Kawasaki Disease Patients Research Articles

Identification of rare coding variants associated with Kawasaki disease by whole exome sequencing.

Kawasaki disease (KD) is an acute pediatric vasculitis that affects genetically susceptible infants and children. To identify coding variants that influence susceptibility to KD, we conducted whole exome sequencing of 159 patients with KD and 902 controls, and performed a replication study in an independent 586 cases and 732 controls. We identified five rare coding variants in five genes (FCRLA, PTGER4, IL17F, CARD11, and SIGLEC10) associated with KD (odds ratio [OR], 1.18 to 4.41; p = 0.0027–0.031). We also performed association analysis in 26 KD patients with coronary artery aneurysms (CAAs; diameter > 5 mm) and 124 patients without CAAs (diameter < 3 mm), and identified another five rare coding variants in five genes (FGFR4, IL31RA, FNDC1, MMP8, and FOXN1), which may be associated with CAA (OR, 3.89 to 37.3; p = 0.0058–0.0261). These results provide insights into new candidate genes and genetic variants potentially involved in the development of KD and CAA.

RADIATION DOSE FOR PATIENTS WITH KAWASAKI DISEASE UNDERGOING FLUOROSCOPICALLY GUIDED CARDIAC CATHETERIZATION.

The goal of the present study was to estimate the radiation dose for a group of 45 Kawasaki disease (KD) patients undergoing fluoroscopically guided cardiac catheterization. The sample of procedures corresponds to a single hospital and was collected in 10years. Anthropometric characteristics and the quantities of air kerma-area product (PKA) among others were recorded for each procedure. Monte Carlo PCXMC 2.0 software was used to estimate organ and effective doses. The PKA value of 7.2Gycm2 was proposed as the local Diagnostic Reference Level for KD. For organ absorbed doses, median values for thyroid, heart, lungs, esophagus, skin, active bone and breast were 1.2; 2.2; 4.6; 2.7; 1.1; 1.2 and 2.7mGy, respectively. For effective dose, the mean value was 2.7±2.5mSv. This paper presents the first patient dose values for the KD using catheterization techniques, in Latin America and the Caribbean Region.

Diagnostic Value of Immune-Related Genes in Kawasaki Disease.

Kawasaki disease (KD) is a systemic vasculitis that predominantly damages medium- and small-sized vessels, and mainly causes coronary artery lesions (CALs). The diagnostic criterion of KD mainly depends on clinical features, so children could be easily misdiagnosed and could suffer from CALs. Through analysis, a total of 14 immune-related DEGs were obtained, of which IL1B, ADM, PDGFC, and TGFA were identified as diagnostic markers of KD. Compared with the non-KD group, KD patients contained a higher proportion of naive B cells, activated memory CD4 T cells, gamma delta T cells, and neutrophils, while the proportions of memory B cells, CD8 T cells, activated memory CD4 T cells, and activated NK cells were relatively lower. In conclusion, immune-related genes can be used as diagnostic markers of KD, and the difference in immune cells between KD and non-KD might provide new insight into understanding the pathogenesis of KD.

The clinical implications of serum ferritin in Kawasaki disease: a helpful biomarker for evaluating therapeutic responsiveness, coronary artery involvement and the tendency of macrophage activation syndrome.

IntroductionSerum ferritin (SF) is an acute-phase reactant in inflammatory diseases. Our aim was to analyze the clinical implications of SF in Kawasaki disease (KD).Methods244 KD children were divided into 6 subgroups. SF, inflammatory mediators and blood cell counts were detected.Results(1) SF dramatically increased in the acute phase of KD and maintained after IVIG therapy; (2) SF increased in IVIG-nonresponsive KD patients (AUC = 0.705; sensitivity: 57.10%; specificity: 82.90%); SF positively correlated with the internal diameter of the coronary artery (AUC = 0.603; sensitivity: 92.30%; specificity: 37.70%); (3) SF increased in 4 patients with the macrophage activation syndrome (MAS)/MAS tendency (979.03 ±474.19 μg/l).ConclusionsSF is implied to be a helpful biomarker for forecasting IVIG-nonresponsive KD, coronary artery abnormalities (CAAs) and MAS tendency.

