Kawasaki Disease Research Articles

Proteomic Signatures of Multisystem Inflammatory Syndrome in Children (MIS-C) Associated with COVID-19: A Narrative Review.

Multisystem Inflammatory Syndrome in Children (MIS-C) is a post-infectious complication of COVID-19. MIS-C has overlapping features with other pediatric inflammatory disorders including Kawasaki Disease (KD), Macrophage Activation Syndrome (MAS), Toxic Shock Syndrome and sepsis. The exact mechanisms responsible for the clinical overlap between MIS-C and these conditions remain unclear, and biomarkers that could distinguish MIS-C from its clinical mimics are lacking. This study aimed to provide an overview of how proteomic methods, like Mass Spectrometry (MS) and affinity-based proteomics, can offer a detailed understanding of pathophysiology and aid in the diagnosis and prognosis of MIS-C. A narrative review of relevant studies published up to July 2024 was conducted. We identified 15 studies and summarized their key proteomic findings. These studies investigated the serum or plasma proteome of MIS-C patients using MS, Proximity Extension, or Aptamer-based assays. The studies associated the proteomic profile of MIS-C with laboratory and clinical parameters and/or compared it with that of other diseases including acute COVID-19, KD, MAS, pediatric rheumatic diseases, sepsis and myocarditis or pericarditis following COVID-19 mRNA immunization. Depending on the method and the control group, different proteins were increased or decreased in the MIS-C group. The limitations and challenges in MIS-C proteomic research are also discussed, and future research recommendations are provided. Although proteomics appear to be a promising approach for understanding the pathogenesis and uncovering candidate biomarkers in MIS-C, proteomic studies are still needed to recognize and validate biomarkers that could accurately discriminate MIS-C from its clinical mimics.

Spatiotemporal analysis of the association between Kawasaki disease incidence and PM2.5 exposure: a nationwide database study in Japan

BackgroundKawasaki disease (KD) is an acute vasculitis primarily affecting children. While some studies suggest a link between KD and PM2.5 exposure, findings remain inconsistent. This study aimed to perform spatiotemporal...

Systemic Juvenile Idiopathic Arthritis and arthralgia - can it be diagnosed early within the window period? – An observation of serum biomarkers and analysis with other differential conditions in children

Background: Systemic juvenile idiopathic arthritis (sJIA)is a cause of persisting arthralgia which is often missed. Diagnosing sJIA can be challenging, especially when overt arthritis is absent at presentation, highlighting the need for a diagnostic biomarker. Few recent studies have assessed potential biomarkers for sJIA, however, there is no consensus in detecting early. We conducted a study evaluating serum IL-1, IL-6, IL-18, S100A8, and S100A9 as potential diagnostic markers to distinguish sJIA from other conditions presenting as joint pain in children. Methods: A prospective study was conducted in our institute from May-2019 to October-2020 in children under 16 years, who had persisting arthralgia. Serum concentrations of IL-1, IL-6, IL-18, S100A9, and S100A8 were determined using ELISA kits. Receiver operating curve (ROC) analysis was used to determine the cut-off values for IL-1, IL-6, IL-18, S100A8, and S100A9 for differentiating sJIA from other causes of joint pain and fever. Results- Out of 47 children who presented with joint pain and fever 19 of them were eventually diagnosed with sJIA. In the other 28 children, arthralgia and fever was attributed to conditions other than sJIA (non-sJIA). The non-sJIA group comprised children with acute lymphoblastic leukemia, hemophagocytic histiocytosis, systemic lupus erythematosus, Kawasaki disease, Kikuchi disease, and inflammatory bowel disease. Serum levels of IL-18, S100A8, and S100A9 were significantly higher in patients with sJIA compared to the non-sJIA group (p<0.05). The area under the curve (AUC) was significant for IL-18(77.9%), S100A8 (74.9%), and S100A9(71.2%). A serum IL-18 cut-off level of > 2030.45 pg/ml was useful for differentiating between sJIA and other diseases with a sensitivity of 66.67% and specificity of 75.86% for the diagnosis of sJIA. Conclusion- Serum IL-18, S100A8, and S100A9 can be useful in differentiating sJIA early from other causes of persisting arthralgia in children provided with appropriate identification of symptomatology and suspicion.

