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

BACKGROUND: Coronary 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 PRESENTATION: In 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. CONCLUSIONS: This 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.

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 development of KD vasculitis. While in vitro treatment of macrophages, which highly express Padi4, with Cl-amidine inhibited IL-1ßsecretion, 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 is not limited to PAD4 inhibition and may include decreased citrullination in the inflammasome pathway.

Identification of novel mitophagy-related biomarkers for Kawasaki disease by integrated bioinformatics and machine-learning algorithms.

Background: Kawasaki disease (KD) is a systemic vasculitis primarily affecting the coronary arteries in children. Despite growing attention to its symptoms and pathogenesis, the exact mechanisms of KD remain unclear. Mitophagy plays a critical role in inflammation regulation, however, its significance in KD has only been minimally explored. This study sought to identify crucial mitophagy-related biomarkers and their mechanisms in KD, focusing on their association with immune cells in peripheral blood. Methods: This research used four datasets from the Gene Expression Omnibus (GEO) database that were categorized as the merged and validation datasets. Screening for differentially expressed mitophagy-related genes (DE-MRGs) was conducted, followed by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses. A weighted gene co-expression network analysis (WGCNA) identified the hub module, while machine-learning algorithms [random forest-recursive feature elimination (RF-RFE) and support vector machine-recursive feature elimination (SVM-RFE)] pinpointed the hub genes. Receiver operating characteristic (ROC) curves were generated for these genes. Additionally, the CIBERSORT algorithm was used to assess the infiltration of 22 immune cell types to explore their correlations with hub genes. Interactions between transcription factors (TFs), genes, and Gene-microRNAs (miRNAs) of hub genes were mapped using the NetworkAnalyst platform. The expression difference of the hub genes was validated using quantitative reverse transcriptase polymerase chain reaction (qRT-PCR). Results: Initially, 306 DE-MRGs were identified between the KD patients and healthy controls. The enrichment analysis linked these MRGs to autophagy, mitochondrial function, and inflammation. The WGCNA revealed a hub module of 47 KD-associated DE-MRGs. The machine-learning algorithms identified cytoskeleton-associated protein 4 (CKAP4) and serine-arginine protein kinase 1 (SRPK1) as critical hub genes. In the merged dataset, the area under the curve (AUC) values for CKAP4 and SRPK1 were 0.933 [95% confidence interval (CI): 0.901 to 0.964] and 0.936 (95% CI: 0.906 to 0.966), respectively, indicating high diagnostic potential. The validation dataset results corroborated these findings with AUC values of 0.872 (95% CI: 0.741 to 1.000) for CKAP4 and 0.878 (95% CI: 0.750 to 1.000) for SRPK1. The CIBERSORT analysis connected CKAP4 and SRPK1 with specific immune cells, including activated cluster of differentiation 4 (CD4) memory T cells. TFs such as MAZ, SAP30, PHF8, KDM5B, miRNAs like hsa-mir-7-5p play essential roles in regulating these hub genes. The qRT-PCR results confirmed the differential expression of these genes between the KD patients and healthy controls. Conclusions: CKAP4 and SRPK1 emerged as promising diagnostic biomarkers for KD. These genes potentially influence the progression of KD through mitophagy regulation.

Ferulic acid suppresses the inflammation and apoptosis in Kawasaki disease through activating the AMPK/mTOR/NF-κB pathway.

