Treatment Of Kawasaki Disease Research Articles

Knowledge framework of intravenous immunoglobulin resistance in the field of Kawasakidisease: A bibliometric analysis (1997-2023).

Kawasaki disease (KD) is an autoimmune disease with cardiovascular disease as its main complication, mainly affecting children under 5 years old. KD treatment has made tremendous progress in recent years, but intravenous immunoglobulin (IVIG) resistance remains a major dilemma. Bibliometric analysis had not been used previously to summarize and analyze publications related to IVIG resistance in KD. This study aimed to provide an overview of the knowledge framework and research hotspots in this field through bibliometrics, and provide references for future basic and clinical research. Through bibliometric analysis of relevant literature published on the Web of Science Core Collection (WoSCC) database between 1997 and 2023, we investigated the cooccurrence and collaboration relationships among countries, institutions, journals, and authors and summarized key research topics and hotspots. Following screening, a total of 364 publications were downloaded, comprising 328 articles and 36 reviews. The number of articles on IVIG resistance increased year on year and the top three most productive countries were China, Japan, and the United States. Frontiers in Pediatrics had the most published articles, and theJournal of Pediatricshad the most citations. IVIG resistance had been studied by 1889 authors, of whom Kuo Ho Chang had published the most papers. Research in the field was focused on risk factors, therapy (atorvastatin, tumor necrosis factor-alpha inhibitors), pathogenesis (gene expression), and similar diseases (multisystem inflammatory syndrome in children, MIS-C). "Treatment," "risk factor," and "prediction" were important keywords, providing a valuable reference for scholars studying this field. We suggest that, in the future, more active international collaborations are carried out to study the pathogenesis of IVIG insensitivity, using high-throughput sequencing technology. We also recommend that machine learning techniques are applied to explore the predictive variables of IVIG resistance.

Features of diagnosis of incomplete Kawasaki disease in young children. A clinical case of Kawasaki disease with the formation of giant coronary artery aneurysms

Kawasaki disease (KD) is a mucocutaneous lymphonodular syndrome, a vasculitis of unknown etiology that mainly affects children under the age of 5 years. Today, KD is the most common cause of acquired heart disease in children in developed countries. Given the absence of pathognomonic diagnosis of the disease, the diagnosis is based solely on the identification of clinical signs and the exclusion of other clinically similar diseases. Timely therapy with intravenous immunoglobulin has significantly reduced the incidence of complications, such as coronary artery aneurysms, from 25 to ≈ 4 %. The long-term prognosis of the disease depends on the initial and current level of coronary artery damage. Patients with coronary artery aneurysms remain at high risk of developing myocardial ischaemia due to thrombosis and stenosis of the coronary arteries, which can occur in case of untimely treatment for KD. Therefore, the life of these patients depends on lifelong thromboprophylaxis and timely diagnosis of stenosis. The article presents a clinical case of incomplete Kawasaki disease, which was complica­ted by the development of giant coronary artery aneurysms.

Consensus Committee of experts on Kawasaki Disease and Chinese Journal of Contemporary Pediatrics – the expert consensuses on intravenous immunoglobulin, aspirin, and glucocorticoid

Introduction and aim. Kawasaki disease (KD) is an acute vasculitis with unknown etiology, usually occurring in chil dren under 5 years old. This article will summarize the three consensuses formulated in China about KD. Material and methods. English databases for consensus search include UpToDate, BMJ Clinical Evidence, National Guideline Clearinghouse, Joanna Briggs Institute Library, Cochrane Library, and PubMed, etc.; Chinese databases in clude China Biomedical Literature Service, China Knowledge Network, Wanfang database, etc. All literature searches ended on February 28, 2022. Analysis of the literature. KD is a common acquired heart disease in children and can lead to severe complications such as coronary injury. However, intravenous immunoglobulin (IVIG) combined with oral aspirin (Asp) is currently recognized as the most effective treatment in KD acute stage and the first-line treatment to prevent cardiovascular complications. Glucocorticoid (GC) is mainly used for KD patients with a high risk of coronary artery aneurysm (CAA), no immunoglobulin response, and confirmed CAA. There are already consensus guidelines on diagnosing and treat ing KD in different countries. This article summarizes the relevant expert consensus on aspirin, glucocorticoids and IVIG for the treatment of Kawasaki disease in China. Conclusion. Still, there are inconsistent opinions in the literature on the mechanism, optimal timing, and dosage of medication for KD.

