling pathways in Kawasaki disease.
Bijnens Jeroen,Missiaen Ludwig,Bultynck Geert,Parys Jan B
Cell calcium
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 Ca signaling: inositol 1,4,5-trisphosphate 3-kinase C, caspase-3, the store-operated Ca-entry channel ORAI1, the type-3 inositol 1,4,5-trisphosphate receptor, the Na/Ca exchanger 1, and phospholipase Cß4 and Cß1. An increase of the free cytosolic Ca 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/Ca exchanger 1, the free cytosolic Ca concentration was actually measured and shown to be increased. Excessive cytosolic Ca 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.
10.1016/j.ceca.2018.01.002
Adeno-associated Virus Vector-mediated Interleukin-10 Induction Prevents Vascular Inflammation in a Murine Model of Kawasaki Disease.
Nakamura Jun,Watanabe Sachiko,Kimura Hiroaki,Kobayashi Motoi,Karasawa Tadayoshi,Kamata Ryo,Usui-Kawanishi Fumitake,Sadatomo Ai,Mizukami Hiroaki,Nagi-Miura Noriko,Ohno Naohito,Kasahara Tadashi,Minota Seiji,Takahashi Masafumi
Scientific reports
Kawasaki disease (KD), which is the leading cause of pediatric heart disease, is characterized by coronary vasculitis and subsequent aneurysm formation. Although intravenous immunoglobulin therapy is effective for reducing aneurysm formation, a certain number of patients are resistant to this therapy. Because interleukin-10 (IL-10) was identified as a negative regulator of cardiac inflammation in a murine model of KD induced by Candida albicans water-soluble fraction (CAWS), we investigated the effect of IL-10 supplementation in CAWS-induced vasculitis. Mice were injected intramuscularly with adeno-associated virus (AAV) vector encoding IL-10, then treated with CAWS. The induction of AAV-mediated IL-10 (AAV-IL-10) significantly attenuated the vascular inflammation and fibrosis in the aortic root and coronary artery, resulting in the improvement of cardiac dysfunction and lethality. The predominant infiltrating inflammatory cells in the vascular walls were Dectin-2CD11b macrophages. In vitro experiments revealed that granulocyte/macrophage colony-stimulating factor (GM-CSF) induced Dectin-2 expression in bone marrow-derived macrophages and enhanced the CAWS-induced production of tumor necrosis factor-α (TNF-α) and IL-6. IL-10 had no effect on the Dectin-2 expression but significantly inhibited the production of cytokines. IL-10 also inhibited CAWS-induced phosphorylation of ERK1/2, but not Syk. Furthermore, the induction of AAV-IL-10 prevented the expression of TNF-α and IL-6, but not GM-CSF and Dectin-2 at the early phase of CAWS-induced vasculitis. These findings demonstrate that AAV-IL-10 may have therapeutic application in the prevention of coronary vasculitis and aneurysm formation, and provide new insights into the mechanism underlying the pathogenesis of KD.
10.1038/s41598-018-25856-0
Interleukin-6 is prone to be a candidate biomarker for predicting incomplete and IVIG nonresponsive Kawasaki disease rather than coronary artery aneurysm.
Wu Yue,Liu Fei Fei,Xu Yao,Wang Jing Jing,Samadli Sama,Wu Yang Fang,Liu Hui Hui,Chen Wei Xia,Luo Huang Huang,Zhang Dong Dong,Wei Wei,Hu Peng
Clinical and experimental medicine
Kawasaki disease (KD) is an acute, systemic vasculitis and occurs mainly in childhood. Interleukin-6 (IL-6) is a pleiotropic cytokine synthesized predominantly by neutrophils and monocytes/macrophages and plays an important role in systemic inflammatory disease. However, a little information is currently available on the relationship of serum IL-6 with conventional inflammatory mediators, clinical classification, IVIG response and coronary artery aneurysm (CAA). 165 Chinese children with KD were enrolled and divided into six subgroups, including complete KD, incomplete KD, IVIG-responsive KD, IVIG-nonresponsive KD, coronary artery noninvolvement KD and coronary artery involvement KD. Blood samples were collected from all subjects within 24-h pre- and 48-h post-IVIG therapy, respectively. Serum IL-6 and conventional inflammatory mediators were detected. (1) Serum IL-6 markedly increased in the acute phase of KD, whereas declined to normal after IVIG therapy; it was positively correlated with C-reactive protein and erythrocyte sedimentation rate. (2) Serum IL-6 was significantly elevated in patients with incomplete KD when compared with their complete counterparts. The area under receiver operating characteristic curve (AUC) value for serum IL-6 in prediction of incomplete KD was 0.596, and the estimated sensitivity and specificity were 77.80% and 54.40% with a cutoff of IL-6 > 13.25 pg/ml, respectively. (3) Serum IL-6 was significantly elevated in patients with IVIG-nonresponsive KD when compared with their IVIG-responsive counterparts; the AUC value for serum IL-6 in prediction of IVIG-nonresponsive KD was 0.580, and the estimated sensitivity and specificity were 60.00% and 66.30% with a cutoff of IL-6 > 26.40 pg/ml, respectively. (4) No significant differences in IL-6 were found between KD patients with and without CAA. IL-6 is prone to be a candidate biomarker for predicting incomplete and IVIG nonresponsive KD rather than CAA.