A Prospective Study on Different Doses of Gammaglobulin Plus Aspirin in the Pediatric Kawasaki Disease and the Impacts on CRP and WBC Levels

Abstract Objective To evaluate the efficacy of different doses of gammaglobulin combined with aspirin in treating pediatric Kawasaki disease and its impact on C-reactive protein (CRP) and white blood cell (WBC) levels. Methods A prospective study was conducted with 150 children (3groups) diagnosed with Kawasaki disease. Group A received a higher dose of intravenous gammaglobulin (2.5 g/kg) combined with aspirin, Group B received a standard dose of intravenous gammaglobulin (2 g/kg) combined with aspirin, and Group C received a lower dose of intravenous gammaglobulin (1 g/kg) combined with aspirin. All groups received oral aspirin therapy (30 mg/kg/day) for a standard duration. The time to symptom improvement, treatment efficacy, laboratory parameters, and adverse reactions were monitored and analyzed. Results Group B showed a shorter time to symptom relief compared to Groups A and C, particularly in fever reduction, mucosal congestion, cervical lymph node enlargement, and limb symptoms. The total effective rate was higher in Group B compared to Groups A and C. Group B showed improvements in WBC, CRP, ESR, and PLT levels. Conclusion Standard-dose intravenous gammaglobulin combined with aspirin was more effective in treating pediatric Kawasaki disease compared to higher and lower doses. The treatment regimen in Group B resulted in shorter time to symptom relief, higher total effective rate, improved biochemical markers. Incidence of adverse reactions was similar among the three groups, demonstrating the safety of standard dosage.

Analysis of the etiology and clinical indicators of infantile cholestasis

Objective: To explore the disease spectrum and corresponding clinical indicators of infantile cholestasis so as to provide a basis for the diagnosis of this type of disease at an early stage. Methods: The clinical data was collected from 203 hospitalized children diagnosed with infantile cholestasis at the Department of Gastroenterology of Maternal and Child Health Care, Guiyang City, from January 2018 to March 2023, including 130 males and 73 females. Patients general condition, personal history, and blood biochemical test indicators, including liver and coagulation function, blood ammonia, blood lipid profile, blood sugar, TORCH, thyroid function, and others, were retrospectively analyzed after admission. Cholangiography and high-throughput gene sequencing were performed in certain patients. The etiology of the enrolled cases were analyzed. Children's clinical data were compared with distinct inherited metabolic liver diseases (Group A) and biliary atresia (Group B). The statistical analysis was conducted using the t-test, Mann-Whitney test, Kruskal-Wallis test, or χ2 test, according to different data. Results: In 33 cases, infectious factors-primarily CMV infection-were the etiology of cholestasis. Forty cases had aberrant bile duct development, primarily biliary atresia, choledochal cysts, and intrahepatic bile duct dysplasia. In 26 cases, genetic metabolic factors mainly included citrin protein deficiency, sodium-taurocholate co-transporting polypeptide deficiency, and Alagille syndrome. 11 cases had drug/poisoning factors (parenteral nutrition-associated cholestasis). 19 cases had idiopathic infantile cholestasis. Three cases had other factors; however, all of them had Kawasaki disease. 71 cases had an unclear diagnosis. There was no statistically significant difference in terms of gender and age between groups A and B (P>0.05). The alkaline phosphatase (ALP) and bile acid levels were significantly higher in Group A than Group B, with a P<0.05, while the gamma glutamyltransferase (GGT), direct bilirubin (DBil), and albumin levels were lower than those in Group B, with a P<0.05. The cytomegalovirus infection rate was higher in Group B (62.50%) than Group A (34.62%), and the difference between the two groups was statistically significant (χ2=3.89, P<0.05). The alanine aminotransferase, aspartate aminotransferase, GGT, DBil, and albumin were significantly lower in patients with citrin protein deficiency than those in patients with biliary atresia, while ALP, bile acid, and blood ammonia were higher than those in patients with biliary atresia. Patients with sodium-taurocholate co-transporting polypeptide deficiency had higher bile acid than patients with biliary atresia, while the DBil was lower than that in patients with biliary atresia, and the difference was statistically significant (P<0.05). Conclusion: Infantile cholestasis etiology is diverse. ALP, bile acids, GGT, DBil, and albumin levels can serve as simple indicators for early-stage differentiation between inherited metabolic liver disease and biliary atresia. The cholestasis etiology should be determined as early as possible following biliary atresia exclusion by actively completing genetic metabolic gene detection.

