Plasma cell-free RNA signatures of inflammatory syndromes in children.

Inflammatory syndromes, including those caused by infection, are a major cause of hospital admissions among children and are often misdiagnosed because of a lack of advanced molecular diagnostic tools. In this study, we explored the utility of circulating cell-free RNA (cfRNA) in plasma as an analyte for the differential diagnosis and characterization of pediatric inflammatory syndromes. We profiled cfRNA in 370 plasma samples from pediatric patients with a range of inflammatory conditions, including Kawasaki disease (KD), multisystem inflammatory syndrome in children (MIS-C), viral infections, and bacterial infections. We developed machine learning models based on these cfRNA profiles, which effectively differentiated KD from MIS-C-two conditions presenting with overlapping symptoms-with high performance [test area under the curve = 0.98]. We further extended this methodology into a multiclass machine learning framework that achieved 80% accuracy in distinguishing among KD, MIS-C, viral, and bacterial infections. We further demonstrated that cfRNA profiles can be used to quantify injury to specific tissues and organs, including the liver, heart, endothelium, nervous system, and the upper respiratory tract. Overall, this study identified cfRNA as a versatile analyte for the differential diagnosis and characterization of a wide range of pediatric inflammatory syndromes.

Proteomic mapping identifies serum marker signatures associated with MIS-C specific hyperinflammation and cardiovascular manifestation.

Multisystem inflammatory syndrome in children (MIS-C) shares several clinical and immunological features with Kawasaki Disease (KD) and pediatric hyperinflammation, but the immuno-phenotypic overlap among these clinical mimics is still incompletely understood. Here we analyzed serum samples from treatment-naïve patients with MIS-C (n = 31) and KD (n = 11), pediatric hyperinflammation (n = 13) and healthy controls (HC, n = 10) by proximity extension assay (PEA) to profile 184 blood biomarkers. Collectively, immunophenotypic overlap between MIS-C and hyperinflammation exceeds overlap with KD. Overexpression of IL-17A in MIS-C and KD could best separate these conditions from hyperinflammatory conditions, while those were hallmarked by overabundance of adenosin deaminase and IL-18. Depletion in serum TNF-related subfamily member 9 (TNFRSF9) and apoptosis inducing ligand (TRAIL) linked with cardiovascular manifestations and myocarditis in MIS-C. Altogether, our analysis highlights important differences in molecular marker signatures also across different MIS-C and KD cohorts and suggests several previously unidentified molecular associations in context of cardiovascular inflammation.

Multi-modal immune dynamics of pre-COVID-19 Kawasaki Disease following intravenous immunoglobulin.

Despite progress, the molecular mechanisms underlying Kawasaki Disease (KD) and intravenous immunoglobulin's (IVIG) ability to mitigate the inflammatory process remain poorly understood. To characterize this condition, plasma proteomic profiles, flow cytometry, and gene expression of T cell subsets were investigated in longitudinal samples from KD patients and compared with two control groups. Systems-level analysis of samples in the acute phase revealed distinctive inflammatory features of KD, involving mainly Th-1 and Th-17 mediators and unveiled a potential disease severity signature. APBB1IP demonstrated an association with coronary artery involvement (CAI) and was significantly higher in CAI+ compared to CAI- patients. Integrative analysis revealed a transient reduction in CD4+ EM T cells and a comprehensive immune activation and exhaustion. Following treatment, Tregs at both frequency and gene expression levels revealed immune dynamics of recovery. Overall, our data provide insights into KD, which may offer valuable information on prognostic indicators and possible targets for novel treatments.

Pathogenic role and diagnostic utility of interferon-α in histiocytic necrotizing lymphadenitis.