Background: Kawasaki disease (KD) is a self-limiting and acute systemic vasculitis of unknown etiology, mainly affecting children. Ferulic acid (FA), a natural phenolic substance, has multiple pharmacological properties, including anti-inflammatory, anti-apoptosis, and anti-fibrosis, and so on. So far, the protective effects of FA on KD have not been explored. Methods: In this study, we established Candida albicans water soluble fraction (CAWS)-induced mouse coronary artery vasculitis of KD model and the tumor necrosis factor α (TNF-α)-induced human umbilical vein endothelial cells (HUVECs) injury model to investigate the anti-inflammatory and anti-apoptosis effects of FA on KD, and try to elucidate the underlying mechanism. Results: Our in vivo results demonstrated that FA exerted anti-inflammatory effects on KD by inhibiting the infiltration of CD45-positive leukocytes and fibrosis around the coronary artery. Additionally, FA downregulated the levels of inflammatory and chemotactic cytokines, alleviated splenomegaly, and exhibited anti-apoptotic effects on KD by reducing TUNEL-positive cells, downregulating BAX expression, and upregulating BCL-2 expression. In addition, Our in vitro findings showed that FA could effectively inhibit TNF-α-induced HUVEC inflammation like NF-κB inhibitor QNZ by downregulating the expression of pro-inflammatory cytokines as well as attenuated TNF-α-induced HUVEC apoptosis by reducing apoptotic cell numbers and the BAX/BCL-2 ratio, which could be reversed by the AMPK inhibitor compound c (CC). The further mechanistic study demonstrated that FA could restrain vascular endothelial cell inflammation and apoptosis in KD through activating the AMPK/mTOR/NF-κB pathway. However, FA alone is hard to completely restore KD into normal condition. Conclusion: In conclusion, FA has potential protective effects on KD, suggesting its promising role as an adjuvant for KD therapy in the future.

Kawasaki disease with profound systemic vascular involvements: An insightful pediatric case.

Key Clinical Message: Kawasaki disease (KD), a self-limiting vasculitis, can present with a broader spectrum of vascular involvements, necessitating early recognition and prompt management. This case exemplifies the importance of involving multiple teams on board in managing complex presentations of KD. It also highlights the importance of close monitoring for the progression of the disease spectrum as well as family education to ensure favorable outcomes. The case also emphasizes the importance of long-term follow-up and further research to understand the prognosis, early screening tools, and possible complications due to multi-organ involvement in KD along with their management strategies. Abstract: Kawasaki disease (KD) is a multisystem vascular inflammatory syndrome, which predominantly affects the small and medium vessels in children within the age group of less than 5 years. The most threatened complication is the development of coronary artery aneurysms (CAAs). We present an extremely rare case of KD in a 2-month, 21-day-old male infant with extensive vascular involvement, expanding the disease spectrum beyond the involvement of coronary arteries. These included aneurysmal dilatations of both internal carotid arteries, the descending aorta, bilateral multilevel intercostal arteries, coeliac artery, superior mesenteric artery, and both renal arteries. Implementing a multidisciplinary approach with early treatment via intravenous immunoglobulin (IVIG) and dexamethasone proved to be most effective in the patient's management. Despite unique challenges such as severe coronary dilation and pseudomonas sepsis during the special care, the patient was stabilized and discharged after 11 days of hospital stay, highlighting the importance of early prompt management and a centered approach to evaluate in a broader spectrum. This case emphasizes the importance of long-term follow-up and further research to understand the prognosis, early screening tools, and possible complications due to multi-organ involvement in KD along with their management strategies.

Predictive value of coagulation profiles for Kawasaki disease shock syndrome: a prospective cohort study.