Relationships between acute generalized eruptive pustulosis, age, sex, primary disease, and prescription medications: Further analysis of the Japanese Adverse Drug Event Report database

BackgroundAcute generalized eruptive pustulosis (AGEP) is a rare, but serious, drug-related adverse event. This study aimed to determine the relationships between AGEP and age, sex, primary disease, and prescription medications using a database of adverse drug events, namely, the Japanese Adverse Drug Event Report (JADER) database. MethodsIn this retrospective observational study, we analyzed AGEP reports extracted from the JADER database based on the preferred term for AGEP (code 10048799). We evaluated the effects of causative drugs, underlying diseases, age, and sex. The association between AGEP and prescription drugs was analyzed using the reporting odds ratio and adjusted for covariates using multiple logistic regression. Association rule mining was performed to evaluate the correlation between each combination of factors and AGEP. ResultsBetween April 2004 and March 2023, 823,662 reports, including 869 reports on AGEP, were entered in the JADER database. The highest percentage of reports in each age group was in males aged <10 years, and clarithromycin was the most used drug in males aged <10 years. Nasopharyngitis was the most common reason for use, and Kawasaki disease was reported as a reason for use among males under 10 years of age, but not among females. ConclusionsIn boys aged <10 years, attention should be paid to the occurrence of AGEP when prescribing clarithromycin and treating Kawasaki disease.

Protective role of forsythoside B in Kawasaki disease-induced cardiac injury: Inhibition of pyroptosis via the SIRT1–NF-κB–p65 signaling pathway

Kawasaki disease (KD), an acute exanthematous febrile pediatric illness involving systemic non-specific inflammatory reactions in small- and medium-sized arteries, poses a significant risk of coronary artery and myocardial inflammatory injury. Developing new KD treatments with improved safety and fewer side-effects is highly desirable. Forsythoside B (FTS-B), extracted from the Forsythia suspensa plant, exerts anti-inflammatory activity by inhibiting NF-κB, which is regulated by SIRT1, the reduced expression of which is strongly associated with cardiovascular disease. However, it has yet to be established whether FTS-B influences KD-related inflammatory damage. In this study, we investigated the effects of FTS-B on inflammation in cellular and murine models of KD. Our findings revealed that KD is associated with cardiac dysfunction and inflammatory injury to myocardial and human coronary artery endothelial cells (HCAECs), resulting in a pyroptosis-feedback loop. Both cellular and KD models were characterized by reduced SIRT1 expression and increased NF-κB p65 expression. Contrastingly, the rates of pyroptosis in both murine model myocardial tissues and HCAECs were significantly alleviated in response to FTS-B treatment. Also in both models, we detected an increase of SIRT1 expression and a decrease in the expression of p65. Further examination of the protective mechanism of FTS-B using the SIRT1-specific inhibitor, EX 527, revealed that this inhibitor blocked the palliative effects of FTS-B on inflammatory injury-induced pyroptosis. These results highlight the potential utility of the SIRT1–NF-κB–p65 pathway as a therapeutic target for KD treatment and demonstrate that FTS-B can alleviate KD-induced cardiac and HCAEC inflammatory injury via inhibition of pyroptosis.

Identification of hub genes and pathogenesis in Kawasaki disease based on bioinformatics analysis.