PURPOSE: Histiocytic necrotizing lymphadenitis (HNL) is an inflammatory disease of unknown etiology clinically characterized by painful lymphadenopathy. This study aimed to investigate the role of interferon (IFN)-α in the pathogenesis of HNL and the clinical significance of serum IFN-α levels for the diagnosis and monitoring of HNL disease activity. METHODS: This study enrolled 47 patients with HNL and 43 patients with other inflammatory diseases that require HNL differentiation including malignant lymphoma (ML), bacterial lymphadenitis, and Kawasaki disease. Expression of IFN-stimulated genes (ISGs) and MX1 in the lymph nodes was measured by real-time quantitative reverse transcription polymerase chain reaction and immunofluorescence staining, respectively. Enzyme-linked immunosorbent assay was used to quantify serum cytokine levels. The results were compared with the clinical features and disease course of HNL. RESULTS: Patients with HNL had a significantly elevated ISG expression in the lymph nodes compared with those with ML. MX1 and CD123, a specific marker of plasmacytoid dendritic cells (pDCs), were colocalized. In patients with HNL, serum IFN-α levels were significantly elevated and positively correlated with disease activity. The serum IFN-α level cutoff value for differentiating HNL from other diseases was 11.5 pg/mL. CONCLUSION: IFN-α overproduction from pDCs may play a critical role in HNL pathogenesis. The serum IFN-α level may be a valuable biomarker for the diagnosis and monitoring of disease activity in patients with HNL.

Serum NLRP3: A potential marker for identifying high-risk coronary arterial aneurysm in children with Kawasaki disease.

BACKGROUND: Kawasaki disease (KD) is a vasculitis of unknown etiology in children aged under 5 years. Coronary arterial aneurysm (CAA) is the major complication of KD. It is no longer though to be a self-limiting disease because its cardiovascular sequelae might persist into adulthood. NLRP3 is a key protein of the NLRP3 inflammasome that participates in sterile inflammatory disease. This study investigated the serum levels of NLRP3 in patients with KD at different stages to explore the relationships between serum NLRP3 and clinical parameters. METHODS: A total of 247 children enrolled in this study. There were 123 patients in the acute stage of KD, and 93 healthy children made up the healthy control (HC) group. Among the acute KD patients, 52 had coronary arterial aneurysm (KD-CAA) and 71 did not (KD-NCAA). 36 patient samples were collected after IVIG and aspirin treatment. Additionally, 29 patients were in the cardiovascular sequelae stage. Enzyme-linked immunosorbent assay was used to measure serum NLRP3 levels in all subjects. RESULTS: Serum NLRP3 was elevated in the KD group and was even higher in the KD-CAA subgroup than in the KD-NCAA subgroup of acute-stage patients. Serum NLRP3 declined when the patients were treated with IVIG and aspirin, but during the convalescent (coronary sequelae) stage, serum NLRP3 re-increased. Serum NLRP3 was higher in the ≥ 6-mm-coronary-arterial-diameter group than that the < 6-mm-diameter group. The ROC curve of serum NLRP3 indicated its utility in the prediction of both KD and KD-CAA. CONCLUSIONS: NLRP3 may be involved in the development of KD and CAA in children with KD. Targeting NLRP3 might mitigate CAA, thereby reducing the risk of cardiovascular events in adulthood.

The effect of vitamin D status on the occurrence of Kawasaki Disease: a meta-analysis.

AIM: The relationship between vitamin D status and Kawasaki Disease (KD), as well as coronary artery lesion (CAL), has yet to be established. METHODS: A meta-analysis was conducted to assess the correlation between vitamin D status and KD, as well as the impact of vitamin D status on the progression of KD into CAL. RESULTS: The meta-analysis revealed a consistent and significant association between serum 25(OH)D level and the occurrence KD (studies N = 22; z = -3.51, P < 0.001). Patients with KD had markedly lower levels of vitamin D than healthy controls (SMD: -1.30 ng/mL, 95%CI: -2.05 to -0.55 ng/mL). CONCLUSION: The study provided evidence supporting a significant association between lower serum vitamin D levels and the occurrence of KD, particularly within the Chinese population. However, the findings did not suggest a direct impact of vitamin D on the development of CAL in KD patients.

Serum salicylic acid levels in children with Kawasaki disease.

BACKGROUND: This study aimed to clarify serum salicylic acid (SA) levels in patients with Kawasaki disease (KD) after the administration of moderate-dose acetylsalicylic acid (ASA) and their relationship with the therapeutic effect. METHODS: We retrospectively analyzed the clinical data of 142 children with KD. We measured serum SA trough levels during the acute and recovery periods and determined their relationship with clinical and laboratory parameters. RESULTS: The median age of patients was 2.4 years. Thirty-one patients had incomplete KD, 29 were intravenous immunoglobulin (IVIG) non-responders, and one patient had coronary artery lesions. The median ASA dose was 49.7 mg/kg/day. The median serum SA level was 22 µg/mL in the acute period and 15 µg/mL in the recovery period, with 45 (33%) in the acute period and 60 (44%) in the recovery period below the limit of measurement (< 10 µg/mL). Serum SA levels during the recovery period were significantly lower in patients who received steroids. There were no significant differences in IVIG responsiveness based on serum SA levels. CONCLUSIONS: Serum SA trough levels in KD patients treated with moderate-dose ASA were highly variable and did not reach sufficient levels. Serum SA levels were not associated with IVIG responsiveness.