Background: Kawasaki disease (KD) is characterized as an acute febrile inflammatory disorder, which may potentially escalate into a more severe condition termed Kawasaki disease shock syndrome (KDSS). The objective of this research is to understand the clinical attributes of KDSS and to explore the predictive significance of coagulation profiles in the incidence of KDSS. Method: Patients with Kawasaki disease (KD) were prospectively enrolled and divided into the KDSS group (n = 29) and the non-KDSS group (n = 494). Multivariate logistic regression analysis was used to ascertain the relationship between coagulation profiles and KDSS. Furthermore, ROC curve analysis was conducted to evaluate the predictive value of the coagulation profile for the occurrence of KDSS. Result: Among the KDSS patients, the median age was higher and cervical lymph node involvement was greater compared to the non-KDSS group. Additionally pericardial effusion, valve regurgitation, cardiac enlargement, coronary artery lesions (CALs), and Intravenous immunoglobulin (IVIG) resistance were significantly more frequent in the KDSS group than in non-KDSS group. Notably, Prothrombin time (PT), activated partial thromboplastin time (APTT), D-dimer, and fibrin degradation products (FDP) were significantly elevated in the KDSS group compared to the non-KDSS group. Conversely, total thrombin time (TT), fibrinogen, and antithrombin III (ATIII) activity were significantly reduced. Multivariate logistic regression analysis revealed that PT, APTT, D-dimer, and ATIII were independent risk factors for predicting KDSS occurrence. ROC curve analysis established critical values for PT, D-dimer, FDP, and ATIII as 13.45 s, 2.03 mg/L, 7.45 µg/ml, and 77.5%, respectively. Sensitivity for predicting KDSS occurrence was 76%, 79%, 83%, and 76%, while specificity was 51%, 72%, 63%, and 80%, respectively. When we performed a combined ROC curve analysis of the four indicators, we found that its predictive sensitivity was much higher. Moreover, the Delong test results showed that the AUC of the combined analysis was significantly higher than that of the individual analyses. Conclusion: Characteristic features of KDSS include older age, a greater likelihood of experiencing pericardial effusion, valve regurgitation, cardiac enlargement, CALs, and IVIG resistance. KD patients with a hypercoagulable state during the acute phase are at a higher risk of developing KDSS.

Regression effect of renin-angiotensin-aldosterone system inhibitors on Kawasaki disease patients with coronary artery aneurysm: a prospective, observational study.

PURPOSE: This study is to investigate whether angiotensin type 1 receptor blockers (ARBs) or angiotensin-converting enzyme inhibitors (ACEis) can regress coronary artery aneurysm (CAA) in patients with Kawasaki disease (KD). METHODS: This multicenter, prospective, observational study was conducted at 53 institutions throughout Japan. We enrolled patients who were diagnosed with KD after January 2015 and had a medium or large CAA (maximum luminal diameter ≥ 4 mm or z score ≥ + 5) 30 days or later after KD onset. RESULTS: Of the 209 patients, 47 (22%) were taking ARBs/ ACEis. Compared with those in the non-ARB/ACEi group, the baseline CAA diameter was significantly greater (6.7 mm vs. 5.5 mm, p < 0.01), and bilateral CAA (70% vs. 59%, p = 0.01) and giant CAA (32% vs. 20%, p = 0.08) were more frequently observed in the ARB/ACEi group. Although the overall regression rates did not differ between the groups (67% vs. 65%), the regression rates of giant CAA were approximately 1.6 times greater in the ARB/ACEi group than in the non-ARB/ACEi group (36% vs. 23%). Multivariate Cox regression analysis after adjustment for other clinical variables suggested that ARBs/ACEis may be a factor in CAA regression (hazard ratio [HR]: 1.5, 95% confidence interval [CI]: 0.91-2.46). CONCLUSIONS: Although ARBs/ ACEis were used more frequently in patients with severe CAA, these patients had similar CAA regression rates to patients not taking ARBs/ACEis. ARBs/ACEis may be beneficial agents aimed at inducing CAA regression in KD patients. WHAT IS KNOWN: • Large CAAs are less likely to regress and are always at risk of life-threatening cardiac events. • Moderate CAA, age less than 1 year, and female sex have been reported to be factors that promote the regression of CAA. WHAT IS NEW: • Although ARBs/ACEis were used more frequently in patients with severe CAA, these patients had a similar rate of CAA regression to patients who did not take ARBs/ACEis. • The regression rates of giant CAA were approximately 1.6 times greater in the ARB/ACEi group than in the non-ARB/ACEi group.

Circle of Vieussens: Its Importance in the Presence of Significant Coronary Artery Stenosis in a 26-Year-Old Female With Kawasaki Disease.

