Search Results (215)

Medium and variable vessel vasculitides are a heterogeneous group of rare, immune-mediated vascular disorders that are associated with significant morbidity and mortality. The standard treatment approach involves glucocorticoids and immunosuppressive agents. However, many patients exhibit poor tolerance or respond inadequately to these medications. Recent advances in biologic therapies and Janus Kinase inhibitors (JAKis) offer promising alternatives. This review consolidates current knowledge on the pathogenesis, immunology, and therapeutic efficacy of biologics and JAKis in the management of medium and variable vessel vasculitis. While further research is needed to establish long-term safety and optimize treatment protocols, biologics and JAKis represent emerging therapeutic strategies with the potential to improve outcomes. Full article

Although Kawasaki disease (KD) has been known since 1967, when it was first described by Dr. Tomisaku Kawasaki, the literature indicates that its etiology—similarly to Multisystem Inflammatory Syndrome in Children (MIS-C)—remains largely unclear and is the subject of intensive research. The former disease, which typically occurs shortly after infection, is the most common cause of primary vasculitis in children worldwide. The latter—MIS-C, associated with SARS-CoV-2 infection—is characterized by involvement of at least two organ systems. Undoubtedly, both diseases exhibit heightened immune system activity and significant inflammation. In recent years, increasing attention has been directed towards alterations in the microbiota observed in affected patients. We undertake an analysis and systematic review of the current scientific findings in this field. We emphasize the role of the microbiome—which encompasses not only bacteria but also viruses, fungi, parasites, and archaea—in health and disease. We track its composition from birth and highlight factors influencing its diversity, such as the mode of delivery. We recognize the microbiome’s role in reducing the likelihood of allergic diseases in children and its interactions with the immune system. In addition to comparing the pathomechanisms and clinical manifestations of KD and MIS-C, also known as Pediatric Inflammatory Multisystem Syndrome (PIMS), we investigate microbiota alterations in these conditions and analyze potential applications of microbiome knowledge, for example, in identifying diagnostic markers. We also point out potential directions for future research, such as the use of short-chain fatty acids (SCFAs) in MIS-C and the long-term changes in the gut microbiota associated with these diseases, which remain poorly documented and currently represent significant gaps in knowledge. Full article

Kawasaki disease (KD), first identified in 1967 by Dr. Tomisaku Kawasaki, is an acute, self-limited vasculitis and remains the leading cause of acquired heart disease in children worldwide, particularly affecting those under the age of five. Clinically, it presents with persistent fever, mucocutaneous inflammation, skin rashes, and lymphadenopathy, with a marked tendency to involve the coronary arteries, potentially leading to serious complications such as coronary artery aneurysms. Despite extensive research spanning more than five decades, the precise etiology of KD remains unclear. However, accumulating evidence supports the significant role of genetic predisposition, highlighting the contribution of inherited factors in modulating immune responses and influencing disease susceptibility and severity. Emerging evidence highlights genetic susceptibility as pivotal, with genome-wide studies identifying polymorphisms in immune-related genes, such as ITPKC, CASP3, BLK, CD40, and ORAI1, which modulate disease risk and coronary complications. Epigenetic mechanisms, including DNA methylation and non-coding RNAs, bridge the gap between genetic and environmental factors, regulating immune responses and endothelial activation. Furthermore, emerging insights into autophagy-related processes provide a deeper understanding of the molecular mechanisms underlying the disease. This review aims to explore the current knowledge on the genetic landscape of KD, examine how these findings contribute to our understanding of its pathophysiology, and investigate the potential for genetically targeted therapeutic strategies in the future. Full article