Semaphorin 7A promotes endothelial permeability and inflammation via plexin C1 and integrin ß1 in Kawasaki disease.

BACKGROUND: Kawasaki disease (KD) is a pediatric systemic vasculitis characterized by endothelial cell dysfunction. Semaphorin 7A (Sema7A) has been reported to regulate endothelial phenotypes associated with cardiovascular diseases, while its role in KD remains unknown. This study aims to investigate the effect of Sema7A on endothelial permeability and inflammatory response in KD conditions. METHODS: Blood samples were collected from 68 KD patients and 25 healthy children (HC). The levels of Sema7A and A Disintegrin and Metalloprotease 17 (ADAM17) in serum were measured by enzyme-linked immunosorbent assay (ELISA), and Sema7A expression in blood cells was analyzed by flow cytometry. Ex vivo monocytes were used for Sema7A shedding assays. In vitro human coronary artery endothelial cells (HCAECs) were cultured in KD sera and stimulated with Sema7A, and TNF-α, IL-1ß, IL-6, and IL-18 of HCAECs were measured by ELISA and qRT-PCR. HCAECs monolayer permeability was measured by FITC-dextran. RESULTS: The serum level of Sema7A was significantly higher in KD patients than in HC and correlated with disease severity. Monocytes were identified as one of the source of elevated serum Sema7A, which implicates a process of ADAM17-dependent shedding. Sera from KD patients induced upregulation of plexin C1 and integrin ß1 in HCAECs compared to sera from HC. Sema7A mediated the proinflammatory cytokine production of HCAECs in an integrin ß1-dependent manner, while both plexin C1 and integrin ß1 contributed to Sema7A-induced HCAEC hyperpermeability. CONCLUSIONS: Sema7A is involved in the progression of KD vasculitis by promoting endothelial permeability and inflammation through a plexin C1 and integrin ß1-dependent pathway. Sema7A may serve as a potential biomarker and therapeutic target in the prognosis and treatment of KD.

The Future of Kawasaki Disease Diagnosis: Liquid Biopsy May Hold the Key.

Kawasaki disease (KD) is a febrile illness characterised by systemic inflammation of small- and medium-sized blood vessels, which commonly occurs in young children. Although self-limiting, there is a risk of developing coronary artery lesions as the disease progresses, with delay in diagnosis and treatment. Unfortunately, the diagnosis of KD continues to remain a clinical dilemma. Thus, this article not only summarises the key research gaps associated with KD, but also evaluates the possibility of using circulating endothelial injury biomarkers, such as circulating endothelial cells, endothelial microparticles and vascular endothelial cell-free DNA, as diagnostic and prognostic tools for KD: a "liquid biopsy" approach. The challenges of translating liquid biopsies to use in KD and the opportunities for improvement in its diagnosis and management that such translation may provide are discussed. The use of endothelial damage markers, which are easily obtained via blood collection, as diagnostic tools is promising, and we hope this will be translated to clinical applications in the near future.

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OBJECTIVES: To investigate the changes in the serum levels of oxidized phospholipids (OxPLs) and endothelial nitric oxide synthase (eNOS) and their association with coronary artery disease (CAL) in children in the acute stage of Kawasaki disease (KD), as well as the clinical significance of OxPLs and eNOS. METHODS: A prospective study was conducted on 95 children in the acute stage of KD (KD group). According to the presence of absence of CAL, the KD group was further divided into a CAL subgroup and a non-CAL (NCAL) subgroup. Thirty children with fever due to lower respiratory tract infection were enrolled as the fever group. Thirty healthy children who underwent physical examination were enrolled as the healthy control group. The above groups were compared in terms of general information and serum levels of OxPLs, eNOS and other laboratory indexes, and the correlation between OxPLs level and eNOS level was analyzed. RESULTS: The KD group had a significantly higher level of OxPLs and a significantly lower level of eNOS compared with the fever group and the healthy control group (P<0.05). After treatment, the children with KD had a significantly decreased OxPLs level and a significantly increased eNOS level (P<0.05). Compared with the NCAL subgroup, the CAL subgroup had a significantly higher level of OxPLs and a significantly lower level of eNOS (P<0.05). Among the children of KD, the level of OxPLs was negatively correlated with that of eNOS (rs=-0.353, P<0.05). CONCLUSIONS: Serum OxPLs and eNOS in the acute stage of KD may be involved in the development of CAL in children with KD, and therefore, they may be used as the biomarkers to predict CAL in these children.