In patients with coronary artery disease (CAD), collateral circulation aids in sustaining myocardial perfusion and cardiac function. The circle of Vieussens is a rare collateral pathway between the right coronary artery and the left anterior descending artery (LAD) that plays a significant role specifically in patients with chronic total occlusions (CTOs). This article presents a unique case of the circle of Vieussens in a 26-year-old Asian female with a history of Kawasaki disease and CTO of the proximal LAD. Despite the CTO, the patient remains asymptomatic and maintains normal left ventricular function, attributed to an effective collateral network including a right-to-left arterial ring providing TIMI 3 flow. The case illustrates the crucial role of collateral circulation in managing complex coronary anomalies and underscores the need for comprehensive cardiac evaluations in patients with Kawasaki disease. This finding also highlights the potential of the circle of Vieussens as a lifesaving alternate conduit in severe CAD scenarios.

The value of CT coronary angiography for a comprehensive assessment of left circumflex artery in Kawasaki disease: 9 years of experience from a tertiary center.

Background: Transthoracic echocardiography (TTE) has traditionally been the primary method for coronary imaging in children with Kawasaki disease (KD). We aimed to evaluate coronary artery lesions (CALs) of the left circumflex artery (LCx) in KD on computed tomography coronary angiography (CTCA). Methods: Over a 9-year period (November 2013-December 2022), 225 children with KD underwent radiation-optimized CTCA on a 128-slice dual-source platform. TTE was performed on the same day, or a day prior or after CTCA. Findings: On CTCA, LCx CALs were seen in 41/225 (18.2%) patients. However, TTE detected CALs in only one third of these patients [15/41 (36.6%)]. CTCA showed 47 LCx CALs in 41 patients-aneurysms in 39 patients (40 fusiform, 2 saccular; 7 giant aneurysms), stenoses in 3, and thrombosis in 2. Thromboses and stenoses were both missed on TTE. Proximal LCx aneurysms were seen in 39 patients-of these, 12 had distal extension. Six patients had distal LCx aneurysms without proximal involvement and 2 non-contiguous multiple aneurysms. Four (9.75%) patients had isolated LCx involvement. Based on CTCA findings, treatment protocols had to be modified in 3/41 (7.3%) patients. Interpretation: This study highlights anatomical findings of LCx involvement in KD. Isolated LCx CALs were noted in 4/41 (9.75%) patients. TTE alone proved inadequate for LCx assessment in children with KD. With abnormalities detected in 18.2% of cases, including those missed by TTE, CTCA emerges as an essential imaging modality. The findings have implications for treatment planning and follow-up strategies in children with KD. Funding: None.

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.

A large thrombus within a giant coronary artery aneurysm in a child with Kawasaki disease: A case report.

Kawasaki disease (KD) is an acute systemic vasculitis that preferentially involves coronary arteries in young children, and predominantly affects young children. Cardiovascular lesions are the most severe complications of this disease. Even though giant aneurysms are rare, they can complicate thrombus formation, leading to myocardial ischemia, myocardial infarction, and even cardiac death. Later in life, it can lead to steno-occlusive lesions. Follow-up led to coronary artery stenosis. In this article, we report a case of a pediatric patient with KD who presented with a large thrombus within a giant coronary aneurysm as a consequence of delayed treatment with intravenous immunoglobulin (IVIG) and IVIG resistance, which contributed to the formation of coronary artery lesions. Transthoracic echocardiography is a valuable tool for detecting coronary artery abnormalities; however, computed tomography coronary angiography is valuable for precisely delineating coronary anatomy and complications. It is important to maintain a slightly higher international normalized ratio to decrease the risk of thrombosis in coronary artery aneurysms.

Single-cell RNA sequencing: an emerging tool revealing dysregulated innate and adaptive immune response at single cell level in Kawasaki disease.