Co-culture of peripheral blood mononuclear cell (PBMC) and human coronary artery endothelial cell (HCAEC) reveals the important role of autophagy implicated in Kawasaki disease.

BackgroundKawasaki disease (KD) is a systemic vasculitis syndrome that commonly occurs in children. Autophagy has been increasingly shown to be involved in various cardiovascular diseases, including endothelial dysfunction and vascular endothelial injury. However, whether autophagy is implicated in the pathogenesis of KD remains poorly understood, and particularly, how the dysfunction of human coronary artery endothelial cells (HCAECs) is associated with autophagy in peripheral blood mononuclear cells (PBMCs) from KD patients awaits further investigation.MethodsPeripheral blood samples were collected from KD patients, common fever patients, and healthy controls. The PBMC samples were isolated from KD blood samples collected at three different phases: the acute phase before therapy (acute-KD), 1 week (subacute-KD), and 4 weeks (convalescent-KD) after drug administration.ResultsThe autophagy flux was significantly increased in the PBMCs of KD patients at acute phase. The PBMCs of acute KD patients could induce autophagy in HCAECs and promote the secretion of chemokines and pro-inflammatory factors after cocultured with HCAECs whereas 3-methyladenine (3-MA) drug could partly reverse this process.ConclusionsAutophagy is involved in the inflammatory injury of vascular endothelial cells associated with PBMCs in KD patients, and may play a crucial role in regulating inflammation. Hence, we identify a novel regulatory mechanism of vascular injury in this disease.

Human umbilical cord mesenchymal stem cells regulate CD54 and CD105 in vascular endothelial cells and suppress inflammation in Kawasaki disease

ObjectiveThe objective was to evaluate the expression levels of CD31+CD54+ and CD31+CD105+ endothelial microparticles (EMPs) before and after intravenous immunoglobulin (IVIG) treatment of Kawasaki disease (KD). To explore the role of human umbilical cord mesenchymal stem cells (hucMSCs) in inhibiting endothelial inflammation in KD, the effects of hucMSCs on the expression of CD54 and CD105 in endothelial cells in KD were analyzed in vivo and in vitro. MethodsThe concentrations of IL-1β and VEGF in the peripheral blood of KD or healthy children were detected, and the distributions of CD31+CD54+ and CD31+CD105+ EMPs in platelet-poor plasma (PPP) were analyzed by flow cytometry. Human umbilical vein endothelial cells (HUVECs) were first cocultured with the patients’ peripheral blood mononuclear cells (PBMCs). Next, HUVECs were cocultured with hucMSCs after stimulation with inactivated serum from patients. Cell proliferation and migration activities were assessed, and the expression of CD54, CD105 and IL-1β was analyzed. In an in vivo study, hucMSCs were transplanted into KD mice. The locations and expression levels of CD54, CD105 and IL-1β in the heart tissues of mice were analyzed. ResultsThe levels of IL-1β and CD31+CD54+ EMPs were significantly higher before IVIG treatment and 2 weeks after treatment in KD patients (P < 0.01). However, the levels of VEGF and CD31+CD105+ EMPs increased significantly in KD only after IVIG treatment (P < 0.01). KD-inactivated serum stimulation combined with cocultivation of PBMCs can activate inflammation in HUVECs, leading to reduced cell proliferation and migration activities. Cocultivation also increased the expression of CD54 and decreased the expression of CD105 (P < 0.001). Cocultivation with hucMSCs can reverse these changes. Additionally, hucMSC transplantation downregulated the expression of IL-1β and CD54 and significantly upregulated the expression of CD105 in KD mice. ConclusionThe expression levels of CD31+CD54+ and CD31+CD105+ EMPs showed inconsistent changes at different KD statuses, providing potential markers for clinical application. HucMSCs suppress inflammation and regulate the expression levels of CD54 and CD105 in vascular endothelial cells in KD, possibly providing a new basis for stem cell therapy for KD.