Frequencies of Human Leukocyte Antigen Alleles in Turkish Children with Kawasaki Disease

Abstract Objective Kawasaki disease (KD) is an acute systemic vasculitis that is one of the major causes of acquired heart disease especially in young children. The pathogenesis of KD is still unclear. The increased incidence of the disease among Japanese children and siblings of affected patients suggests a genetic component to KD susceptibility. Several reports have studied human leukocyte antigen (HLA) polymorphisms in different populations with KD and found various results. In the present study, we aimed to evaluate the association of HLA-A, -B, -C, -DRB1, and -DQB1 allele frequencies in Turkish children with KD. Methods The study was conducted between January 2016 and February 2018. HLA Class I (A, B, and C) and Class II (DRB1 and DQB1) alleles of patients and healthy controls were studied using the low-resolution DNA-based sequence-specific oligonucleotide method. Results Fifty children with KD and 500 healthy controls were included in this study. In the analysis of HLA-A, HLA-B, HLA-C, and HLA-DRB1 alleles, no statistical difference was found in the frequency of alleles between the patients with KD and the control group. However, a significantly lower frequency of the HLA-DQB1*03 allele was observed in the KD group than in the control group (p &lt; 0.001, odds ratio [OR]: 0.29, 95% confidence interval [CI]: 0.15–0.55). When the patients with KD were divided into two subgroups with or without coronary artery lesions (CALs), the frequency of the HLA-DQB1*03 allele was also found lower in the KD group with CALs than the KD group without CALs (p = 0.008, OR: 0.19, 95% CI: 0.05–0.68). Conclusion The study may guide future studies on HLA-DQB1*03 whether it is a protective allele for KD and CALs in Turkish children.

Shared neutrophil and T cell dysfunction is accompanied by a distinct interferon signature during severe febrile illnesses in children

Severe febrile illnesses in children encompass life-threatening organ dysfunction caused by diverse pathogens and other severe inflammatory syndromes. A comparative approach to these illnesses may identify shared and distinct features of host immune dysfunction amenable to immunomodulation. Here, using immunophenotyping with mass cytometry and cell stimulation experiments, we illustrate trajectories of immune dysfunction in 74 children with multi-system inflammatory syndrome in children (MIS-C) associated with SARS-CoV-2, 30 with bacterial infection, 16 with viral infection, 8 with Kawasaki disease, and 42 controls. We explore these findings in a secondary cohort of 500 children with these illnesses and 134 controls. We show that neutrophil activation and apoptosis are prominent in multi-system inflammatory syndrome, and that this is partially shared with bacterial infection. We show that memory T cells from patients with multi-system inflammatory syndrome and bacterial infection are exhausted. In contrast, we show viral infection to be characterized by a distinct signature of decreased interferon signaling and lower interferon receptor gene expression. Improved understanding of immune dysfunction may improve approaches to immunomodulator therapy in severe febrile illnesses in children.

FCGR2/3 polymorphisms are associated with susceptibility to Kawasaki disease but do not predict intravenous immunoglobulin resistance and coronary artery aneurysms.