INTRODUCTION: Kawasaki disease [KD] is a systemic disorder characterized by acute febrile illness due to widespread medium-vessel vasculitis, mainly affecting children. Despite the ongoing advanced research into the disease pathophysiology and molecular mechanisms, the exact etiopathogenesis of KD is still an enigma. Recently, single-cell RNA sequencing [scRNA-seq], has been utilized to elucidate the pathophysiology of KD at a resolution higher than that of previous methods. AREA COVERED: In the present article, we re-emphasize the pivotal role of this high-resolution technique, scRNA-seq, in the characterization of immune cell transcriptomic profile and signaling/response pathways in KD and explore the diagnostic, prognostic, and therapeutic potential of this new technique in KD. Using combinations of the search phrases 'KD, scRNA-seq, CAA, childhood vasculitis' a literature search was carried out on Scopus, Google Scholar, and PubMed until the beginning of 2024. EXPERT OPINION: scRNA-seq presents a transformative tool for dissecting KD at the cellular level. By revealing rare cell populations, gene expression alterations, and disease-specific pathways, scRNA-seq aids in understanding the intricacies of KD pathogenesis. This review will provide new insights into pathogenesis of KD and the field of applications of scRNA-seq in personalized therapeutics for KD in the future.

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.

A novel scoring system based on sIL-2R for predicting IVIG resistance in Chinese children with KD.

OBJECTIVE: This study aimed to develop a novel scoring system utilizing circulating interleukin (IL) levels to predict resistance to intravenous immunoglobulin (IVIG) in Chinese patients with Kawasaki disease (KD). We further compared this scoring system against six previously established scoring methods to evaluate its predictive performance. METHODS: A retrospective analysis was conducted on KD patients who were treated at the cardiovascular medical ward of our institution from January 2020 to December 2022. Six scoring systems (Egami, Formosa, Harada, Kobayashi, Lan and Yang) were analyzed, and a new scoring system was developed based on our data. RESULTS: In our study, 521 KD patients were recruited, 42 of whom (8.06%) were identified as resistant to IVIG. Our study indicated that IVIG-resistant KD patients were at an increased risk for the development of coronary arterial lesions (CALs) (P = 0.001). The evaluation of IVIG resistance using various scoring systems revealed differing levels of sensitivity and specificity, as follows: Egami (38.10% and 88.52%), Formosa (95.24% and 41.13%), Harada (78.57% and 43.22%), Kobayashi (66.67% and 74.95%), Lan (66.67% and 73.49%), and Yang (69.05% and 77.24%). Our novel scoring system utilizing sIL-2R demonstrated the highest sensitivity and specificity of 69.29% and 83.91%, respectively, and calibration curves indicated a favorable predictive accuracy of the model. CONCLUSION: Our newly developed scoring system utilizing sIL-2R demonstrated superior predictive performance in identifying IVIG resistance among Chinese patients with KD.

Metagenomic analysis demonstrates distinct changes in the gut microbiome of Kawasaki diseases children.

Background: Kawasaki disease (KD) has been considered as the most common required pediatric cardiovascular diseases among the world. However, the molecular mechanisms of KD were not fully underlined, leading to a confused situation in disease management and providing precious prognosis prediction. The disorders of gut microbiome had been identified among several cardiovascular diseases and inflammation conditions. Therefore, it is urgent to elucidate the characteristics of gut microbiome in KD and demonstrate its potential role in regulating intravenous immunoglobulin (IVIG) resistance and coronary artery injuries. Methods: A total of 96 KD children and 62 controls were enrolled in the study. One hundred forty fecal samples had been harvested from KD patients, including individuals before or after IVIG treatment, with or without early coronary artery lesions and IVIG resistance. Fecal samples had been collected before and after IVIG administration and stored at -80°C. Then, metagenomic analysis had been done using Illumina NovaSeq 6000 platform. After that, the different strains and functional differences among comparisons were identified. Results: First, significant changes had been observed between KD and their controls. We found that the decrease of Akkermansia muciniphila, Faecalibacterium prausnitzii, Bacteroides uniformis, and Bacteroides ovatus and the increase of pathogenic bacteria Finegoldia magna, Abiotrophia defectiva, and Anaerococcus prevotii perhaps closely related to the incidence of KD. Then, metagenomic and responding functional analysis demonstrated that short-chain fatty acid pathways and related strains were associated with different outcomes of therapeutic efficacies. Among them, the reduction of Bacteroides thetaiotaomicron, the enrichment of Enterococcus faecalis and antibiotic resistance genes had been found to be involved in IVIG resistance of KD. Moreover, our data also revealed several potential pathogenetic microbiome of that KD patients with coronary artery lesions. Conclusion: These results strongly proved that distinct changes in the gut microbiome of KD and the dysfunction of gut microbiomes should be responsible for the pathogenesis of KD and significantly impact the prognosis of KD.