Temporal clustering of Kawasaki disease cases around the world

In a single-site study (San Diego, CA, USA), we previously showed that Kawasaki Disease (KD) cases cluster temporally in bursts of approximately 7 days. These clusters occurred more often than would be expected at random even after accounting for long-term trends and seasonality. This finding raised the question of whether other locations around the world experience similar temporal clusters of KD that might offer clues to disease etiology. Here we combine data from San Diego and nine additional sites around the world with hospitals that care for large numbers of KD patients, as well as two multi-hospital catchment regions. We found that across these sites, KD cases clustered at short time scales and there were anomalously long quiet periods with no cases. Both of these phenomena occurred more often than would be expected given local trends and seasonality. Additionally, we found unusually frequent temporal overlaps of KD clusters and quiet periods between pairs of sites. These findings suggest that regional and planetary range environmental influences create periods of higher or lower exposure to KD triggers that may offer clues to the etiology of KD.

Abstract 13544: Inflammasome Activation In Kawasaki Disease And Multisystem Inflammatory Syndrome In Children

Introduction: Multisystem Inflammatory Syndrome in Children (MIS-C) is a newly identified syndrome elicited by infection of acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Although MIS-C shares several clinical features with Kawasaki disease (KD), a greater magnitude of systemic inflammation is usually associated with MIS-C. Inflammasome activation induces the secretion of pro-inflammatory cytokines, IL-1β and IL-18 and the inflammatory form of cell death, pyroptosis. To provide mechanistic insights into MIS-C and KD, we compared the expression and activation of the inflammasome in blood samples from MIS-C and KD patients. Methods: Expression levels of canonical and non-canonical inflammasome components, including NLRP3 , CASP1 , CASP4 , CASP5 , IL1B , and the inflammatory mediator, TIFA in whole blood from KD and convalescent patients were analyzed from microarray datasets. The expression of these inflammasome-related genes was further examined in whole blood samples from MIS-C, KD, KD shock syndrome (KDSS) and convalescent patients using RT-qPCR. Inflammasome activation and TIFA expression were validated in granulocytes of febrile control, KD and MIS-C patients by Western blotting. Results: TIFA , NLRP3 , CASP1 , CASP4 , CASP5 , IL1B were upregulated in whole blood from MIS-C, KD, and KDSS patients as compared to convalescent patients. However, the differences were not significant among diseases. Although gene expression profiles were similar in KD, KDSS and MIS-C whole blood RNA, the processing of canonical and non-canonical inflammasome caspases, caspase-1, and caspase-4 were only observed in granulocytes isolated from MIS-C patients, but not KD and febrile controls. Moreover, TIFA was upregulated along with the activation of the inflammasome in granulocytes of MIS-C patients. Conclusions: Our results suggest that activation of inflammasomes, especially non-canonical inflammasome induction in granulocytes, is a hallmark of MIS-C, and differentiates it from KD.

Association of left ventricular systolic dysfunction with coronary artery dilation in Kawasaki disease patients: Assessment with cardiovascular magnetic resonance

PurposeTo quantify global and regional left ventricular (LV) strain parameters in patients with Kawasaki disease (KD) using cardiovascular magnetic resonance (CMR) tissue tracking and assess the association of coronary artery dilation (CA dilation) with LV systolic dysfunction. MethodsThirty-one KD patients with CA dilation, 22 patients without CA dilation and 27 age- and sex-matched normal controls underwent 3.0 T CMR examination. Z score of >2 was defined as CA dilation. Global LV strain parameters and regional LV strain parameters in 16 American Heart Association segmentation, including radial, circumferential and longitudinal peak strain (PS) and LV function were measured and compared among groups. ResultsNo significant difference in LV ejection fraction has been observed among controls, KD patients with CA dilation and without CA dilation (all p > 0.05). However, global longitudinal PS (GLPS) was lower in groups with CA dilation than those without CA dilation (−12.6 ± 4.1% vs −14.9 ± 2.6%, p < 0.05). For regional strain parameters, the segments with CA dilation (n = 301) were lower than those in both normal controls (n = 416) and segments without CA dilation (n = 547) in regional radial, circumferential and longitudinal PS (all p < 0.05). The severity of CA dilation was positively correlated to GLPS and regional longitudinal PS (r = 0.388 and r = 0.222; both p < 0.05) in KD patients. After adjusting for clinical characteristics, the multivariate analysis demonstrated that Z score was independently associated with GLPS in KD patients (β = 0.469, p = 0.000, model R2 = 0.355). ConclusionsCMR tissue tracking could sensitively identify subclinical LV dysfunction in KD patients with CA dilation. LV systolic dysfunction occurs particularly in the myocardium dominated by the dilated coronary artery. CA dilation is an independent predictor of LV systolic dysfunction.