Kawasaki disease (KD) is a pediatric vasculitis that can result in coronary artery aneurysm (CAA) formation, which is a dangerous complication. Treatment with intravenous immunoglobulin (IVIg) significantly decreases the risk of CAA, possibly through competitive binding to Fc-gamma receptors (FcγRs), which reduces the binding of pathological immune complexes. However, ~20% of children have recrudescence of fever and have an increased risk of CAA. Therefore, we aimed to identify genetic markers at the FCGR2/3 locus associated with susceptibility to KD, IVIg resistance, or CAA. We investigated the association of single-nucleotide polymorphisms (SNPs) and copy number variations (CNVs) at the FCGR2/3 locus with KD susceptibility, IVIg resistance, and CAA risk using a family-based test (KD susceptibility) and case-control analyses (IVIg resistance and CAA risk) in different cohorts, adding up to a total of 1,167 KD cases. We performed a meta-analysis on IVIg resistance and CAA risk including all cohorts supplemented by previous studies identified through a systematic search. FCGR2A-p.166His was confirmed to be strongly associated with KD susceptibility (Z = 3.17, p = 0.0015). In case-control analyses, all of the investigated genetic variations at the FCGR2/3 locus were generally not associated with IVIg resistance or with CAA risk, apart from a possible association in a Polish cohort for the FCGR3B-NA2 haplotype (OR = 2.15, 95% CI = 1.15-4.01, p = 0.02). Meta-analyses of all available cohorts revealed no significant associations of the FCGR2/3 locus with IVIg resistance or CAA risk. FCGR2/3 polymorphisms are associated with susceptibility to KD but not with IVIg resistance and CAA formation. Currently known genetic variations at the FCGR2/3 locus are not useful in prediction models for IVIg resistance or CAA risk.

Unravel the Enigma of Kawasaki Disease: Groping in the Dark

Kawasaki disease is one of the leading causes of acquired cardiac disease in childhood especially in Asian countries. Research efforts are extensive and focus on finding the molecular origin of Kawasaki disease. Kawasaki disease shows initially typical symptoms followed by coronary artery lesions in a few percentage of cases. Some patients develop coronary artery lesions, some do not. Research focus on finding biomarkers to predict the development of coronary artery lesions in a child with Kawasaki disease. Kawasaki-like features of the disease are known like MIS-C or Kawasaki-like syndrome, not clearly showing the classical clinical picture of Kawasaki disease. From that point, Kawasaki is not Kawasaki. This manuscript attempts to unravel the molecular and immunological enigma of a rare pediatric disease with to date, unknown etiology.

Transcriptome meta-analysis of Kawasaki disease in humans and mice.

Kawasaki Disease (KD) affects young children less than five years old with severe blood vessel inflammation. Despite being treatable, the causes and mechanisms remain elusive. This study conducted a meta-analysis of RNA sequencing (RNA-seq) data from human and animal models to explore KD's transcriptomic profile and evaluate animal models. We retrieved bulk and single-cell RNA-seq data from Gene Expression Omnibus, with blood and coronary artery samples from KD patients, aorta samples from KD mouse models (Lactobacillus casei cell wall extract-injected mice), and their controls. Upon consistent quality control, we applied Fisher's exact test to assess differential gene expression, followed by an enrichment analysis of overlapping genes. These studies identified 400 differentially expressed genes in blood samples of KD patients compared to controls and 413 genes in coronary artery samples. The data from KD blood and KD coronary artery samples shared only 16 differentially expressed genes. Eighty-one genes overlapped between KD human coronary arteries and KD mouse aortas, and 67 of these 81 genes were regulated in parallel in both humans and mice: 30 genes were up-regulated, and 37 were down-regulated. These included previously identified KD-upregulated genes: CD74, SFRP4, ITGA4, and IKZF1. Gene enrichment analysis revealed significant alterations in the cardiomyopathy pathway. Single-cell RNAseq showed a few significant markers, with known KD markers like S100A9, S100A8, CD74, CD14, IFITM2, and IFITM3, being overexpressed in KD cohorts. Gene profiles obtained from KD human coronary artery are more compatible with data from aorta samples of KD mice than blood samples of KD humans, validating KD animal models for identifying therapeutic targets. Although blood samples can be utilized to discover novel biomarkers, more comprehensive single-cell sequencing is required to detail gene expression in different blood cell populations. This study identifies critical genes from human and mouse tissues to help develop new treatment strategies for KD.