10.1007/s10238-018-00544-5
Recognition of alpha-mannan by dectin 2 is essential for onset of Kawasaki disease-like murine vasculitis induced by cell-wall polysaccharide.
Oharaseki Toshiaki,Yokouchi Yuki,Enomoto Yasunori,Sato Wakana,Ishibashi Kenichi,Miura Noriko,Ohno Naohito,Takahashi Kei
Modern rheumatology
Using a murine model of systemic Kawasaki disease (KD)-like vasculitis induced by cell-wall-derived mannan · β-glucan · protein complexes, the objective was to elucidate the relationships of β-glucan receptor dectin-1 (D1) and α-mannan receptor dectin-2 (D2) to the onset of that vasculitis. The incidence and histological severity of vasculitis were compared among mice lacking the genes for D1 or D2 (i.e. D1 and D2) and wild-type (WT) mice. The incidences of vasculitis in the three animal groups were 100% (18/18) in the WT group, 100% (18/18) in the D1 group, and 0% (0/18) in the D2 group. In the WT and D1 mice, severe inflammatory cell infiltration, consisting mainly of neutrophils and macrophages, was seen in the aortic root and the coronary arteries. On the other hand, in the D2 mice, not even mild vascular lesions such as endoarteritis were seen. Recognition of α-mannan by D2 played an important role in the onset of vasculitis in the studied murine model.
10.1080/14397595.2019.1601852
M1 macrophage is the predominant phenotype in coronary artery lesions following Kawasaki disease.
Ohashi Ryuji,Fukazawa Ryuji,Shimizu Akira,Ogawa Shunichi,Ochi Masami,Nitta Takashi,Itoh Yasuhiko
Vascular medicine (London, England)
Kawasaki disease (KD) is a systemic inflammatory process that affects the medium-sized arteries, causing various cardiovascular complications. However, it is not clear if the vascular sequelae following KD can predispose to the development of atherosclerosis later in life. Our aim was to examine the macrophage phenotypes in the coronary arteries forming giant aneurysms after KD to gain insight into the pathogenesis of vascular lesions in KD. We examined histological sections of the coronary arteries from five patients with KD who underwent coronary bypass grafting procedure as treatment for giant aneurysms and subsequent stenosis. Immunohistochemical expression of M1- and M2-macrophage markers was assessed to determine the macrophage phenotype of KD to compare with that of atherosclerosis in eight adult patients. All the KD specimens showed a mild to moderate degree of intimal thickening consisting of mature fibrous tissue and distortion of elastic fibers, mimicking the histological features of atherosclerosis. The total number of CD68 positive macrophages was higher in atherosclerosis than in KD specimens. Among the CD68 positive macrophages, the proportion of M1 phenotype, detected by CD86 or SOCS3, was higher in KD than in atherosclerosis. In contrast, the proportion of M2 phenotype, detected by CD163 or MRC1, was higher in patients with atherosclerosis. Despite similar histological features, KD and atherosclerosis appear to have a different immunological etiology for progression of the chronic vascular lesions. A further study enrolling a larger number of cases is required to delineate underlying mechanisms of vascular complications in KD.
10.1177/1358863X19878495
The pathology of Kawasaki disease aortitis: a study of 37 cases.