Abstract 13032: Endothelial Cell Response to Intravenous Immunoglobulin, Infliximab and Atorvastatin Treatment During the Acute Phase of Kawasaki Disease

Introduction: Damage to coronary arteries (CA) during the acute phase of Kawasaki disease (KD) is linked to inflammatory cell infiltration, myofibroblast generation (EndMT: endothelial-mesenchymal transition), and endothelial cell (EC) dysfunction. To promote EC health, we performed a Phase I/IIa clinical trial (6-week course) of atorvastatin in patients with acute KD and coronary artery Z score &gt; 2.5. We demonstrated that atorvastatin was safe and well-tolerated. However, its effect on EC in KD has not been systematically studied. Hypothesis: Treatment with atorvastatin added to intravenous immunoglobulin (IVIG) and infliximab (IFX) promotes EC health in acute KD patients. Methods: We performed RNAseq on human umbilical vein ECs (HUVECs) incubated with pooled sera from KD patients (pre-treatment or subacute illness day 17-25) treated with IVIG and IFX with or without atorvastatin added to their initial treatment. Results: Differentially expressed genes (DEGs) from HUVECs incubated with sera pooled from 5 KD patients collected pre- and post-treatment (IVIG + IFX) that were suppressed by treatment included IL-8 , CCL2 and ICAM1 , molecules in the TNFα and IL1β pathways that have key roles in recruitment of inflammatory cells to EC. Subacute sera pooled from 5 patients treated with IVIG + IFX + atorvastatin induced expression of NOS3 , KLF2 and KLF4 , molecules that promote EC homeostasis and angiogenesis, and suppressed expression of TGFB2 and Dickkopf WNT signaling pathway inhibitor 1 ( DKK1 ), molecules in the TGFβ and WNT signaling pathways. These results were validated by RT-PCR on HUVECs incubated with independent individual sera from patients treated with/without atorvastatin. Conclusions: HUVECs incubated with pre- or post-treatment sera from KD patients showed upregulation of IL1 and TNFα pathway genes that were dramatically suppressed after treatment with IVIG and IFX. Incubation of HUVECs with post-treatment sera from patients who also received atorvastatin showed reduced expression of DKK1 and TGFB2 , suggesting reduced EndMT, and increased NOS3 and KLF4 , key mediators of EC homeostasis. These results suggest that atorvastatin improves EC health and may block KD-induced myofibroblast proliferation in the CA wall.

Abstract 10512: Sialic Acid-rich Fc Having A Strong Anti-inflammatory Effect In Kawasaki Disease Model

Introduction: Kawasaki disease (KD), which is the most common multisystem vasculitis with unknown causes in childhood, causes coronary artery (CA) aneurysms. High-dose intravenous immunoglobulin (IVIG) is the most standard treatment. However, the problem with current high-dose IVIG therapy is that it is inefficient for both patients and cost because it contains ineffective parts and requires a high total dose. It has recently been reported that sialic acid in the fragment crystallizable (Fc) region has an anti-inflammatory effect. Hypothesis: In the KD model, a small amount of sialic acid-rich (SR-)Fc has an anti-inflammatory effect equivalent to that of high-dose IVIG. Methods: A Candida albicans cell wall extract (CAWE)-induced KD-like vasculitis model was established in DBA/2 mice. IgG, antigen-binding fragment (Fab), and Fc with 2g/kg/0.5ml, and IgG, SR-IgG, and SR-Fc with 0.2g/kg/0.5ml, and placebo 0.5ml were administered intraperitoneally 3 times every other day (n=5, respectively). Four weeks after treatment, we compared the incidence of CA inflammation between each group. Histological analysis was performed by using a quantified scoring system: grade 1; &amp;lt;20 cells /HPF, grade 2; &amp;lt;100cells/HPF, grade 3; &amp;gt;100cels/HPF, grade 4; distraction of elastic lamina, grade 5; neointimal proliferation. Results: All five mice in placebo group had the infiltration grade 3 or higher (100%), whereas none of the mice in IgG group had the infiltration (0%). In Fab group, three out of four had the infiltration (75%, one mouse died), whereas in Fc group, only one out of five had the infiltration (20%). In one-tenth dose IgG group, two out of four had the infiltration (50%, one mouse died), whereas in one-tenth dose SR-IgG and SR-Fc group, 20% or less of them had the infiltration (one out of five, zero out of five, respectively). Treatment with one-tenth dose SR-IgG and SR-Fc significantly suppressed CAWE-induced vasculitis ( p &amp;lt;0.05 and 0.01, respectively). Conclusions: It was shown that the immunoglobulin effect was mainly in the Fc region and one-tenth dose SR-Fc had an anti-inflammatory effect equivalent to that of high-dose IgG in a Candida -induced KD mouse model. One-tenth doses SR-Fc may be an alternative treatment to high-dose IVIG in KD patients.