Lo que un exantema esconde

Since the SARS-CoV-2 virus pandemic alert broke out 3 years ago, in the child population the majority of symptoms have been mild, although an emerging entity has been described, SIM-Ped, capable of producing serious symptoms with cardiovascular involvement, gastrointestinal and rash. A clinical case related to this pathology is described, where a differential diagnosis with Kawasaki disease is made and a new classification of this entity as a clinical spectrum is described.

MTOR signalling controls the formation of smooth muscle cell-derived luminal myofibroblasts during vasculitis

The accumulation of myofibroblasts within the intimal layer of inflamed blood vessels is a potentially catastrophic complication of vasculitis, which can lead to arterial stenosis and ischaemia. In this study, we have investigated how these luminal myofibroblasts develop during Kawasaki disease (KD), a paediatric vasculitis typically involving the coronary arteries. By performing lineage tracing studies in a murine model of KD, we reveal that luminal myofibroblasts develop independently of adventitial fibroblasts and endothelial cells, and instead derive from smooth muscle cells (SMCs). Notably, the emergence of SMC-derived luminal myofibroblasts—in both mice and patients with KD, Takayasu’s arteritis and Giant Cell arteritis—coincided with activation of the mechanistic target of rapamycin (mTOR) signalling pathway. Moreover, SMC-specific deletion of mTOR signalling, or pharmacological inhibition, abrogated the emergence of luminal myofibroblasts. Thus, mTOR is an intrinsic and essential regulator of luminal myofibroblast formation that is activated in vasculitis patients and therapeutically tractable. These findings provide molecular insight into the pathogenesis of coronary artery stenosis and identify mTOR as a therapeutic target in vasculitis.

Maximum Diameter of Ileocecal Lymph Nodes Measured Using Abdominal Ultrasonography Allows for the Discrimination of Yersinia pseudotuberculosis Infection from Kawasaki Disease.

This study aimed to determine whether the maximum diameter of ileocecal lymph nodes measured using abdominal ultrasonography is useful for differentiating Yersinia pseudotuberculosis infection from Kawasaki disease in the acute phase. The optimal maximum diameter cutoff of the ileocecal lymph nodes was also explored to optimize differentiation between these 2 diseases. We included pediatric patients <15 years old who met the diagnostic criteria for Kawasaki disease. Stool culture testing, loop-mediated isothermal amplification of stool specimens, and serological diagnosis were performed to confirm the presence or absence of Y. pseudotuberculosis infection. Of the 122 patients included in the analysis, 17 were confirmed to have Y. pseudotuberculosis infection and 105 were not. The age (in months), white blood cell count, C-reactive protein level, prediction score (risk score) for nonresponse to intravenous immunoglobulin, and number of intravenous immunoglobulin doses did not differ significantly between the Y. pseudotuberculosis-positive and -negative groups. The maximum diameter of ileocecal lymph nodes was 6.0 (5.5-9.5) mm in the Y. pseudotuberculosis-positive group and 3.0 (2.5-3.8) mm in the Y. pseudotuberculosis-negative group (numbers presented as median, interquartile range), with a significantly larger diameter in the Y. pseudotuberculosis-positive group (P < 0.01, Mann-Whitney U test), suggesting potency of ultrasonography. In patients meeting the diagnostic criteria for Kawasaki disease, the possibility of Y. pseudotuberculosis infection is significantly higher if the maximum ileocecal lymph node diameter ≥5.1 mm. Its sensitivity and specificity being 100%, and 89.5%, respectively.

