Search Results (246)

Aneurysms represent a life-threatening disease due to their risk of rupture. Recent research points towards a role of endothelial–mesenchymal transition (EndMT) in their pathophysiology. EndMT acts as a cellular program during which endothelial cells undergo phenotypic and functional transformation into cells with mesenchymal properties. EndMT is implicated in embryogenesis, tissue repair, remodeling, angiogenesis and fibrosis. The studies performed in the last decade have gained new insights in the cell signaling pathways during aneurysm development in the context of EndMT and suggested new drug targets to prevent aneurysmal growth. This review summarizes the current knowledge on EndMT in various forms of aneurysm, such as abdominal and thoracic aortic aneurysms, intracranial aneurysms and coronary artery aneurysm due to Kawasaki disease. Full article

Background: Patients with Kawasaki disease (KD) who develop coronary artery aneurysms (CAAs) are at increased risk of future fatal coronary events. Pharmacotherapeutic strategies to prevent coronary stenosis are still lacking. In this exploratory study, the therapeutic effect of the angiotensin receptor blocker (ARB) losartan on coronary artery (CA) stenosis was investigated in a murine model. Methods: Five-week-old male C57BL/6J mice were intraperitoneally injected with 1000 μg of Lactobacillus casei cell wall extract (LCWE) (n = 12) to induce CA stenosis. Two weeks later, the LCWE-injected mice (n = 12) were divided into two groups: six received drinking water containing losartan (100 mg/L) (LCWE+ARB), while six received normal drinking water (LCWE group). A control group (n = 5) received phosphate-buffered saline (PBS) instead of LCWE. Sixteen weeks after LCWE administration—corresponding to the peak of CA stenosis and 14 weeks after treatment initiation—the mice were euthanized for histological evaluation of the coronary arteries. Results: Losartan treatment significantly reduced the coronary arteritis score (median [IQR (interquartile range)]: 0 [0–9.5] vs. 21.5 [15–24.3], p = 0.003). LCWE-induced neointimal formation with vascular smooth muscle cell proliferation and subsequent CA stenosis were markedly attenuated in losartan-treated mice (25% vs. 100%, p < 0.001). Losartan-associated attenuation of CA stenosis was accompanied by the preservation of medial calponin expression, a reduction in the number of proliferating cell nuclear antigen (PCNA)-positive cells in the neointima, and a decrease in serum MMP-9 (matrix metalloproteinase-9) levels. Conclusions: These findings from a murine model of KD provide preliminary evidence that losartan may attenuate coronary artery remodeling. Further mechanistic studies are warranted to clarify its potential translational relevance. Full article

Intravenous immunoglobulin (IVIG) resistance occurs in 10–20% of children with Kawasaki disease (KD) and is associated with a 3- to 5-fold higher risk of coronary artery lesions (CALs). Yet the mechanistic basis for why some patients progress from reversible inflammation to irreversible vascular damage after IVIG remains poorly understood. Most existing reviews have focused on risk prediction rather than the mechanistic chain linking resistance to CALs. Here, we synthesize current evidence across three interconnected pathways. First, autophagy dysfunction—particularly impaired mitophagy—sustains inflammation through cGAS-STING activation. Second, neutrophil extracellular traps (NETs) play a controversial role in KD vasculitis, with PAD2 and PAD4 possibly acting redundantly via the NLRP3 inflammasome. Third, endothelial-to-mesenchymal transition (EndMT), driven by the IL-1β/TNF axis and the USP7-TGFβ2/SMAD pathway, emerges as a core event in vascular remodeling. Building on these findings, we propose the “autophagy–inflammasome axis” as a candidate molecular switch that dictates whether inflammation resolves or persists. This hypothesis is actionable: it generates three explicit, testable predictions linking autophagic integrity to inflammatory outcomes and therapeutic response. Direct experimental validation in IVIG-resistant KD models and patient samples is now urgently needed. This review provides a systematic framework for understanding how IVIG resistance transitions to irreversible CALs. It also identifies candidate biomarkers (e.g., S100A12, mtDNA, and MCM8) and therapeutic targets (autophagy inducers, NLRP3 inhibitors, USP7 inhibitors, and anakinra) that could enable earlier intervention. Full article