Abstract 10405: Associations Between Ivig Dose and Outcome of Kawasaki Disease Patients in Acute Phase

Background: The standard treatment of Kawasaki Disease (KD) is intravenous immunoglobulin (IVIG) 2g/kg and aspirin. However, the most effective dosage of IVIG to prevent coronary artery abnormalities (CAA) is not known. The purpose of this study was to identify the dose of IVIG for KD patients in acute phase using a national inpatient database in Japan. Method: We used the Diagnostic Procedure Combination database to identify KD patients treated with IVIG between 2010 and 2017. We used multiple logistic regression models to estimate the risk of proportion of CAA and IVIG resistance, and multiple regression models to estimate the difference of length of stay and medical cost. In all models, demographic characteristics and comorbidities were adjusted for as covariates. We generated restricted cubic splines models with the same covariate specification as the fully adjusted model with five knots to examine non-linear associations between IVIG dose and the different outcomes. Results: We extracted 42,331 eligible patients from the database. The age was 1.7 years (1.6 SD), male 24432 (58%), and body weight 11.1kg (4.9 SD). The mean dose of IVIG was 1.7g/kg (1.3 SD), proportion of CAA 1325(3.1%), and medical cost 6596 USD (5160- 8689). We found a reverse J-shaped association between the dose of IVIG and the proportion of CAA. IVIG dosage was also found to have U-shaped associations with length of stay and medical costs. Conclusion: When IVIG dose was less than 2g/kg, the proportion of CAA increased, and the length of stay and medical cost also increased; when IVIG dose was more than 2g/kg, the length of stay and medical cost could be increased, and 2g/kg IVIG was considered appropriate for the initial treatment of KD.

Distinguishing Between Multisystem Inflammatory Syndrome, Associated With COVID-19 in Children and the Kawasaki Disease: Development of Preliminary Criteria Based on the Data of the Retrospective Multicenter Cohort Study.

Objectives: Diagnostic between multisystem inflammatory syndrome associated with COVID-19 in children (MIS-C) and Kawasaki disease (KD) can make difficulties due to many similarities. Our study aimed to create a Kawasaki/MIS-C differentiation score (KMDscore) allowing discrimination of MIS-C and KD.Study design: The retrospective multicenter cohort study included clinical, laboratory, and instrumental information about MIS-C (n = 72) and KD (n = 147). The variables allowed to discriminate both conditions used to construct and validate the diagnostic score called the KMDscore.Results: Patients with MIS-C were older, had earlier admission to the hospital, had a shorter time before fever resolution, two times frequently had signs of GI and CNS involvement observed, and had more impressive thrombocytopenia, higher level of CRP, ferritin, ALT, AST, LDH, creatinine, triglycerides, troponin, and D-dimer compared to KD patients. Respiratory signs in MIS-C were presented with pleuritis, acute respiratory distress syndrome, oxygen dependency, lung infiltration, and ground-glass opacities in CT. The heart involvement with fast progression of myocarditis provided the severity of MIS-C and ICU admission due to 12 times higher arterial hypotension or shock and required cardiotonic. No differences in the frequency of CA lesions were seen in the majority of cases. Five criteria, CRP >11 mg/dl (18 points), D-dimer >607 ng/ml (27 points), age >5 years (30 points), thrombocytopenia (25 points), and GI involvement (28 points), were included in the KMDscore. The summa >55 points allowed to discriminate MIS-C from KD with a sensitivity of 87.5% and specificity of 89.1%.Conclusion: The KMDscore can be used to differentiate the diagnostic of MIS-C from KD.