Whole-exome sequencing reveals Kawasaki disease susceptibility genes and their association with coronary artery lesion.

This study aimed to explore Kawasaki disease (KD) susceptibility genes and their complications like coronary artery lesions (CAL) using whole exome sequencing (WES). Between April 1, 2021, and December 31, 2022, our study included 55 pediatric patients diagnosed KD at our center, alongside a cohort of healthy children who sought medical care at our institution during the same timeframe. We extracted peripheral blood DNA from all participants and employed the advanced high-throughput Illumina Next-Generation Sequencing technology for comprehensive analysis. Through bioinformatics evaluation, we identified potential susceptibility genes. Moreover, from the 55 KD patients, we selected 15 for the CAL group and 40 for the non-CAL group. We aimed to investigate whether there were significant differences in the allele frequencies of the targeted susceptibility genes between these subgroups, to explore the risk alleles associated with the development of CAL in KD. HLA-DRB1 rs17882084 and IL6ST rs781455079 genotypes and alleles differed significantly between KD and non-KD (P < 0.05). No differences existed for IL17RC rs143781415 and VEGFB rs776229557 (P > 0.05). No differences in HLA-DRB1 rs17882084, IL6ST rs781455079, and VEGFB rs776229557 genotypes existed between CAL and non-CAL groups (P > 0.05). However, the IL17RC rs143781415 genotype differed significantly between them (P < 0.05). HLA-DRB1 rs17882084 and IL6ST rs781455079 genotypes may be potential KD susceptibility gene candidates. Specifically, HLA-DRB1 rs17882084 GA genotype and A allele, and IL6ST rs781455079 TC genotype and C allele may increase KD risk. Additionally, the IL17RC rs143781415 genotype may increase CAL risk in KD patients.

Incidence of Kawasaki disease among children in Chandigarh, India during 2015–2019: a trend analysis

Only limited information exists regarding the epidemiology of Kawasaki disease (KD) in low-income and middle-income countries. The present study provides the incidence of KD during 2015-2019 in Chandigarh, north India. Our centre follows the largest KD cohort in India. Children with KD at Chandigarh diagnosed during January 2015-December 2019 were enrolled in the study. Annual incidence rates were determined using decadal growth rates of the National Census 2011. We computed the incidence of KD in children aged <5, and <15 years. We also undertook linear trend analysis using our incidence data from 1994 to2019. During 2015-2019, 83 patients (66 males, 17 females) were diagnosed with KD in Chandigarh. Incidence rates during these 5 years were 5.64, 9.25, 9.11, 9.87, and 9.72/100,000 in children aged <5 years, and 2.65, 4.44, 3.86, 5.07, 4.74/100,000 in children aged <15 years. The median age at diagnosis was 48 months (range: 12 days to 15 years). Compared to previous data (2009-2014), there was a 53.1% increase in annual incidence of KD in children aged <5 years, and a 53.7% increase in children aged <15 years. Coronary artery abnormalities during acute phase were noted in 16.9%, and in 7.2% of patients at 6 weeks of follow-up. The trend analysis indicated a monthly rise of 0.002 cases per 100,000 children aged <5 years, and 0.0165 cases per 100,000 children aged <15 years. The incidence of KD has continued to show an upward trend in Chandigarh over the period 2015-2019. This may indicate a true rise in the occurrence of KD or may reflect better disease ascertainment as a result of greater awareness about KD amongst healthcare professionals. None.