Coronary artery aneurysm (CAA) and ectasia (CAE) are characterized by an abnormal dilation exceeding 1.5 times the reference diameter of the adjacent normal vessel segment. Usually, these vascular anomalies are detected incidentally during coronary computed tomography angiography or invasive coronary angiography. Their clinical significance has become increasingly recognized over time because they may be associated with myocardial ischemia, thrombosis, distal embolization, acute coronary syndromes, and adverse long-term outcomes. In adults, atherosclerosis remains the most frequent cause, while Kawasaki disease is the leading etiology in children. Many patients remain asymptomatic, and the diagnosis is often incidental. Given their variable natural history and poorly delineated prognostic implications, individualized clinical risk stratification is essential. Coronary angiography remains the gold standard for invasive assessment. Management remains controversial in the absence of randomized controlled trials establishing an optimal therapeutic strategy. Full article

Multisystem inflammatory syndrome in children (MIS-C) and Kawasaki disease (KD) are pediatric inflammatory conditions which share overlapping clinical features, yet their long-term cardiovascular trajectories remain incompletely characterized. Understanding differences in myocardial strain evolution and coronary artery Z-score progression is essential for optimizing surveillance strategies and risk stratification. Aims of this review were to comprehensively compare the long-term evolution of myocardial strain parameters and coronary artery Z-scores in children with MIS-C versus KD through mid- and long-term follow-up assessment studies, and to identify clinical implications for monitoring and management. A comprehensive literature search was conducted in PubMed to identify studies evaluating myocardial strain and coronary artery Z-scores in MIS-C and KD. Publications from January 2020 to February 2026 were considered for MIS-C, with earlier key studies on KD included to contextualize established cardiac outcomes. Observational studies and cohort reports describing echocardiographic findings and follow-up data were reviewed. Available evidence indicates that MIS-C commonly presents with acute myocardial dysfunction, frequently characterized by reduced global longitudinal strain despite preserved or mildly reduced ejection fraction; in most cases, myocardial strain abnormalities substantially improve within weeks to a few months following treatment. In contrast, myocardial strain impairment in KD, which typically presents at less than 5 years of age, is less pronounced; coronary artery involvement shows an opposite trend, as KD is more frequently associated with coronary dilations and aneurysm formation, reflected by persistent elevations in coronary artery Z-scores, whereas coronary abnormalities in MIS-C are milder and often transient. Recovery patterns therefore differ, with MIS-C demonstrating rapid myocardial functional recovery, and KD carrying a greater risk of long-term coronary artery sequelae. MIS-C and KD exhibit distinct cardiovascular phenotypes: MIS-C is primarily characterized by reversible myocardial dysfunction, whereas KD remains a condition most strongly associated with a risk of persistent coronary artery abnormalities. Deciphering these differences may help guide disease-specific cardiac monitoring and long-term follow-up strategies in affected children. Full article