A Machine Learning Model to Predict Intravenous Immunoglobulin-Resistant Kawasaki Disease Patients: A Retrospective Study Based on the Chongqing Population.

Objective: We explored the risk factors for intravenous immunoglobulin (IVIG) resistance in children with Kawasaki disease (KD) and constructed a prediction model based on machine learning algorithms.Methods: A retrospective study including 1,398 KD patients hospitalized in 7 affiliated hospitals of Chongqing Medical University from January 2015 to August 2020 was conducted. All patients were divided into IVIG-responsive and IVIG-resistant groups, which were randomly divided into training and validation sets. The independent risk factors were determined using logistic regression analysis. Logistic regression nomograms, support vector machine (SVM), XGBoost and LightGBM prediction models were constructed and compared with the previous models.Results: In total, 1,240 out of 1,398 patients were IVIG responders, while 158 were resistant to IVIG. According to the results of logistic regression analysis of the training set, four independent risk factors were identified, including total bilirubin (TBIL) (OR = 1.115, 95% CI 1.067–1.165), procalcitonin (PCT) (OR = 1.511, 95% CI 1.270–1.798), alanine aminotransferase (ALT) (OR = 1.013, 95% CI 1.008–1.018) and platelet count (PLT) (OR = 0.998, 95% CI 0.996–1). Logistic regression nomogram, SVM, XGBoost, and LightGBM prediction models were constructed based on the above independent risk factors. The sensitivity was 0.617, 0.681, 0.638, and 0.702, the specificity was 0.712, 0.841, 0.967, and 0.903, and the area under curve (AUC) was 0.731, 0.814, 0.804, and 0.874, respectively. Among the prediction models, the LightGBM model displayed the best ability for comprehensive prediction, with an AUC of 0.874, which surpassed the previous classic models of Egami (AUC = 0.581), Kobayashi (AUC = 0.524), Sano (AUC = 0.519), Fu (AUC = 0.578), and Formosa (AUC = 0.575).Conclusion: The machine learning LightGBM prediction model for IVIG-resistant KD patients was superior to previous models. Our findings may help to accomplish early identification of the risk of IVIG resistance and improve their outcomes.

Increased Expression of Pyroptosis in Leukocytes of Patients with Kawasaki Disease.

Background: Kawasaki disease (KD) is a form of febrile vasculitis that primarily occurs in children. It can cause inflammation of the coronary arteries, which leads to aneurysms. The pathogenesis of coronary arteries may be associated with apoptosis or pyroptosis mediated by caspases activity, but this idea has not been discussed much in KD. Materials and Methods: We enrolled 236 participants in this study. In the Affymetrix GeneChip® Human Transcriptome Array 2.0 study, there were 18 KD patients analyzed prior to receiving intravenous immunoglobulin (IVIG) treatment, at least 3 weeks after IVIG treatment, and 36 non-KD control subjects. We also recruited 24 KD patients prior to receiving IVIG treatment, at least 3 weeks after IVIG treatment, and 24 non-KD control subjects for Illumina HumanMethylation450 BeadChip study. A separate cohort of 134 subjects was analyzed to validate real-time quantitative PCR. Results: The mRNA levels of caspase-1, -3, -4, and -5 were significantly increased in KD patients compared with control subjects (p < 0.05). After administration of IVIG, the expression of these genes decreased considerably. Of particular note, the methylation status of the CpG sites of the caspase-4 and -5 genes demonstrated significant opposite tendencies between the KD patients and controls. Furthermore, compared with patients who responded to IVIG, refractory KD patients had a lower expression of the caspase-3 gene prior to IVIG treatment. Conclusion: Our study is the first to report the upregulation of pyroptotic caspase-1, -4, and -5 in peripheral leukocytes of KD patients. Moreover, the expression of caspase-3 may be associated with IVIG resistance in KD.

The Network of Pro-Inflammatory Factors CD147, DcR3, and IL33 in the Development of Kawasaki Disease.