Background: Kawasaki disease (KD) is a systemic vasculitis and the leading cause of acquired heart disease in children. Early identification of coronary artery abnormalities (CAAs) is crucial to guide treatment and improve outcomes. While transthoracic 2D echocardiography (TTE) remains the first-line imaging modality, it has limitations, particularly in visualizing distal coronary artery segments and detecting thrombi. Computed tomography coronary angiography (CTCA) offers enhanced visualization, but its role at initial presentation of KD remains underexplored. Methods: We reviewed the records of 71 children with KD who underwent CTCA at their initial presentation at a tertiary center between November 2013 and December 2024. The CTCA findings were compared with those of TTE. CTCA was performed after stabilization using radiation-minimized protocols. Results: Of 71 patients, 62 had CAAs on baseline TTE. CTCA confirmed CAAs in 39 patients, identified additional lesions in 23, and detected distal aneurysms and coronary branch involvement missed by TTE. In 20 patients with initially abnormal TTE, CTCA demonstrated normal coronaries, facilitating treatment de-escalation. CTCA identified coronary thrombi missed on TTE in two patients and congenital coronary anomalies in three patients. CTCA findings led to modification of therapy in multiple cases. Conclusions: CTCA is a valuable adjunct to TTE in evaluating coronary artery involvement at the time of initial presentation of children with KD. Given its superior visualization of the entire length of coronary arteries, CTCA has a vital role in therapeutic decision-making in KD. Full article

Kawasaki disease (KD) is a rare yet potentially life-threatening pediatric vasculitis that, if left undiagnosed or untreated, can result in serious cardiovascular complications. Its heterogeneous clinical presentation poses diagnostic challenges, often failing to meet classical criteria and increasing the risk of oversight. Leveraging routine laboratory tests with AI offers a promising strategy for enhancing early detection. However, due to the extremely low prevalence of KD, conventional models often struggle with severe class imbalance, limiting their ability to achieve both high sensitivity and specificity in practice. To address this issue, we propose a multi-stage AI-based predictive framework that incorporates clustering-based undersampling, data augmentation, and stacking ensemble learning. The model was trained and internally tested on clinical blood and urine test data from Chang Gung Memorial Hospital (CGMH, n = 74,641; 2010–2019), and externally validated using an independent dataset from Kaohsiung Medical University Hospital (KMUH, n = 1582; 2012–2020), thereby supporting cross-institutional generalizability. At a fixed recall rate of 95%, the model achieved a specificity of 97.5% and an F1-score of 53.6% on the CGMH test set, and a specificity of 74.7% with an F1-score of 23.4% on the KMUH validation set. These results underscore the model’s ability to maintain high specificity even under sensitivity-focused constraints, while still delivering clinically meaningful predictive performance. This balance of sensitivity and specificity highlights the framework’s practical utility for real-world KD screening. Full article

Objectives: Kawasaki Disease (KD) is an acute vasculitis associated with systemic inflammation. This study aimed to investigate the level and clinical significance of soluble ST2 (sST2) in children with KD. Methods: A retrospective analysis was conducted on 287 pediatric KD patients treated at the Pediatric Cardiology Department of Shengjing Hospital, China Medical University, from November 2021 to December 2022. Patients were stratified into subgroups based on the presence of myocardial damage (MD), coronary artery lesions (CAL), multi-organ involvement (MOD; ≥3 organs) and/or intravenous immunoglobulin-resistant KD (IVIG-R KD). In each group, we analyzed the correlation between sST2 levels and various laboratory parameters, including white blood cell count (WBC), hemoglobin (HB), platelet count (PLT), C-reactive protein (CRP), interleukin-6 (IL-6), erythrocyte sedimentation rate (ESR), N-terminal pro-brain natriuretic peptide (NT-pro BNP), D-dimer, and albumin (ALB). Results: Patients in the CAL group were significantly younger and predominantly male (p < 0.05). In the MD, CAL, MOD, and IVIG-R KD groups, levels of sST2, CRP, NT-pro BNP, and D-dimer were significantly higher than in their respective comparison groups (p < 0.05). sST2 showed weak positive correlations with WBC, CRP, IL-6, NT-pro BNP, and D-dimer, and weak negative correlations with HB and ALB (p < 0.05). sST2, HB, and IL-6 were identified as independent risk factors for MOD (p < 0.05). sST2 and HB were independent risk factors for IVIG-R KD (p < 0.05). Among acute-phase patients, four cases had sST2 levels > 200 ng/mL—all were classified as IVIG-R KD and MOD; three of these also developed coronary artery aneurysms (CAA). Conclusions: Elevated sST2 levels in the acute phase of KD may serve as a clinical indicator of IVIG-R KD, CAA, MOD, and MD. Full article