Objective: Kawasaki disease (KD) is characterized as an acute systemic vasculitis predominantly affecting young children, with coronary artery lesions (CALs) representing the most serious complication. Therapeutic resistance to intravenous immunoglobulin (IVIG) remains a significant clinical challenge. Consequently, numerous investigations have sought to identify predictive risk factors for IVIG resistance (IVIGR) and CAL development. Limited research has systematically evaluated the prognostic utility of electrocardiographic (ECG) parameters in KD outcome prediction. This study was therefore undertaken to assess the contributory value of ECG analysis in determining KD prognosis and therapeutic responses. Methods: This prospective cohort study enrolled 255 hospitalized children diagnosed with KD at West China Second University Hospital between July 2022 and December 2024. Initially, univariate analysis was performed to identify risk factors differentiating IVIGR from non-IVIGR patients and CAL from non-CAL patients. Statistically significant parameters were subsequently incorporated into machine learning analyses. Random forest algorithms were employed to construct predictive models based on the following: (1) complete blood count parameters, (2) biochemical and metabolic profiles, (3) electrocardiographic features, and (4) a comprehensive multimodal model integrating all parameters. These models generated feature importance scores, providing hierarchical rankings that quantified the relative contribution of each predictor to outcome prediction. Results: Univariate analysis demonstrated that alterations in hematological parameters, biochemical and metabolic profiles, and electrocardiographic features were significantly associated with therapeutic responses to IVIG and CAL development. Machine learning analysis revealed that ECG parameters individually contributed modest predictive weight for KD prognosis. However, the integration of ECG features into the comprehensive model substantially enhanced the discriminatory capacity, elevating the area under the curve (AUC) to 0.92 for CAL prediction. For IVIGR prediction, ECG-exclusive models demonstrated suboptimal performance in early disease management. Nevertheless, the multimodal integration of ECG with inflammatory and metabolic biomarkers achieved a comparable AUC of 0.92 for IVIGR prediction. Conclusions: This study establishes that ECG parameter alterations are significantly associated with CAL development and IVIGR in KD patients. Although ECG features demonstrate a limited independent predictive capacity compared to inflammatory and metabolic biomarkers, their integration into comprehensive predictive models substantially enhances discriminatory performance. These findings underscore the complementary value of electrocardiographic assessment in multimodal risk stratification strategies for KD management, supporting the clinical utility of ECG analysis as an adjunctive prognostic tool when combined with conventional laboratory parameters. Full article

Background: Kawasaki disease (KD) is an acute childhood vasculitis with well-recognized coronary involvement, but subtle long-term myocardial dysfunction may persist despite preserved conventional systolic indices. Two-dimensional speckle-tracking echocardiography enables sensitive assessment of left ventricular global longitudinal strain (GLS). Methods: A systematic review and meta-analysis were conducted in accordance with PRISMA 2020. PubMed, Scopus, Web of Science, and Google Scholar were searched for studies evaluating post-acute GLS in children or adolescents with prior KD compared with healthy controls. The outcome measure was the mean difference (MD) in GLS (KD minus control). Random-effects models were used for the primary analysis. Results: Four case–control studies involving 192 patients with prior KD and 138 healthy controls were included in the quantitative synthesis. Compared with controls, patients with prior KD had significantly less negative GLS values, indicating worse longitudinal deformation (pooled MD, 0.77%; 95% CI, 0.18 to 1.36; Z = 2.34; p = 0.019). Between-study heterogeneity was low (Q = 3.17, I² = 5.3%, tau² = 0.030). Leave-one-out analysis showed that the overall direction of effect remained positive, although confidence intervals widened when individual studies were omitted. Interpretation of the funnel plot was limited by the small number of studies. Conclusions: Children and adolescents with a history of KD demonstrate a modest but significant reduction in LV GLS during follow-up, consistent with persistent subclinical myocardial dysfunction. Speckle-tracking echocardiography may provide incremental value in the long-term cardiac assessment of selected patients with prior KD. Full article

Kawasaki disease (KD) represents the foremost cause of acquired pediatric heart disease, with coronary artery injury being the principal factor contributing to adverse prognoses. A significant clinical challenge is that 20–30% of patients demonstrate resistance to intravenous immunoglobulin (IVIG), which markedly elevates the risk of coronary artery lesions and long-term cardiovascular sequelae. Consequently, there is an urgent need to investigate novel pathogenic mechanisms beyond the conventional cytokine storm theory and to identify effective therapeutic targets. This review systematically summarizes the key role of the autophagy–inflammation axis in KD vasculopathy. Current evidence indicates that defective mitophagy and lysosomal dysfunction induce mitochondrial DNA release, resulting in overactivation of the NLRP3 inflammasome and cGAS-STING pathways, which amplify inflammatory responses and aggravate endothelial damage. The regulation of this axis is dynamic during both the acute and recovery phases and is influenced by metabolic reprogramming and epigenetic modifications, which may partially explain the lack of response to IVIG. Pharmacological agents, such as rapamycin and metformin, as well as natural compounds, such as resveratrol and urolithin A, have demonstrated beneficial anti-inflammatory effects in preclinical studies. Targeting the autophagy–inflammation axis represents a significant research direction with the potential to evolve into a promising therapeutic strategy. Mechanistically, restoring the balance of the autophagy–inflammation axis holds promise for mitigating coronary complications and improving long-term cardiovascular outcomes in children with KD; however, this prospect requires validation through prospective clinical studies. Full article