Elevated Serum IL-17A in Kawasaki Disease Patients Predicts Responsiveness to Intravenous Immunoglobulin Therapy

Introduction: This study aimed to investigate the correlation between serum interleukin (IL)-17A levels and responsiveness to intravenous immunoglobulin (IVIG) therapy in Kawasaki disease (KD) patients. Methods: A retrospective analysis on data from 192 KD patients admitted to the Anqing Municipal Hospital between January 2021 and January 2024 was conducted. Patients were categorized into IVIG-nonresponsive and IVIG-sensitive groups as per the treatment outcomes. Outcome measures included serum IL-17A levels, left coronary artery (LCA) Z scores, and relevant laboratory parameters. Logistic regression analysis was performed to identify predictive factors for IVIG responsiveness, and diagnostic performance was assessed using receiver operating characteristic (ROC) curves and calculation of the area under the curve (AUC). Results: A total of 40 IVIG-nonresponsive cases and 152 IVIG-sensitive cases were included. Prior to intervention, IVIG-nonresponsive patients had significantly higher serum IL-17A levels compared to IVIG-sensitive patients, with a statistically significant difference. After intervention, serum IL-17A levels significantly decreased in IVIG-sensitive patients while remaining elevated in IVIG-nonresponsive patients. IVIG-nonresponsive patients exhibited significantly higher levels of C-reactive protein (CRP), white blood cell count (WBC), NE, and ALT compared to IVIG-sensitive patients, whereas no significant differences in LCA Z scores between the two groups existed. Multivariable logistic regression analysis identified pre-IL-17A, CRP, WBC, and ALT as independent predictors of IVIG-nonresponsiveness in KD. When pre-IL-17A was ≥39.96 pg/mL, the specificity and sensitivity for predicting IVIG-nonresponsive KD were 63.9% and 71.9%, respectively, with an AUC of 0.637. The combined diagnosis of IL-17A, CRP, WBC, and ALT yielded an AUC of 0.780. Conclusion: Serum IL-17A levels were remarkably elevated in IVIG-nonresponsive KD patients both before and after intervention. A serum IL-17A level (≥39.96 pg/mL) demonstrated good predictive profile for IVIG-nonresponsive KD, and combining IL-17A with CRP, WBC, and ALT improved diagnostic performance.

Coronary Artery Aneurysms: A Clinical Case Report and Literature Review Supporting Therapeutic Choices.

Coronary artery aneurysms (CAAs) are uncommon but significant cardiovascular abnormalities characterized by an abnormal increase in vascular diameter. CAAs are classified based on their shape as either saccular or fusiform, and their causes can range from atherosclerosis, Kawasaki disease, to congenital and iatrogenic factors. CAAs often present asymptomatically, but when symptoms occur, they can include angina, myocardial infarction, or even sudden cardiac death due to intravascular thrombosis involving the CAA. Diagnosis is typically confirmed through coronary angiography, though CT and other imaging techniques can provide additional details. The management of CAAs is variable depending on their size, location, and the presence of symptoms or complications. Treatment options include medical therapy, percutaneous coronary intervention (PCI), or surgical approaches. In this paper, we describe the case report of a 79-year-old male who presented with palpitations and was diagnosed with a right coronary artery aneurysm, and a review of the literature is delineated, underscoring the importance of individualized treatment strategies for CAAs.

Redundant role of PAD2 and PAD4 in the development of cardiovascular lesions in a mouse model of Kawasaki disease vasculitis.

Kawasaki disease (KD) is the leading cause of acquired heart disease in children. While circulating neutrophils are increased and activated during acute KD, it is unclear whether neutrophils and neutrophil extracellular traps (NETs) contribute to the pathogenesis of KD. Peptidylarginine deiminase 4 (PAD4), an enzyme involved in protein citrullination and essential for NETs formation, is implicated in the pathogenesis of various diseases. Here, we used the Lactobacillus casei cell wall extract (LCWE)-induced mouse model of KD vasculitis to determine the contribution of PAD4 in KD vasculitis. We found that the pan-PADs inhibitor, Cl-amidine, significantly reduced LCWE-induced cardiovascular lesions, but neutrophil-specific Padi4 KO mice did not impact the development of KD vasculitis. While in vitro treatment of macrophages, which highly express Padi4, with Cl-amidine inhibited IL-1β secretion, macrophage-specific Padi4 KO mice did not reduce the lesions. Padi4-/- mice also developed KD vasculitis, AFM30a, a PAD2 inhibitor, significantly reduced KD vasculitis in Padi4-/- mice, indicating a compensatory role of PAD2 in PAD4 deficiency. We also identified several citrullinated proteins in macrophages with constitutively active NLRP3 inflammasome that were inhibited by Cl-amidine treatment, suggesting that protein citrullination participates in NLRP3 inflammasome activation. These data indicate a dispensable role for PAD4-dependent NETs formation, and a redundant role of PAD2 and PAD4 in this murine KD vasculitis. The cardioprotective effects of Cl-amidine to reduce the severity of murine KD vasculitis are not limited to PAD4 inhibition and may include decreased citrullination in the inflammasome pathway.