Sato Wakana,Yokouchi Yuki,Oharaseki Toshiaki,Asakawa Nanae,Takahashi Kei
Cardiovascular pathology : the official journal of the Society for Cardiovascular Pathology
BACKGROUND:Kawasaki disease (KD) is a systemic vasculitis syndrome that occurs most frequently in children. Most clinical and pathological studies have focused on its coronary artery lesions. To date, no detailed studies of the aorta have been conducted. We studied KD autopsy cases with the aims of clarifying the time-course of changes in aortic lesions, the differences in the inflammatory cells and degree of inflammation at various aortic sites, and the progression of the inflammation. MATERIALS AND METHODS:The study materials were aortic specimens taken from 37 KD autopsy cases (acute phase: 19; remote phase: 18). Twenty-seven of the cases also had coronary aneurysms. We chose 3 aortic sites, i.e., the thoracic aorta, aortic root and aortic bifurcation, and we histologically observed and compared those sites in regard to the changes with time, the kinds of infiltrating cells and the number of inflammatory cells. We also observed the relationship between the vasa vasorum and inflammatory cell localization in the tunica media, and examined the progression of inflammation in the tunica media. RESULTS:Destruction of the vascular architecture was not seen in any of the 37 cases, but inflammatory cell infiltration was observed in 90% of the acute-phase cases. The inflammatory cell infiltration involved the tunica intima and tunica adventitia of the aorta on the 6th disease-day, and all layers of the aorta on the 13th disease-day; the infiltration peaked on the 18th disease-day. The infiltration gradually disappeared thereafter, and no significant infiltration was seen in the remote phase. The infiltrating inflammatory cells consisted mainly of CD163-positive macrophages. Comparison of the 3 sites of the aorta showed that the inflammatory cell infiltration was more severe in the aortic root and aortic bifurcation than in the thoracic aorta. The progression of inflammation to the aortic tunica media from the adventitia showed 2 patterns: 1 in which macrophages were aggregated around the vasa vasorum; and a second in which there was no such aggregation around the vasa vasorum, but there was diffuse inflammatory cell infiltration of the tunica media. In addition to this, there were findings of direct infiltration of cells from the tunica intima into the tunica media. CONCLUSION:Inflammation in KD occurs in the aorta. The changes with time and the kinds of infiltrating cells were the same as reported to date for coronary arteries in KD. There were differences in the degree of inflammation among the 3 aortic sites. It can be thought that the inflammation from the adventitia to the media progresses via the vas vasorum, and also, there is a possibility of spreading directly. From the intima to the media, inflammation spreads directly. However, formation of aneurysms and destruction of the vascular architecture of the aorta were absent in this study, unlike in coronary arteries.
10.1016/j.carpath.2020.107303
Histologic and Immunohistochemical Evaluation of Infiltrating Inflammatory Cells in Kawasaki Disease Arteritis Lesions.
Kobayashi Mikiko,Matsumoto Yuki,Ohya Maki,Harada Kenichi,Kanno Hiroyuki
Applied immunohistochemistry & molecular morphology : AIMM
Kawasaki disease (KD) is a systemic vasculitis of unknown etiology which predominantly affects medium- and small-sized muscular arteries. Histopathologic studies of KD vasculitis lesions have demonstrated characteristic T cell infiltration and an abundance of CD8 T cells; however, the contribution of cytotoxic lymphocytes to KD vasculitis lesions has not been identified. Here, we histopathologically and immunohistochemically examined infiltrating inflammatory cells, particularly cytotoxic protein-positive cells, such as granzyme B cells and TIA-1 cells, in KD vasculitis lesions. Three autopsy specimens with acute-phase KD were observed and contained 24 vasculitis lesions affecting medium-sized muscular arteries, excluding pulmonary arteries. Infiltrating neutrophils in vasculitis lesions were evaluated by hematoxylin and eosin staining, and monocytes/macrophages and lymphocytes were evaluated by immunohistochemistry. The predominant cells were CD163 monocytes/macrophages and CD3 T cells. CD8 T cells, granzyme B cells, and TIA-1 cells were also observed, but CD56 natural killer cells were rare. To the best of our knowledge, the current study is the first histopathologic report confirming the infiltration of inflammatory cells with cytotoxic proteins in vasculitis lesions in patients with KD. Cytotoxic T cells may play a role in the development of vasculitis lesions in KD patients.
10.1097/PAI.0000000000000860
Atlas of circulating immune cells in Kawasaki disease.