Clinical significance of serum cytokine profiles for differentiating between Kawasaki disease and its mimickers.

OBJECTIVES: To investigate the clinical significance of serum cytokine profiles for differentiating between Kawasaki disease (KD) and its mimickers. METHODS: Patients with KD, including complete KD, KD shock syndrome (KDSS), and KD with macrophage activation syndrome (KD-MAS), and its mimickers, including multisystem inflammatory syndrome in children, toxic shock syndrome, and Yersinia pseudotuberculosis infection, were enrolled. Serum levels of interleukin (IL)-6, soluble tumor necrosis factor receptor type II (sTNF-RII), IL-10, IL-18, and chemokine (C-X-C motif) ligand 9 (CXCL9) were measured using enzyme-linked immunosorbent assay and compared them with clinical manifestations. RESULTS: Serum IL-6, sTNF-RII, and IL-10 levels were significantly elevated in patients with KDSS. Serum IL-18 levels were substantially elevated in patients with KD-MAS. Patients with KD-MAS and KD mimickers had significantly elevated serum CXCL9 levels compared with those with complete KD. Area under the receiver operating characteristic curve analysis showed that serum IL-6 was the most useful for differentiating KDSS from the others, IL-18 and CXCL9 for KD-MAS from complete KD, and CXCL9 for KD mimickers from complete KD and KD-MAS. CONCLUSION: Serum cytokine profiles may be useful for differentiating between KD and its mimickers.

Kawasaki disease and increased cardiovascular risk: Is there a link to circulating glycocalyx biomarkers?

AIMS: Kawasaki disease (KD) is an acute systemic vasculitis with possible long-term impact of general cardio-vascular health. An endothelial glycocalyx disorder during the disease's acute phase might predispose to long-term vascular anomalies leading to endothelial dysfunction and atherosclerosis. To investigate any association between increased cardiovascular risk and endothelial glycocalyx, we assessed circulating glycocalyx components in patients with a KD history, and analysed their association with acute-phase clinical features and more importantly, with patients' current cardiovascular risk factors. METHODS: This prospective observational cohort study included 51 subjects: 31 patients with a history of KD, and 20 healthy subjects matched for age and sex. We analysed serum syndecan-1 and hyaluronan via ELISA. We assessed features reported during the acute phase of KD such as blood counts, C-reactive protein (CRP) levels and coronary artery aneurysms (CAA), and their current blood pressure and lipid markers in relation to measured glycocalyx components. RESULTS: Our multivariate analysis revealed that hyaluronan and syndecan-1 levels were not associated with KD. However, the latter exhibited a significant association with acute-phase blood count alterations in patients with KD. Furthermore, significant interactions of hyaluronan and syndecan-1 with certain cardiovascular risk factors like blood lipids and blood pressure were only present in KD patients. CONCLUSION: Vasculitis during KD's acute phase might predispose to a long-term endothelial glycocalyx alteration, influenced by other factors having a vascular impact such as blood pressure and circulating lipids. CLINICAL TRIAL REGISTRATION: German Clinical Trials Register on 25th February 2016, DRKS00010071 https://www.drks.de/drks_web/.

Reduced Platelet miR-223 Induction in Kawasaki Disease Leads to Severe Coronary Artery Pathology Through a miR-223/PDGFRß Vascular Smooth Muscle Cell Axis.