IntroductionKawasaki disease (KD) is an acute febrile systemic vasculitis, but the etiology remains unknown. We studied serum levels of CD147, DcR3, and IL33 in different stages of KD to explore the value of CD147, DcR3, and IL33 in the pathophysiology of KD.MethodsWe measured serum levels of CD147, DcR3, and IL33 by enzyme-linked immunosorbent assay (ELISA) at different stages with 71 KD patients and 66 healthy control children. We apply for network tools GeneMANIA and Cytoscape APP to analyze the functions of these pro-inflammatory factors at the gene and protein level.ResultsSerum levels of CD147, DcR3, and IL33 were significantly increased in KD patients before IVIG treatment. Serum levels of CD147, DcR3, and IL33 gradually decreased over time after the treatment of IVIG. Eight cases were IVIG non-responders, while nine KD patients got CALs, but they did not overlap. And there were no statistical differences between group IVIG responders and IVIG non-responders or between groups without CALs and with CALs. We explored the functions of CD147, DcR3, and IL33 from GeneMANIA and Cytoscape APP and found these third pro-inflammatory factors were coexpressed, physical interactions, genetic interactions with other KD-related factors.ConclusionCD147, DcR3, and IL33 are involved in the pathophysiology of KD, which provides novel evidence for diagnosing and treating KD with their inhibitors.

Aspirin-Induced Delayed Urticaria in Children with Kawasaki Disease: A Retrospective Case-Control Study.

BackgroundAspirin remains a key component of the standard therapy for Kawasaki disease (KD) in children. Although it is well known that aspirin can cause hypersensitivity such as aspirin-induced urticaria (AIU), AIU in children with KD has not been described.MethodsA retrospective case-control study was conducted to investigate AIU clinical features, biochemical parameters, treatment and outcomes in children with KD. Furthermore, biomarkers for predicting AIU were explored using the receiver operating characteristic (ROC) curve analysis.ResultsWe identified 46 AIU cases with 22 boys and 24 girls during April 2015–May 2019. Eighty-nine age-matched KD patients without AIU were randomly chosen as controls. The proportions of children with allergy history and aspirin doses administered in the 2 groups were found not to be significantly different. AIU group had substantially higher baseline C-reactive protein and NT-proBNP levels, and increased neutrophil percent. AIU appeared 6.0 (4.0, 8.0) days after aspirin treatment. Aspirin withdrawal and anti-allergic treatment were applied for AIU, and AIU disappeared in 1–3 days. Baseline NT-proBNP predicted AIU with an AUC of 0.70 (95% CI [0.60 to 0.79]) for sensitivity and specificity of 72.1% and 62.5%, respectively, for a cut-off value of 612.9 mg/L. The length of hospital stay for AIU patients was significantly greater compared with controls.ConclusionAIU in KD children is not related to gender or aspirin dose, and those with AIU have more severe inflammation at admission. Aspirin should be withdrawn for AIU management. Baseline NT-proBNP may serve as a valuable biomarker to predict AIU.

Characteristics of Kawasaki Disease Patients during the COVID-19 Pandemic in Japan: A Single-Center, Observational Study.

Background: Under the Coronavirus disease 2019 (COVID-19) pandemic, manifestations in children with Kawasaki disease (KD) are different between the Western and the Eastern countries. Particularly, there has not been a report comparing a series of KD in Japan, where KD was originally discovered and has a large number of registered cases. Methods: We compared patients with KD under the period of the COVID-19 pandemic in Japan with the report from Italy during its reported period by a retrospective, cohort, observational study in a Japanese single center. Results: Thirty-two patients with typical KD were treated during the study period, while the Italian study reported 10 patients with the signs of KD. Concerning the proof of severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) infection, none (0%) of our KD cases showed a positive result and one and no patients developed the macrophage activation syndrome (MAS) and Kawasaki disease shock syndrome (KDSS), respectively; however, eight (80%) patients in the Italian series were confirmed with SARS-CoV-2 infection. MAS and KDSS developed in six and five patients, respectively. Conclusions: Cases reported as COVID-19 pandemic-related KD in Italy showed significantly different clinical characteristics from the typical KD symptoms known in Japan. Although they show KD-like manifestations, we cannot conclude that SARS-CoV-2 has the same etiology of our ‘classic’ KD at the present stage.