Kawasaki disease (KD) is a systematic inflammatory condition that results in vasculitis and possible progression to the development of coronary artery lesions if left untreated. Disease pathogenesis is not fully understood, and diagnosis is based on clinical symptoms, with limited reliability considering that KD progression is time sensitive. This is further complicated by the shared clinical characteristics with other febrile diseases. Early diagnosis and prompt treatment start are associated with good prognosis in most patients. However, up to 20% of patients are resistant to available therapeutic agents and would benefit from alternative regimens. Therefore, identification of biomarkers that can provide insights on disease pathogenesis are necessary to enable early diagnosis and initiation of treatment, as well as to predict treatment responses. To this end, immunophenotyping, most commonly by flow cytometry, has been crucial in identifying central factors in KD pathogenesis. The available literature on such factors is vast and may include contradictory findings. Therefore, we aimed to summarize the available literature of the last decade on the immunophenotype of KD, focusing on biomarkers associated with disease pathogenesis and those associated with treatment response. Our review highlights the role of cells of both the innate and adaptive immune system in disease pathogenesis, as well as the role of various secreted and cell surface proteins, including inflammatory cytokines, chemokines, complement receptors, and chemoattractants both in KD pathogenesis and in treatment response. Full article

Background/Objectives: The possibility of progressive liver fibrosis remains even when alanine aminotransferase (ALT) levels are <30 IU/L. Therefore, we aimed to investigate factors that can predict fibrosis progression in patients with metabolic dysfunction-associated steatotic liver disease (MASLD) with ALT levels ≤ 30 U/L. Methods: This multicenter retrospective cohort study was conducted using data collected between December 1994 and December 2021. Among the 1381 patients with MASLD (CLIONE study) who underwent liver biopsy, we performed decision-tree analysis on factors for stage ≥ 3 in 115 with ALT levels ≤ 30 U/L. Of the 818 patients with MASLD (Kawasaki cohort) who underwent liver biopsy, we included 174 with ALT levels ≤ 30 U/L for validation. Results: In the decision-tree analysis of patients with stage ≥ 3 with ALT levels ≤ 30 U/L, 57% of patients with a fibrosis-4 (FIB-4) index ≥ 2.67 and 70% with both FIB-4 index ≥ 2.67 and type-2 diabetes mellitus (DM) were detected. However, no cases of stage ≥ 3 were observed among patients without type-2 DM with ALT ≤ 30 U/L and a FIB-4 index < 2.67. After verifying the decision-tree analysis, the model construction and validation datasets showed a close correlation. Conclusions: Among patients with MASLD with ALT levels ≤ 30 U/L, those with an FIB-4 index ≥ 2.67, particularly with comorbid type-2 DM, should consider consultation with a hepatologist. Full article

Background/objectives: Kawasaki disease is the leading cause of acquired heart disease in children within developed countries. Although treatment with intravenous immunoglobulin (IVIG) significantly reduces the incidence of coronary artery aneurysm (CAA), the risk of it persists, affecting long-term patient outcomes. While intensified primary treatment is recommended for patients at high risk of IVIG resistance or CAA development, a universally accepted predictive model for such resistance remains unestablished. This study aims to develop a machine learning model to predict the occurrence of CAAs prior to initiating IVIG therapy. Methods: Data from two nationwide epidemiological surveys conducted between 2012 and 2017 were analyzed, encompassing 17,189 patients with calculable coronary artery z-scores and Harada scores. Various supervised machine learning algorithms were applied to develop a model for predicting CAA. Afterward, unsupervised learning techniques were employed to explore the data’s inherent structure. Results: The Harada score’s receiver operating characteristic (ROC) analysis yielded an area under the curve (AUC) of 0.558. The highest AUC among the machine learning models was 0.661, achieved by the Light Gradient Boosting Machine. However, this model’s sensitivity was 0.615, and specificity was 0.647, indicating limited clinical applicability. Unsupervised learning revealed no distinct distribution patterns between patients with/without CAAs. Conclusions: Despite utilizing a large dataset to develop a machine learning-based prediction model for CAAs, the performance was unsatisfactory. Future studies should focus on enhancing predictive models by incorporating additional clinical data, such as acute-phase coronary artery diameter measurements, to improve accuracy and clinical utility. Full article