Relationship between serum plasminogen activator and D-dimer levels and the severity of Kawasaki disease in children as well as their predictive value for coronary artery lesion.

OBJECTIVE: To evaluate the relationships between serum plasminogen activator (PA) and D-dimer levels, the severity of Kawasaki disease (KD) in children, and their ability to predict coronary artery lesions (CAL). METHODS: This retrospective study analyzed the clinical data of 102 children diagnosed with KD at the Affiliated Hospital of Jiangnan University from January 2020 to September 2023. The cohort was divided into two groups: 31 children with CAL in the CAL group and 71 without it in the non-CAL group. The study assessed the incidence of CAL and investigated the correlations between serum PA and D-dimer levels and various inflammatory markers (white blood cell (WBC) count, platelet count, and erythrocyte sedimentation rate (ESR)). Receiver operating characteristic (ROC) curves were used to evaluate the predictive value of these biomarkers for CAL. RESULTS: CAL was present in 30.04% of the children. Pearson correlation analysis revealed that serum PA levels were inversely correlated with WBC count (P = 0.0187), platelet count (P = 0.0116), and ESR (P = 0.0041), while D-dimer levels were positively correlated with these markers (P < 0.001). A negative correlation between PA and D-dimer levels was also observed (P < 0.001). The combined use of PA and D-dimer levels to predict CAL achieved an area under the curve of 0.871. CONCLUSION: Serum PA levels were negatively associated with the severity of KD, whereas D-dimer levels were positively associated. Together, these markers showed significant predictive value for CAL, highlighting their utility in assessing disease severity and guiding management in children with KD.

The History of Macrophage Activation Syndrome in Autoimmune Diseases.

In 1979, it became recognized in the literature that what we call hemophagocytic lymphohistiocytosis (HLH) was a nonmalignant disease of histiocytes. Subsequently a familial form and a secondary form of HLH were differentiated. When HLH is secondary to an autoimmune disease, rheumatologists refer to this entity as macrophage activation syndrome (MAS) to differentiate it from HLH itself. Although the first cases of MAS likely appeared in the literature in the 1970s, it was not until 1985 that the term activated macrophages was used to describe patients with systemic juvenile idiopathic arthritis (sJIA) complicated by MAS and the term macrophage activation syndrome first appeared in the title of a paper in 1993.MAS is one of the many types of secondary HLH and should not be confused with primary HLH. Experience has taught that MAS secondary to different autoimmune diseases is not equal. In the 30 years since initial description in patients with sJIA, the clinical spectrum, diseases associated with MAS, therapy, and understanding the pathogenesis have all made significant gains. The diagnostic/classification criteria for MAS secondary to sJIA, SLE, RA, and KD differ based on the different laboratory abnormalities associated with each (Ahn et al., J Rheumatol 44:996-1003, 2017; Han et al., Ann Rheum Dis 75:e44, 2016; Ravelli et al., Ann Rheum Dis 75:481-489, 2016; Borgia et al., Arthritis Rheumatol 70:616-624, 2018). These examples include the thrombocytosis associated with sJIA, a chronic generalized activation of the immune system, leading to elevations of fibrinogen and sIL-2R, low platelet count associated with SLE, and more acute inflammation associated with KD. Therefore, individual diagnostic criteria are required, and they all differ from the diagnostic criteria for HLH, which are based on a previously non-activated immune system (Ahn et al., J Rheumatol 44:996-1003, 2017; Han et al., Ann Rheum Dis 75:e44, 2016; Ravelli et al., Ann Rheum Dis 75:481-489, 2016; Borgia et al., Arthritis Rheumatol 70:616-624, 2018; Henter et al., Pediatr Blood Cancer 48:124-131, 2007). This helps to explain why the HLH diagnostic criteria do not perform well in MAS.The initial treatment remains high-dose steroids and IVIG followed by the use of a calcineurin inhibitor for resistant cases. IVIG can be used if there is a concern about malignancy to wait for appropriate investigations or with steroids. Interluekin-1 inhibition is now the next therapy if there is a failure to respond to steroids and calcineurin inhibitors. Advances in understanding the mechanisms leading to MAS, which has been greatly aided by the use of mouse models of MAS and advances in genome sequencing, offer a bright future for more specific therapies. More recent therapies are directed to specific cytokines involved in the pathogenesis of MAS and can lead to decreases in the morbidity and mortality associated with MAS. These include therapies directed to inhibiting the JAK/STAT pathway and/or specific cytokines, interleukin-18 and gamma interferon, which are currently being studied in MAS. These more specific therapies may obviate the need for nonspecific immunosuppressive therapies including high-dose prolonged steroids, calcineurin inhibitors, and etoposide.