RATIONALE: Kawasaki disease (KD) is an acute vasculitis of early childhood that can result in permanent coronary artery structural damage. The cause for this arterial vulnerability in up to 15% of patients with KD is unknown. Vascular smooth muscle cell dedifferentiation play a key role in the pathophysiology of medial damage and aneurysm formation, recognized arterial pathology in KD. Platelet hyperreactivity is also a hallmark of KD. We recently demonstrated that uptake of platelets and platelet-derived miRNAs influences vascular smooth muscle cell phenotype in vivo. OBJECTIVE: We set out to explore whether platelet/vascular smooth muscle cell (VSMC) interactions contribute to coronary pathology in KD. METHODS AND RESULTS: We prospectively recruited and studied 242 patients with KD, 75 of whom had documented coronary artery pathology. Genome-wide miRNA sequencing and droplet digital PCR demonstrated that patient with KD platelets have significant induction of miR-223 compared with healthy controls (HCs). Platelet-derived miR-223 has recently been shown to promote vascular smooth muscle quiescence and resolution of wound healing after vessel injury. Paradoxically, patients with KD with the most severe coronary pathology (giant coronary artery aneurysms) exhibited a lack of miR-223 induction. Hyperactive platelets isolated from patients with KD are readily taken up by VSMCs, delivering functional miR-223 into the VSMCs promoting VSMC differentiation via downregulation of PDGFRß (platelet-derived growth factor receptor ß). The lack of miR-223 induction in patients with severe coronary pathology leads to persistent VSMC dedifferentiation. In a mouse model of KD (Lactobacillus casei cell wall extract injection), miR-223 knockout mice exhibited increased medial thickening, loss of contractile VSMCs in the media, and fragmentation of medial elastic fibers compared with WT mice, which demonstrated significant miR-223 induction upon Lactobacillus casei cell wall extract challenge. The excessive arterial damage in the miR-223 knockout could be rescued by adoptive transfer of platelet, administration of miR-223 mimics, or the PDGFRß inhibitor imatinib mesylate. Interestingly, miR-223 levels progressively increase with age, with the lowest levels found in <5-year-old. This provides a basis for coronary pathology susceptibility in this very young cohort. CONCLUSIONS: Platelet-derived miR-223 (through PDGFRß inhibition) promotes VSMC differentiation and resolution of KD induced vascular injury. Lack of miR-223 induction leads to severe coronary pathology characterized by VSMC dedifferentiation and medial damage. Detection of platelet-derived miR-223 in patients with KD (at the time of diagnosis) may identify patients at greatest risk of coronary artery pathology. Moreover, targeting platelet miR-223 or VSMC PDGFRß represents potential therapeutic strategies to alleviate coronary pathology in KD. Graphic Abstract: A graphic abstract is available for this article.

Computational modeling of blood component transport related to coronary artery thrombosis in Kawasaki disease.

Coronary artery thrombosis is the major risk associated with Kawasaki disease (KD). Long-term management of KD patients with persistent aneurysms requires a thrombotic risk assessment and clinical decisions regarding the administration of anticoagulation therapy. Computational fluid dynamics has demonstrated that abnormal KD coronary artery hemodynamics can be associated with thrombosis. However, the underlying mechanisms of clot formation are not yet fully understood. Here we present a new model incorporating data from patient-specific simulated velocity fields to track platelet activation and accumulation. We use a system of Reaction-Advection-Diffusion equations solved with a stabilized finite element method to describe the evolution of non-activated platelets and activated platelet concentrations [AP], local concentrations of adenosine diphosphate (ADP) and poly-phosphate (PolyP). The activation of platelets is modeled as a function of shear-rate exposure and local concentration of agonists. We compared the distribution of activated platelets in a healthy coronary case and six cases with coronary artery aneurysms caused by KD, including three with confirmed thrombosis. Results show spatial correlation between regions of higher concentration of activated platelets and the reported location of the clot, suggesting predictive capabilities of this model towards identifying regions at high risk for thrombosis. Also, the concentration levels of ADP and PolyP in cases with confirmed thrombosis are higher than the reported critical values associated with platelet aggregation (ADP) and activation of the intrinsic coagulation pathway (PolyP). These findings suggest the potential initiation of a coagulation pathway even in the absence of an extrinsic factor. Finally, computational simulations show that in regions of flow stagnation, biochemical activation, as a result of local agonist concentration, is dominant. Identifying the leading factors to a pro-coagulant environment in each case-mechanical or biochemical-could help define improved strategies for thrombosis prevention tailored for each patient.

Inflammasome Activation in Children With Kawasaki Disease and Multisystem Inflammatory Syndrome.

[Figure: see text].

Predictors for Intravenous Immunoglobulin Resistance in Patients with Kawasaki Disease.