The aim of this study was to explore new biomarkers of Kawasaki disease (KD) and provide evidence for clinical diagnosis and treatment. Gene Expression Omnibus (GEO) datasets GSE68004 and GSE73461 were downloaded, and the differentially expressed genes (DGEs) were taken, along with DEGs enrichment analysis and protein interaction network. Finally, five algorithms in CytoHubba plug-in were applied to obtain hub genes. In this study, 32 Co-DEGs were identified, and these genes mainly participated in neutrophil degranulation, neutrophil activation involved in immune response, and negative regulation of cytokine production involved in immune response; meanwhile, they were primarily enriched in starch and sucrose metabolism, fatty acid metabolism, autophagy and apoptosis, ferroptosis, and other pathways. Combined with the results of PPI and CytoHubba, 13 key genes were selected as follows: S100A12, HK3, HP, MMP9, MCEMP1, PYGL, ARG1, HIST2H2AA, ANXA3, HIST2H2AC, HIST2H2AA3, GYG1, DYSF. These 13 key genes may mediate the occurrence and development of KD through various processes such as immune regulation, inflammatory response, glucose metabolism, autophagy, and apoptosis, which provide valuable references for the diagnosis and treatment of KD.

Efficacy and safety of infliximab in the treatment of Kawasaki disease: A systematic review and meta-analysis.

Infliximab is a monoclonal antibody specifically binding tumor necrosis factor-alpha and has been approved for the treatment of several inflammatory disorders. However, the efficacy of infliximab in primary treatment of Kawasaki disease (KD) or retreatment of intravenous immunoglobulin (IVIG)-resistant KD in children is controversial. Therefore, we conducted a meta-analysis to compare the efficacy of infliximab alone or in combination with IVIG to IVIG. Eligible randomized and non-randomized trials were retrieved by searching literature databases prior to May 31, 2023. Pooled odds ratio (OR) and 95% confidence interval (95% CI) were calculated for dichotomous variables, and mean difference (MD) with 95% CI was estimated for continuous variables. A total of 14 eligible studies comprising 1257 participants were included. In refractory KD, infliximab alone was associated with a higher effectiveness rate (OR = 4.48, 95% CI 2.67-7.52) and defervescence rate (OR = 5.01, 95% CI 2.99-8.37) and resulted in a 1.08-day-shorter duration of fever (95% CI 0.61-1.55, P < 0.001) and 1.36-day-shorter length of hospital stay (95% CI 0.65-2.08) compared with IVIG. Incidences of coronary artery lesions (CALs), newly developing CALs, and CAL regression did not differ between both groups. For initial treatment of KD, infliximab in addition to IVIG led to a nominally significant higher effectiveness rate (OR = 2.26, 95% CI 1.02-5.01) and a larger reduction of right coronary artery Z score (MD = -0.24, 95% CI -0.27 to -0.21) but did not show additional efficacy in improving other outcomes. The safety profile was similar between both groups. Conclusion: The meta-analysis demonstrates that infliximab alone is a well-tolerated and effective treatment for IVIG-resistant KD. The additional efficacy of infliximab to IVIG for initial treatment of KD is limited. More large and high-quality trials are needed to confirm the efficacy of infliximab, especially for intensification of primary treatment for KD. What is Known: • Infliximab is a novel monoclonal antibody specifically blocking tumor necrosis factor-alpha and is approved for treatment of several immune-mediated inflammatory disorders. • The efficacy of infliximab in treating children with Kawasaki disease is controversial. What is New: • Infliximab is an effective and safe treatment for children with refractory Kawasaki disease but adds limited efficacy to intravenous immunoglobulin for initial treatment of Kawasaki disease.