Background/Objectives: Kawasaki’s disease (KD) is a leading cause of heart disease in children. The multisystem inflammatory syndrome (MIS) associated with the SARS-CoV-2 virus is similar to KD. The etiologies of KD and MIS are unknown. Both diseases are associated with pathogens and immunizations. Methods: The Vaccine Adverse Event Reporting System (VAERS) was retrospectively examined for etiology insights into both KD and MIS. Results: Statistically significant, elevated AE MIS safety signals were observed for several COVID-19 Pfizer-BioNTech manufacturing lots. Elevated AE MIS normalized frequencies were observed in children of all ages. Immediate-onset AE KD safety signals were detected for specific vaccines and coadministered combinations of these vaccines (including specific live, attenuated virus vaccines and other specific vaccines) for young infants; a subset of these safety signals has a male sex bias, whereas others appear to be unbiased. Conclusions: Both KD and MIS are hypothesized to involve two activation pathways. The first pathway is hypothesized to involve high titers of immune complexes that activate Fc receptors on mast cells, platelets, and other immune cells. Immune complex titers higher than primary immune response levels are hypothesized to be required to activate low-affinity IgGFcγR2α receptors on immune cells and platelets. IVIG treatment is hypothesized to directly compete with immune complex binding to FcγR2α receptors. The second hypothesized pathway is proposed to directly activate mast cells and other immune cells without involving immune complexes and Fc receptors; lack of Fc receptor competition by immune complexes is hypothesized as a possible explanation for IVIG nonresponders for KD and MIS, worthy of future studies. The proposed etiology models for both KD and MIS may be consistent with being novel mast cell activation syndromes (MCAS). MIS is hypothesized to be KD-associated with the SARS-CoV-2 virus or the COVID-19 spike protein (MIS-V). Full article

Background and Objectives: Kawasaki disease (KD) is an acute systemic vasculitis in children, and approximately 10–20% of patients develop resistance to intravenous immunoglobulin (IVIG), which is associated with an increased risk of coronary artery complications. Natural killer (NK) cells play an important role in innate immune regulation, but the temporal dynamics of NK-cell regulatory receptors during KD and their relationship with IVIG response remain unclear. Materials and Methods: In this prospective observational study, we performed longitudinal immunophenotyping in children with KD treated at a tertiary referral center. Peripheral blood samples were obtained before IVIG administration (D0) and at three follow-up timepoints after treatment (D2, D14, and D56). NK-cell subsets and receptor expression—including the activating receptor NKG2D and inhibitory receptor NKG2A—were analyzed using multiparameter flow cytometry. Associations with IVIG response were evaluated using Firth penalized logistic regression for baseline predictors and linear mixed-effects models to assess longitudinal immune trajectories. Results: A total of 69 patients with KD were included, of whom 17 (24.6%) were classified as IVIG resistant. Baseline NK-cell subsets and receptor expression did not differ significantly between IVIG-sensitive and IVIG-resistant patients, although the NKG2D/NKG2A ratio tended to be lower in resistant patients (median 2.51 vs. 3.34, p = 0.054). Longitudinal mixed-effects analysis demonstrated significant temporal changes in NK-cell regulatory signaling following IVIG therapy. Both NKG2A (P(time) = 0.019) and NKG2D (P(time) < 0.001) expression showed significant time effects across the disease course. Importantly, the NKG2D/NKG2A ratio demonstrated a significant time-by-group interaction (P(interaction) = 0.030), indicating divergent trajectories of activating and inhibitory NK-cell signaling according to IVIG response. At the convalescent phase (D56), IVIG-resistant patients showed significantly higher NKG2A expression (p = 0.038) and a lower NKG2D/NKG2A ratio (p = 0.023) than IVIG-sensitive patients. Conclusions: While baseline NK-cell immunophenotypes were not associated with IVIG response, longitudinal analysis revealed that IVIG-resistant patients exhibited a distinct immune trajectory, characterized by increased NKG2A expression and a lower NKG2D/NKG2A ratio during the convalescent phase. These findings suggest that differences in IVIG responsiveness may be related to alterations in immune regulatory processes during the resolution phase of inflammation. However, the clinical implications of these findings remain to be established and require validation in larger, multicenter studies with longitudinal outcome data. Full article