Multisystem inflammatory syndrome in children (MIS-C), also known as pediatric inflammatory multisystem syndrome (PIMS), presents significant challenges in pediatric cardiology, due to its complex molecular pathophysiology. In this retrospective analysis of 15 cases that were managed at a single tertiary care center, we investigated the molecular contributors to myocardial dysfunction, including cytokine storms, hyperinflammation markers, and hypercoagulable states. Transient myocardial involvement was identified in 46.6% of patients, with complete recovery achieved within 2–4 weeks following treatment. Ferritin, NT-ProBNP, and troponin levels were significantly elevated in patients with ventricular dysfunction compared to those without. The neutrophil-to-lymphocyte ratio (NLR), which was previously identified as a severity marker in acute COVID-19, was also significantly higher in patients with ventricular dysfunction, suggesting its potential as a prognostic indicator in MIS-C. Notably, no coronary artery aneurysms were detected in the cohort. These findings underscore the importance of early, standardized therapeutic interventions in mitigating severe outcomes, and they provide valuable insights into the molecular mechanisms driving myocardial dysfunction in MIS-C. Incorporating NLR and ferritin into the initial diagnostic workup may improve the early triage and identification of high-risk MIS-C patients. Full article

Cardio-rheumatology is an evolving and interdisciplinary field lying at the intersection of rheumatology and cardiovascular medicine that recognizes that individuals with autoimmune and inflammatory rheumatic complications have a much higher likelihood of developing cardiovascular diseases (CVDs). Inflammasomes are multiprotein complexes stimulated by the immune system after the detection of pathogens or cellular injury. Inflammasomes undergo a two-stage activation process initiated by nuclear factor (NF)-κB, subsequently playing a crucial role in innate immunity through activation of caspase 1 and the consequent release of proinflammatory cytokines such as IL-18 and IL-1β. However, a loss of control of inflammasome activation can cause inflammatory diseases in humans. Recent studies have focused on the role of inflammasomes in inflammatory cascades implicated in the pathogenesis of several diseases. Here, we review inflammasome activation, its mechanism of action, and its role in CVD. In particular, we describe the role of inflammasomes in rheumatic heart disease, Kawasaki disease, familial Mediterranean fever, ankylosing spondylitis, and rheumatoid arthritis as exemplars to illustrate pathobiological mechanisms and the potential for targeting inflammasomes for therapeutic benefit. Full article

Background and Objectives: Kawasaki disease (KD) is a childhood systematic vasculitis. Emerging evidence suggests a link between KD and long-term neurological implications. This study examines the association between KD and subsequent neuropsychiatric and neurodevelopmental disorders using national health data from South Korea. Materials and Methods: Using the National Health Information Database, we identified KD patients diagnosed between 2002 and 2021 and selected those born between 2008 and 2015. Propensity score matching with a 1:4 ratio was applied to create a control group. The incidence of neuropsychiatric and neurodevelopmental disorders from 2017 to 2021 was analyzed using Cox proportional hazard models, adjusting for age, sex, and urbanicity. Results: This study included 41,806 KD subjects and 163,829 matched controls. KD was associated with an increased risk of certain neuropsychiatric disorders: anxiety disorder (HR: 1.124, 1.047–1.207), sleep-related disorder (HR: 1.257, 1.094–1.444), movement disorder (HR: 1.227, 1.030–1.461), and any neuropsychiatric disorder (HR: 1.102, 1.053–1.153). For neurodevelopmental disorders, KD patients showed a lower incidence of intellectual disability (HR: 0.747, 0.641–0.871) but an increased risk of tic disorder (HR: 1.148, 1.020–1.292). Male gender and urban residency were associated with higher incidence rates for certain conditions. Conclusions: This study demonstrates that KD patients show increased risks for anxiety, sleep-related disorder, movement disorder, and tic disorder, a reduced incidence of intellectual disability, and a higher risk of tic disorder. These findings highlight the need for long-term neurological monitoring in KD patients and provide insights into its potential neurodevelopmental impact. Full article