Xie Zhenyu,Huang Yinde,Li Xinyang,Lun Yu,Li Xin,He Yuzhen,Wu Song,Wang Shiyue,Sun Jianjian,Zhang Jian
International immunopharmacology
Increasing evidence shows that the pathogenesis of Kawasaki disease (KD) is caused by abnormal and unbalanced innate and adaptive immune responses. However, the changes in and functions of adaptive immune cells in the peripheral blood of subjects with KD remain controversial. In this study, three different methods, CIBERSORT, Immune Cell Abundance Identifier (ImmuCellAI), and immune cell markers, were used to evaluate the proportions and abundances of immune cells in eight KD datasets (GSE9863, GSE9864, GSE18606, GSE63881, GSE68004, GSE73461, GSE73463, and GSE64486; a total of 1,251 samples). Compared with those in normal controls and convalescent KD samples, the proportions and abundances of innate immune cells such as neutrophils, monocytes, and macrophages in acute KD peripheral blood samples were significantly increased, while those of adaptive immune cells such as B and T cells were significantly decreased. The change tendencies of these immune cells were similar to those observed in other febrile illnesses but were more significant. However, in the coronary artery tissues of patients with convalescent KD, adaptive immune cells, especially B cells and CD8+ T cell subsets, were significantly increased. This result suggests that adaptive immune cells can be selectively recruited from peripheral blood into the coronary arteries. In addition, we found that elevated neutrophils in peripheral blood could be used as a biomarker to assist in the differential diagnosis of KD, but we did not find immune cells that could accurately predict intravenousimmunoglobulin (IVIG) responses in multiple datasets.
10.1016/j.intimp.2021.108396
Kawasaki disease shock syndrome: Unique and severe subtype of Kawasaki disease.
Gamez-Gonzalez Luisa Berenise,Moribe-Quintero Isabel,Cisneros-Castolo Martin,Varela-Ortiz Javier,Muñoz-Ramírez Mireya,Garrido-García Martin,Yamazaki-Nakashimada Marco
Pediatrics international : official journal of the Japan Pediatric Society
BACKGROUND:Kawasaki disease shock syndrome (KDSS) is an uncommon presentation of Kawasaki disease (KD). KDSS has been associated with more severe markers of inflammation, coronary abnormalities and i.v. immunoglobulin (IVIG) resistance. METHODS:A retrospective, descriptive study of children with KDSS in two hospitals was performed. Relevant articles about KD and shock were collected, and demographic data, clinical presentation, laboratory variables, echocardiogram findings, treatment and special features were analyzed when available. Twelve patients diagnosed with KDSS were retrospectively reviewed from two centers in Mexico, along with 91 additional cases from the literature. RESULTS:Seventy-two patients presented with complete KD (69.9%), and 30.1% (31/103) had unusual KD manifestations. The most frequent diagnosis at the time of admission was toxic shock syndrome (TSS; n = 20). Sixteen of the 20 had coronary artery abnormalities. Overall, abnormalities in the coronary arteries were documented in 65% of the patients. The mortality rate was 6.8%. CONCLUSION:The presence of coronary aneurysms was significantly and positively correlated with male gender, IVIG resistance, inotrope treatment, cardiac failure, abdominal pain and neurological symptoms. IVIG-resistant patients had higher neutrophil : lymphocyte ratio. Abdominal symptoms, hypoalbuminemia and elevated C-reactive protein were present in almost all of the patients. Multisystem involvement with atypical presentation in KDSS is frequent. An important differential diagnosis is TSS. Mechanical ventilation, gastrointestinal and neurological symptoms were associated with IVIG resistance and the presence of coronary aneurysms. The first line of treatment includes IVIG and pulse corticosteroids; in severe cases, infliximab, anakinra, cyclosporine or plasmapheresis are alternative treatment options.
10.1111/ped.13614
Association between breastfeeding and Kawasaki disease: a case-control study.