Background: In the paediatric intensive care unit (PICU), certain drugs should be avoided or administered with strict precautions and close monitoring. This is due to their potential for toxicity or adverse effects or a lack of safety data, especially for critically ill children with organ failure. Additionally, practitioners must assess the unique pharmacokinetic and pharmacodynamic properties of drugs when treating critically ill children. In this narrative review, we highlight the risks, advantages, and disadvantages of three exemplary cases of drugs for paediatric patients hospitalised in the PICU: chloramphenicol, acetylsalicylic acid, and propofol. Methods: Apart from key papers on these drugs, a retrospective analysis of the English literature on chloramphenicol, acetylsalicylic acid (ASA), and propofol was performed on PubMed for papers from January 2014 to December 2025. Results: Chloramphenicol should be avoided in neonates due to the risk of grey baby syndrome. Acetylsalicylic acid (ASA) is contraindicated in children ≤18 years with suspected viral illness because of the risk of Reye’s syndrome, but remains essential for Kawasaki disease and post-cardiac surgery antiplatelet therapy. Propofol should be avoided when used for a longer period at high doses. With proper dosing and monitoring, propofol-related infusion syndrome (PRIS) is preventable, but high-risk patients should receive alternative treatment. Conclusions: This narrative review highlights the significant risks associated with the use of chloramphenicol, ASA, and propofol in paediatric intensive care settings. Their potential for life-threatening and severe adverse reactions emphasises the need for cautious and informed use. Clinicians must carefully consider the risks and benefits of these drugs. To minimise adverse events, strict monitoring, dose adjustments, and the use of safer alternatives are essential. However, it appears that their use in well-defined circumstances in acute illness in children is still warranted. The findings of this narrative review underscore the need for further research to focus on identifying high-risk biomarkers, genetic predispositions, and safer alternatives to improve evidence-based guidelines and reduce morbidity and mortality in paediatric intensive care. Full article

Background: The early identification of high-risk patients is crucial in stratifying treatment algorithms for Kawasaki disease (KD). Our study aimed to develop a new scoring system to predict the risk of developing a coronary artery aneurysm (CAA) and the persistence of giant CAA during follow-up. Methods: A retrospective cohort study included 151 patients treated at our institute for KD between 2011 and 2025. Results: A total of 25 patients (16.5%) developed CAA, while, in the follow-up period, aneurysms were registered in nine patients. Based on the values obtained from the univariate analysis, a scoring system was developed. It included age <6 months, IVIG treatment for >7 days, refractory KD, leucocytosis (>17 × 10⁹), neutrophilia (>16 × 10⁹), thrombocytosis (>400 × 10⁹), anaemia (<103 g/L), hypoproteinaemia (<54 g/L), and hypoalbuminaemia (<32 g/L). Patients with a score ≥5 had an almost nine-fold higher risk of developing CAA (OR 8.7, 95% CI 3.4–22.6; p < 0.001), while, if the score was ≥8, the risk for a chronic giant aneurysm was 71 times higher (OR 71.5, 95%CI 8.5–597.7; p < 0.001). Based on the ROC curve, a score ≥5 has 99% sensitivity and 70% specificity for the development of CAA (AUC = 0.87). A score ≥7 has 100% sensitivity and 85% specificity for the development of giant aneurysms (AUC = 0.87). Conclusions: The KawaCOR score is the first scoring system in our region specifically designed to predict the development of CAA and acute and chronic giant CAA. Full article