Background: Between 10 and 20% of Kawasaki disease (KD) patients are resistant to treatment with initial intravenous immunoglobulin (IVIG) and have a high risk of developing coronary artery lesions. Some studies have been conducted to identify predictive factors. However, the results are controversial. This study aims to identify the risk factors for IVIG-resistant KD patients in a Chinese population. Methods: We performed a retrospective analysis of medical records of consecutive KD patients from two medical centers in South China from January 2015 to December 2017. A total of 1281 KD patients were eligible for inclusion in this study and maintained follow-up for over 12 months. The KD patients were divided into two groups based on IVIG response. Clinical characteristics and laboratory variables were compared between the two groups. Multivariate logistic regression analysis was performed to identify the risk factors of IVIG resistance in KD patients. Results: Of the 1281 KD patients, 141 (11.0%) cases who were IVIG resistant to adjunctive therapies for primary treatment were classified as group 1. The remaining patients were in group 2 (n = 1140), classified as the control group. There was a significant difference in male to female ratio and the length of hospital stay between the two groups (P < 0.05). Group 1 had a higher white blood cell count (P=0.01) and C-reactive protein level (P < 0.01) before IVIG treatment than in group 2. Group 1 had a significantly higher white blood cell count and percentage of neutrophils after the IVIG infusion than in group 2 (P < 0.001). In addition, the mean values of C-reactive protein level and neutrophil percentage before and after treatment difference comparison were significantly different. Multivariate analysis showed that patients presenting with coronary artery lesions in the acute phase and a C-reactive protein level >100 mg/L at diagnosis were associated with IVIG resistance in KD. During the 12-month follow-up period, group 1 had an obviously higher incidence of coronary artery lesions than group 2, and the difference between the groups was statistically significant (P < 0.001). Conclusions: Patients presenting with coronary artery lesions in the acute phase and elevated C-reactive protein levels before IVIG treatment might be a useful and important value for predicting IVIG resistance in KD. Risk assessment based on coronary artery lesions and C-reactive protein levels prior to the treatment may improve the outcome of IVIG resistance.

Comparison of serum cytokine profiles in macrophage activation syndrome complicating different background rheumatic diseases in children.

OBJECTIVES: To compare the cytokines involved in the development of macrophage activation syndrome (MAS) in different background rheumatic diseases and to identify serum biomarkers for MAS diagnosis. METHODS: Serum neopterin, IL-6, IL-18 and soluble TNF receptor (sTNFR) type I (sTNFR-I) and type II (sTNFR-II) levels were determined using ELISA in 12 patients with SLE, including five with MAS; 12 patients with JDM, including four with MAS; 75 patients with Kawasaki disease (KD), including six with MAS; and 179 patients with systemic JIA (s-JIA), including 43 with MAS. These results were compared with the clinical features of MAS. RESULTS: Serum neopterin, IL-18 and sTNFR-II levels were significantly higher during the MAS phase than during the active phase in patients with all diseases. Furthermore, serum sTNFR-I levels were significantly higher during the MAS phase than during the active phase in patients with SLE, KD and s-JIA. Receiver operating characteristic (ROC) curve analysis revealed that serum sTNFR-I levels for SLE, serum IL-18 levels for JDM, and serum sTNFR-II levels for KD and s-JIA had the highest areas under the ROC curve. Serum levels of these cytokines were significantly and positively correlated with serum ferritin levels. CONCLUSIONS: Overproduction of IFN-γ, IL-18 and TNF-α might be closely related to the development of MAS. Serum levels of sTNFR-I for SLE, IL-18 for JDM, and sTNFR-II for KD and s-JIA might be useful diagnostic markers for the transition from active phase to MAS.

Macrophage activation syndrome in children with Kawasaki disease: an experience from a tertiary care hospital in northwest India.

OBJECTIVES: To carry out a review of clinical characteristics, laboratory profiles, management and outcomes of patients with Kawasaki disease (KD) and macrophage activation syndrome (MAS). METHODS: Medical records of patients treated for KD and MAS between January 1994 and December 2019 were reviewed. Patient demographics, clinical signs, laboratory values, coronary artery abnormalities, treatments and outcomes of patients with KD and MAS were recorded. We also performed a review published studies on the subject. RESULTS: Of the 950 cases with KD, 12 (1.3%; 10 boys, 2 girls) were diagnosed with MAS. The median age at diagnosis was 4 years (range 9 months-7.5 years). The median interval between onset of fever and diagnosis of KD was 11 days (range 6-30). Thrombocytopenia was seen in 11 patients. The median pro-brain natriuretic peptide value was 2101 pg/ml (range 164-75 911). Coronary artery abnormalities were seen in 5 (41.7%) patients; 2 had dilatation of the left main coronary artery (LMCA), 1 had dilatation of both the LMCA and right coronary artery (RCA), 1 had dilatation of the RCA and 1 had bright coronary arteries. All patients received IVIG as first-line therapy for KD. MAS was treated with i.v. methylprednisolone pulses followed by tapering doses of oral prednisolone. Additional therapy included i.v. infliximab (n = 4), second-dose IVIG (n = 1) and oral ciclosporin (n = 1). CONCLUSION: MAS is an unusual and underrecognized complication of KD. In our cohort of 950 patients with KD, 1.3% had developed MAS. KD with MAS is associated with an increased propensity towards development of coronary artery abnormalities.