Wang Shun,Xiang Dan,Fang Congcong,Yao Baozhen
European journal of pediatrics
The association between breastfeeding and Kawasaki disease is not fully understood. We performed a case-control study to examine the association between breastfeeding and Kawasaki disease. In this study, 389 children diagnosed with Kawasaki disease and 426 gender- and age-matched controls were identified at Renmin Hospital of Wuhan University between November 2013 and March 2019. Demographic and clinical data were collected from a structured telephone interview and medical record database. Odds ratio and 95% confidence interval for risk of Kawasaki disease were estimated. Children who were breastfed exclusively had a decrease in developing Kawasaki disease (adjusted odds ratios and 95% confidence intervals 0.53 (0.38-0.74). Although the risk reduction was not statistically different, partial breastfeeding also provided a protective effect (adjusted odds ratios and 95% confidence intervals 0.70 (0.48-1.01). In the stratified analysis, we still observed that exclusive breastfeeding was inversely associated with the development of complete Kawasaki disease (adjusted odds ratios and 95% confidence intervals 0.52 (0.31-0.88) and incomplete Kawasaki disease (adjusted odds ratios and 95% confidence intervals 0.54 (0.38-0.77). However, there was no significant association between exclusive breastfeeding and the intravenous immunoglobulin treatment response (adjusted odds ratios and 95% confidence intervals 0.69 (0.27-1.69) and the risk of coronary artery lesions (adjusted odds ratios and 95% confidence intervals 0.79 (0.49-1.31) in Kawasaki disease.Conclusion: Our analysis suggests that exclusive breastfeeding was inversely associated with the development of Kawasaki disease and that breastfeeding might be a potential protective factor against Kawasaki diseaseWhat is known• Previous studies have demonstrated that breastfeeding has been shown to potentially confer protection against several autoimmune disorders of childhood.• The association between breastfeeding and Kawasaki disease is not fully understood.What is newThe first study to evaluate the association between breastfeeding and the development of Kawasaki disease in China with a large sample size.• Exclusive breastfeeding was inversely associated with the development of Kawasaki disease and breastfeeding might be a potential protective factor against Kawasaki disease.
10.1007/s00431-019-03529-y
Effect of Activin A on activation status of monocytes in acute-phase Kawasaki disease.
Wu Qian,Yang Zhi,Huang Yanyan,Wang Linlin,Weng Ruohang,Yang Jun
Clinical and experimental medicine
Kawasaki disease is a kind of self-limited systemic vasculitis involving middle and small arteries, which usually occurs in children under 5 years old. Excessive inflammatory response caused by activation of monocytes is one of the important mechanisms of Kawasaki disease. Activated monocytes secrete large amounts of inflammatory mediators such as TNF-α and IL-1β. Activin A, a member of transforming growth factor-β superfamily, is a multifunctional growth and transforming factor. Several experimental evidences pinpoint that Activin A can regulate multiple biological function of the immune system. However, whether Activin A is involved in regulation of activation of monocytes in Kawasaki disease was not well characterized. Here, this study showed that the expression of Activin A in serum decreased in acute-phase Kawasaki disease. Furthermore, Activin A inhibits activin type IIA receptor, activin type IB receptor, CD86 and CD80 expression in over-activated monocytes. In addition, Activin A inhibited Smad3 expression and NF-κB signaling pathways. Specific function and mechanism of Activin A in acute-phase Kawasaki disease need further study.
10.1007/s10238-021-00695-y
Laboratory parameters between multisystem inflammatory syndrome in children and Kawasaki disease.
Zhou Chunling,Zhao Yan,Wang Xia,Huang Ying,Tang Xuewen,Tang Lei
Pediatric pulmonology
Multisystem inflammatory syndrome in children (MIS-C) associated with coronavirus disease 2019 (COVID-19) has been described to partially overlap with Kawasaki disease (KD) with regard to clinical symptoms, but they are unlikely to share the same disease entity. We conducted a systematic review and meta-analysis to characterize the laboratory parameters of MIS-C compared with those of KD and Kawasaki disease shock syndrome (KDSS). Databases were searched for studies on laboratory parameters of MIS-C (hematology, inflammatory markers, cardiac markers, and biochemistry) through May 31, 2021. Twelve studies with 3073 participants yielded 969 MIS-C patients. In terms of hematology, MIS-C patients had lower levels of leukocytes, absolute lymphocyte count and platelet count (PLT) than KD patients and had similar absolute neutrophil count (ANC) and hemoglobin (Hb) levels. In terms of inflammatory markers, MIS-C patients had higher levels of C-reactive protein, D-dimer and ferritin than KD patients and had similar levels of procalcitonin and erythrocyte sedimentation rate (ESR). In terms of cardiac markers, MIS-C patients had higher CPK levels than KD patients. The levels of N-terminal pro-brain natriuretic peptide, troponin and aspartate aminotransferase were not significantly different between MIS-C and KD patients. In terms of biochemistry, MIS-C patients had lower levels of albumin, sodium and alanine aminotransferase and higher levels of creatinine than KD patients. In addition, MIS-C patients had lower levels of PLT, Hb and ESR and higher levels of ANC than KDSS patients. Measurement of laboratory parameters might assist clinicians with accurate evaluation of MIS-C and further mechanistic research.
10.1002/ppul.25687