Background: Kawasaki disease (KD) is a systemic vasculitis of unknown origin, though recent evidence implicates viral pathogens in its pathogenesis. Given the central role of T cell receptors (TCRs) in antigen recognition and immune response, this study investigated the association between KD and viral infection through comparative analysis of TCR repertoires. Methods: TCR repertoires from KD patients, healthy children, and individuals with viral infections were comparatively analyzed. TCR diversity and V(D)J usage were assessed using Shannon’s entropy, the Mann–Whitney U test, and Fisher’s exact test. Positional motif enrichment analysis within CDR3 regions was performed based on paratope hotspot classification. Results: Relatively reduced TCR clonal abundance and diversity were observed in KD patients compared to healthy controls. While substantial overlap in VJ gene segment usage was detected between KD and cytomegalovirus (CMV) infection, limited overlap in clonal TCRαβ chains was found between KD and viral infection groups. A predominant TCR combination, TRAV14DV4-J13-TRBV20-1-J2-5, enriched with characteristic amino acid motifs (EET, YNE, LAG, GQG, and AYE), was frequently identified in KD. Conclusions: These observations suggest potential differences in TCR repertoire features between KD patients and both healthy and virus-infected groups. However, the relationship between KD pathogenesis and the viruses examined requires further investigation with larger cohorts. Full article

A rare but potentially fatal hyperinflammatory disease that develops following SARS-CoV-2 infection is called multisystem inflammatory syndrome in children (MIS-C). Mucocutaneous manifestations are common and frequently overlap with other pediatric inflammatory illnesses, including Kawasaki disease, and may serve as early diagnostic indicators. We describe a 6-year-old girl who was previously healthy but was hospitalized in the pediatric intensive care unit due to a high-grade fever, toxic appearance, and quickly progressing mucocutaneous symptoms, such as bilateral non-purulent conjunctivitis and broad maculopapular rash. Myocardial dysfunction, severe anemia and thrombocytopenia, respiratory failure necessitating mechanical ventilation, and hypotensive shock complicated the clinical course. Laboratory tests showed positive SARS-CoV-2 serology and significantly increased inflammatory markers. Several microbiological tests came up negative. Bacterial sepsis and Kawasaki diseases were not included. A diagnosis of MIS-C was made based on clinical, laboratory, and epidemiological data. In addition to supportive intensive care, the patient received systemic corticosteroids and intravenous immunoglobulin. After two weeks, she was released in a stable condition after gradually improving clinically and biochemically. This instance emphasizes how crucial it is to identify noticeable mucocutaneous manifestations as early warning signs of MIS-C. Immunomodulatory therapy must be started as soon as possible in order to minimize serious consequences and enhance the prognosis of afflicted infants. Full article

Purpose: Kawasaki disease (KD) is an acute systemic vasculitis that can result in coronary artery lesions (CALs). This study aims to explore the expression levels of serum Ninjurin-1 (NINJ1) and high-mobility group box 1 (HMGB1) in the acute phase of KD and evaluate their clinical significance. Methods: A total of 180 children were enrolled, comprising 113 KD patients, 35 healthy controls (HCs), and 32 febrile controls whose clinical data were collected. Serum levels of NINJ1, HMGB1, Lactate Dehydrogenase (LDH), and routine inflammatory markers were compared across groups. Serum levels of NINJ1 and HMGB1 were measured via ELISA. Correlations were analyzed using Spearman tests. The diagnostic and predictive performance of biomarkers was assessed using Receiver Operating Characteristic (ROC) curve analyses. Results: Serum levels of NINJ1 and HMGB1 were significantly elevated in the KD group compared with both the HC and FC groups (all p < 0.001). NINJ1 levels were positively correlated with the z-scores of coronary arteries and were significantly higher in the CAL subgroup than in the non-CAL subgroup (p = 0.004). A strong positive correlation was observed between serum NINJ1 and HMGB1 levels in the KD group (p < 0.001). Conclusions: Elevated serum NINJ1 levels during the acute phase of KD were associated with the presence of CALs, while HMGB1 shows promise in differentiating KD from other febrile illnesses. These findings collectively suggest that the NINJ1-HMGB1 axis may offer novel insights into the mechanisms underlying KD vasculitis, supporting further investigation into its potential clinical relevance. Full article