Background: Kawasaki disease (KD) is an acute type of vasculitis in children, with coronary artery aneurysm (CAA) being its most serious complication. Intravenous immunoglobulin (IVIg) with acetylsalicylic acid (ASA) is the standard treatment, but concerns about IVIg’s availability and adverse effects have led to interest in corticosteroids (CSs) as an alternative. This study compares the clinical outcomes of IVIg and CSs in KD patients. Methods: Using South Korean Health Insurance Review and Assessment Service (HIRA) data from 2017 and 2020, we identified children under five diagnosed with KD and treated with IVIg and ASA (the IVIg group) or CSs and ASA (the CS group). Propensity score weighting was applied. The primary outcome was the incidence of CAA, and the secondary outcome included cardiovascular complications. Cox proportional hazards models were used to estimate the hazard ratios (HRs) with 95% confidence intervals (CIs). Results: After adjustment, the CAA incidence was higher in the CS group (6.72%) than in the IVIg group (1.86%) (HR = 3.70; 95% CI: 1.96–6.97; p < 0.0001). Cardiovascular complications were also more frequent in the CS group (HR = 2.87; 95% CI: 1.96–6.97; p < 0.0001). Conclusions: The combination treatment, of CSs and ASA, was associated with a higher risk of CAA and cardiovascular complications compared to that when using IVIg in pediatric KD patients. While CSs may be beneficial as an adjunct therapy in IVIg-resistant cases, they should not replace IVIg as a first-line treatment. Alternative strategies, such as reduced-dose IVIg with adjunctive therapies, should be explored. Full article

Kawasaki disease (KD) with coronary artery aneurysms (CAAs) is currently the primary cause of childhood acquired heart disease with an unclear pathogenesis. We established five groups for the discovery of differentially expressed proteins (DEPs): healthy control, febrile control, KD without CAAs, KD with small and medium CAAs, and KD with giant CAAs (n = 8 in each group). The validation of selected DEPs was conducted in another five groups (n = 4 in each group). We conducted comprehensive bioinformatics analyses to elucidate the functional roles of the DEPs in the groups of KD with CAAs and KD without CAAs. A total of 104 DEPs were identified in KD patients, which were primarily associated with complement-related pathways. A trend analysis of these 104 DEPs revealed 54 significantly changed DEPs associated with increased disease severity, which were primarily associated with G-protein-related functions. The alterations in α-1-antitrypsin short peptide (SERPINA1) and guanine nucleotide-binding protein G(i) subunit alpha-2 (GNAI2), which were selected from complement-related and G-protein-related pathways, respectively, were validated by Western blotting, and they were significantly decreased in KD patients with vs. without CAAs. In addition, we conducted an analysis of the DEPs in the groups of KD with CAAs and KD without CAAs, separately. There were 91 DEPs specifically expressed in KD patients with CAAs, associated with the neutrophil extracellular trap and complement pathways, while 16 DEPs were specific to those without CAAs, associated with viral infection and immunity pathways. Additionally, for DEPs among different severities of CAAs, there were 102 DEPs in KD patients with small and medium CAAs, associated with complement pathways and platelet activation pathways, whereas 34 DEPs were specific to giant CAAs, associated with the Rap1 signaling pathway and cell functions. In conclusion, this study provides plasmatic exosomal protein profiles in KD patients with CAAs, suggesting that SERPINA1 and GNIA2 might serve as novel potential diagnostic biomarkers for KD with CAAs. Full article

Missed or delayed heart disease diagnoses pose a major challenge in pediatric primary care. Many cardiac conditions present with subtle or nonspecific symptoms that resemble benign childhood illnesses, making their prompt recognition difficult. This review describes congenital and acquired heart diseases prone to diagnostic delays, including critical congenital heart disease, coarctation of the aorta, atrial and ventricular septal defects, myocarditis, Kawasaki disease, heart failure, and pulmonary arterial hypertension. The atypical presentations of these disorders and the associated diagnostic pitfalls are emphasized. Furthermore, the importance of alarming symptoms and signs, such as chest pain, palpitations, syncope, and abnormal heart murmurs, is underscored. A structured approach to these red flags is presented to assist primary care pediatricians in identifying children at risk, initiating appropriate management, and referring them for specialized evaluation. The importance of preparticipation screening for athletes is also discussed, highlighting how it can be applied to all children during routine health visits to identify those with heart disease. Appropriate training is essential to increase pediatricians’ ability to recognize and manage cardiac patients. Full article