Criteria for Cytokine Storm Syndromes.

In the past two decades, there has been a great deal of work aimed to devise diagnostic guidelines, classification criteria, and diagnostic scores for cytokine storm syndromes (CSSs). The most notable effort has been the large-scale multinational study that led to the development of the 2016 classification criteria for macrophage activation syndrome (MAS) complicating systemic juvenile idiopathic arthritis (JIA). Future studies should scrutinize the validity of the proposed criteria, particularly in systemic JIA patients treated with biologics, in children with subtle or incomplete forms of MAS, and in patients with MAS complicating other rheumatologic disorders. More generic CSS criteria are also available but often lack sensitivity and specificity in a wide variety of patient populations and CSSs of different etiologies. The coronavirus disease 2019 (COVID-19)-related lung disease led to an evolution of the concept of a "cytokine storm." Emerging and unsolved challenges in the diagnosis of the different forms of CSSs highlight the need for diagnostic tools and well-established classification criteria to enable timely recognition and correct classification of patients.

Kawasaki Disease-Associated Cytokine Storm Syndrome.

Kawasaki disease (KD) is a hyperinflammatory syndrome manifesting as an acute systemic vasculitis characterized by fever, nonsuppurative conjunctival injection, rash, oral mucositis, extremity changes, and cervical lymphadenopathy. KD predominantly affects young children and shares clinical features and immunobiology with other hyperinflammation syndromes including systemic juvenile idiopathic arthritis (sJIA) and multisystem inflammatory syndrome in children (MIS-C). Cytokine storm syndrome (CSS) is an acute complication in ~2% of KD patients; however, the incidence is likely underestimated as many clinical and laboratory features of both diseases overlap. CSS should be entertained when a child with KD is unresponsive to IVIG therapy with recalcitrant fever. Early recognition and prompt institution of immunomodulatory treatment can substantially reduce the mortality and morbidity of CSS in KD. Given the known pathogenetic role of IL-1ß in both syndromes, the early use of IL-1 blockers in refractory KD with CSS deserves consideration.

Macrophage Activation Syndrome in the Setting of Rheumatic Diseases.

Patients with established rheumatic disorders may develop complications of macrophage activation syndrome due to severe flares of the underlying disease (adult-onset Still's disease, SLE); however, in most other rheumatic disorders, MAS develops in association with identified viral or other infectious triggers. It is therefore important to pursue appropriate studies to identify potential infectious triggers in rheumatic disease patients who develop MAS. Management is best directed toward treatment of the triggering infections and combinations of high-dose corticosteroids, calcineurin inhibitors, and biologic therapies targeting IL-1 and/or IL-6 to suppress the associated cytokine storm.