Delineating phenotypes of Kawasaki disease and SARS-CoV-2-related inflammatory multisystem syndrome: a French study and literature review.

OBJECTIVE: To better define the clinical distinctions between the new severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-related paediatric inflammatory multisystem syndrome (PIMS) and Kawasaki disease (KD). METHODS: We compared three groups of patients: group 1, cases from our national historic KD database (KD-HIS), before the SARS-CoV-2 pandemic; group 2, patients with KD admitted to an intensive care unit (KD-ICU) from both our original cohort and the literature, before the SARS-CoV-2 pandemic; and group 3, patients with PIMS from the literature. RESULTS: KD-HIS included 425 patients [male:female ratio 1.3, mean age 2.8 years (s.d. 2.4)], KD-ICU 176 patients [male:female ratio 1.3, mean age 3.5 years (s.d. 3.1)] and PIMS 404 patients [male:female ratio 1.4, mean age 8.8 years (s.d. 3.7)]. As compared with KD-HIS patients, KD-ICU and PIMS patients had a higher proportion of cardiac failure, digestive and neurological signs. KD-ICU and PIMS patients also had a lower frequency of typical KD-mucocutaneous signs, lower platelet count, higher CRP and lower sodium level. As compared with KD-HIS and KD-ICU patients, PIMS patients were older and more frequently had myocarditis; they also had fewer coronary abnormalities and lower sodium levels. Unresponsiveness to IVIG was more frequent in KD-ICU than KD-HIS and PIMS patients. CONCLUSION: On clinical grounds, KD-HIS, KD-ICU and PIMS might belong to a common spectrum of non-specific pathogen-triggered hyperinflammatory states. The causes of increasing inflammation severity within the three entities and the different effects on the heart remain to be determined.

Decreased serum Annexin A1 levels in Kawasaki disease with coronary artery aneurysm.

BACKGROUND: Kawasaki disease (KD) is an acute and systemic vasculitis whose etiology remains unclear. The most crucial complication is the formation of coronary artery aneurysm (CAA). Annexin A1 (ANXA1) is an endogenous anti-inflammatory agent and pro-resolving mediator involved in inflammation-related diseases. This study sought to investigate the serum ANXA1 levels in KD patients and further explore the relationship between ANXA1 and CAA, as well as additional clinical parameters. METHODS: Serum samples were collected from 95 KD patients and 39 healthy controls (HCs). KD patients were further divided into two groups: KD with CAAs (KD-CAAs) and KD non-CAAs (KD-NCAAs). Serum levels of ANXA1 and interleukin-6 (IL-6) were determined using enzyme-linked immunosorbent assays. RESULTS: Serum ANXA1 levels in the KD group were significantly lower than in the HC group. In particular, serum ANXA1 levels were substantially lower in the KD-CAA groups. Moreover, serum ANXA1 levels were positively correlated with N%, C-reactive protein (CRP), and IL-6 but negatively correlated with L% in the KD group. Positive correlations between serum ANXA1 levels and erythrocyte sedimentation rate (ESR), IL-6, and D-dimer (DD) were observed in the KD-CAA group. CONCLUSIONS: ANXA1 may be involved in the development of KD, and downregulation of ANXA1 may lead to the hypercoagulability seen in KD. IMPACT: For the first time, it was demonstrated that serum ANXA1 levels were significantly decreased in Kawasaki disease with coronary artery aneurysms. ANXA1 might be involved in the acute phase of Kawasaki disease. Low serum concentrations of ANXA1 might lead to the hypercoagulability stage in Kawasaki disease. ANXA1 might be a potential therapeutic target for patients with Kawasaki disease.