Multiple intravenous antibiotics usage is associated with intravenous immunoglobulin resistance in Kawasaki disease

Kawasaki disease (KD) is a form of systemic vasculitis that primarily affects children under the age of 5 years old. Antibiotics are often prescribed for KD patients even before a diagnosis is made due to their prolonged fever and elevated inflammatory markers. Therefore, the purpose of this study was to investigate the impact of antibiotics usage on the disease outcome of KD. We carried out a retrospective chart review of children between 2005 and 2017 for initial immunoglobulin (IVIG) treatment of KD. KD children with initial IVIG treatment more than 10 days after the onset of symptoms were excluded. In total, 280 children were eligible for this study, among which 209 had been treated with antibiotic(s) and 71 had not been. The IVIG resistance rates were 5.6% (4/71), 8.9% (10/112), and 21.6% (21/97) in non-users, single-drug users, and multiple-drug users, respectively (r=0.205, p=0.003). The IVIG resistance rate of the multiple antibiotics drug users in KD patients was significantly higher than the other two groups. Furthermore, the likelihood of IVIG resistance was found to increase with elevated C-reactive protein (CRP) values (1.010/unit, p<0.001) but not with total white blood cell (WBC) count (p=0.466). The probability of IVIG resistance increases with elevated CRP values and the use of multiple IV antibiotics, thus indicating that physicians should be prudent in administering multiple IV antibiotics when treating assumed infections in KD children.

Coronary lesions suggestive of kawasaki disease in young patients presenting with acute myocardial infarction

Abstract Background Approximately 25% of patients with untreated Kawasaki disease (KD) in childhood develop coronary aneurysms, which represent a higher likelihood for the occurrence of acute myocardial infarction (AMI) in young adults. Although the clinical characteristics of young adults with KD and suspected ischemia have been studied, the available data about suggestive lesions of KD in AMI is scarce. Purpose To describe the prevalence, clinical characteristics and in-hospital mortality of young adults with AMI and coronary artery lesions suggestive of KD. Methods We conducted a retrospective study of consecutive ≤40-year old patients hospitalized with AMI and coronary angiography in a coronary care unit of a Mexican teaching hospital between 2006–2020. Patients were classified according to the presence or absence of suggestive lesions of KD sequelae such as proximal aneurysms, larger size and normal distal segments Results There were included 488 patients of 40 years of age and younger, diagnosed with AMI, in whom a coronary angiography was performed. Among them, 44 patients (9%) showed coronary aneurysm or ectasia, within this group, 16 patients (36.3%) had angiographic lesions compatible with KD. The patients were classified according to the type of coronary lesions: Angiographic lesions compatible with KD, 3.3% (n=16); Diffuse coronary artery ectasia (CAE), 5.7% (n=28); and Obstructive coronary disease (OCD), 91% (n=444). The prevalence of smoking, dyslipidemia, and hypertension were similar between the groups, whereas a history of diabetes was absent in KD patients (0%, 10.7%, and 22.1% for KD, CAE and OCD, respectively; P=0.04). At admission, ST-elevation myocardial infarction was more frequent in patients with KD (81.3%, 75%, and 67.1% for KD, CAE and OCD, respectively; P=0.35). More than half of patients with KD had coronary aneurysms in two or more vessels. The right coronary artery was the most commonly affected artery followed by the left anterior descending artery and left circumflex coronary artery (87.5%, 56.3% and 56.3%, respectively). The presence of intracoronary thrombus identified at the time of angiography was more frequent in patients with KD (62.5%, 60.7% and 44.1% for KD, CAE and OCD, respectively; P=0.09). Overall, unadjusted in-hospital mortality was 3.9% and there were no deaths in the KD group (0%, 0% and 4.3% for KD, CAE, and OCD, respectively; P=0.37). Conclusion In young patients with AMI, the sequelae of KD should be considered as a possible etiology, based on their angiographic characteristics. To bear in mind the nature of the pathogenesis is crucial to assess medical and interventional management strategies, which are not well defined yet, in order to evaluate cardiovascular risk and optimize a patient-tailored treatment, which could differ from the treatment of atherosclerotic coronary artery disease Funding Acknowledgement Type of funding sources: None. Figure 1Figure 2