Coronary thrombosis and myocardial ischemia in Kawasaki disease: a case report

BackgroundCoronary artery thrombosis and myocardial ischemia caused by giant coronary aneurysms are the main causes of death in children with Kawasaki disease. The use of thrombolytic therapy in children with Kawasaki disease who have coronary thrombosis is a controversial topic, especially with respect to the timing of treatment.Case presentationIn this article, we report a case of a child aged two years and nine months with Kawasaki disease whose coronary arteries had no involvement in the acute phase. However, by only one week after discharge, the patient returned because we found giant coronary aneurysms complicated by thrombosis via echocardiography. Despite aggressive thrombolytic therapy, the child developed myocardial ischemia during thrombolytic therapy. Fortunately, because of timely treatment, the child’s thrombus has dissolved, and the myocardial ischemia has resolved.ConclusionsThis case suggests that for patients at high risk of coronary artery aneurysms, echocardiography may need to be reviewed earlier. Low-molecular-weight heparin should be added to antagonize the early procoagulant effects of warfarin when warfarin therapy is initiated. In the case of first-detected coronary thrombosis, aggressive thrombolytic therapy may be justified, particularly during the acute and subacute phases of the disease course.

Kawasaki Disease Diagnosis and Treatment in over 1000 Patients: A Continuum of Dysregulated Inflammatory Responses.

Kawasaki disease (KD) is a pediatric vasculitis, leading to coronary artery aneurysms (CAAs) in ~4-14%. Attention to the etiology and course of KD was generated by the close mimic of a SARS-CoV-2-induced phenotype, called multisystem inflammatory syndrome in children (MIS-C). A total of 1179 cases were collected from 2012 with ~50% of cases retrospectively included. Clinical characteristics were described and risk factors for CAA (persistence) were investigated. Phenotypic patterns of the prospectively included KD patients were evaluated. These patterns were also compared to the seronegative KD and seropositive MIS-C cases identified during the SARS-CoV-2 pandemic. KD mostly affected boys and children < 5 years. IVIG resistance, CAAs, and giant CAAs occurred in 24.5%, 21.4%, and 6.6%, respectively. Giant CAAs were significantly more likely to normalize to a normal Z score in patients that were younger than 2.5 years old at the time of initial giant CAA (χ2 test p = 0.02). In our prospective (SARS-CoV-2-seronegative) KD series, there was a diminishing male predominance over time, whereas the proportions of incomplete presentations (p < 0.001) and patients with circulatory shock (p = 0.04) increased since the COVID-19 pandemic. Pre- and post-pandemic KD cases presented with different levels of C-reactive protein, thrombocyte counts, and hemoglobin levels over the years. Compared to pandemic KD, SARS-CoV-2-seropositive MIS-C patients were older (p < 0.001), and more often required intensive care admission (p < 0.001), with a gradual decrease over time between 2020 and 2022 (p = 0.04). KD carried a substantial risk of CAA development in contrast to MIS-C. the phenotypic changes seen over the last twelve years of our prospective follow-up study suggest a spectrum of hyperinflammatory states with potentially different triggering events within this clinical entity.