Kawasaki Disease Complicated with Giant Coronary Aneurysm in Case of Systematized Epidermal Nevus

Kawasaki disease (KD) is an acute systemic vasculitis that involves coronary arteries. Systematized epidermal nevus is a skin disease characterized by extensive verrucous and hyperchromic plaques. A male patient, previously diagnosed with systematized epidermal nevus, was referred for high fever. Eye injection, red lip, strawberry tongue, and enlarged neck node were accompanied. Intravenous immunoglobulin (IVGG) and high-dose aspirin were given for the treatment of KD. An echocardiogram revealed a small aneurysm in the right coronary artery (RCA). Second IVGG was administered because of refractoriness. The size of the aneurysm was increased to medium in RCA and another medium-sized aneurysm was found in the left anterior descending artery (LAD). Clopidogrel was added. After 3 days of defervescence, he was discharged. Warfarin was added for a giant aneurysm in LAD, aggravated 8 weeks later after the presentation. 11 months later, giant aneurysm was changed to medium sized aneurysm. Patient is at following with dual antiplatelet therapy without warfarin.

Evidence-based guidelines for the diagnosis and treatment of Kawasaki disease in children in China (2023)

Kawasaki disease (KD) is an acute self-limiting vasculitis, and it is the most common cause of acquired heart disease in children under 5 years old. One of the improvement goals in pediatric quality control work for the year 2023, as announced by the National Health Commission, is to reduce the incidence of cardiac events and KD-related mortality in children with KD. In order to standardize the diagnosis, treatment, and long-term management practices of KD in China, and effectively prevent and reduce the incidence of coronary artery lesions and long-term adverse effects, the guideline working group followed the principles and methods outlined by the World Health Organization and referenced existing evidence and experiences to develop the "Evidence-based guidelines for the diagnosis and treatment of Kawasaki disease in children in China (2023)". The guidelines address the clinical questions regarding the classification and definition of KD, diagnosis of different types of KD, treatment during the acute phase of KD, application of echocardiography in identifying complications of KD, and management of KD combined with macrophage activation syndrome. Based on the best evidence and expert consensus, 20 recommendations were formulated, aiming to provide guidance and decision-making basis for healthcare professionals in the diagnosis and treatment of KD in children.

Research advances in genetic polymorphisms in Kawasaki disease

Kawasaki disease (KD) is a systemic inflammatory vascular disorder that predominantly affects children and is the leading cause of acquired heart disease in children. Although the etiology of this disease remains unclear, genome-wide association and genome-wide linkage studies have shown that some susceptible genes and chromosomal regions are associated with the development and progression of KD. With the advancement of high-throughput DNA sequencing techniques, more and more genomic information related to KD is being discovered. Understanding the genes involved in the pathogenesis of KD may provide novel insights into the diagnosis and treatment of KD. By analyzing related articles and summarizing related research advances, this article mainly discusses the T cell activation-enhancing genes that have been confirmed to be closely associated with the development and progression of KD and reveals their association with the pathogenesis of KD and coronary artery lesions.

Integrative Analysis of Clinical and Bioinformatics Databases to Reveal the Role of Peripheral Innate Immunity in Kawasaki Disease

Kawasaki disease (KD) is an immune-response disorder with unknown etiology. KD is an acute systemic immune vasculitis caused by infectious factors that can be complicated by coronary artery lesions. Innate immune cells are closely associated with KD onset, but we know little regarding the expression of immunity-related genes (IRGs) and the possible immune regulatory mechanisms involved in KD. In this study, we analyzed public single-cell RNA sequencing (scRNA-seq) and microarray data of peripheral blood mononuclear cells from normal controls and KD patients. The results of scRNA-seq revealed myeloid cells, T cells, B cells, NK cells, erythrocytes, platelets, plasma cells, hematopoietic stem cells, and progenitor cells in the peripheral blood of patients with KD. In particular, myeloid cells were expanded and heterogeneous. Further analysis of the myeloid cell population revealed that monocytes in KD exhibited higher expression of the inflammatory genes S100A8, S100A9, and S100A12; furthermore, CD14+CD16+ monocyte clusters were associated with inflammatory responses. Microarray data revealed that activation of the innate immune response contributed to KD development and progression. Differential expression and weighted gene coexpression network analysis identified 48 differentially expressed IRGs associated with response to intravenous immunoglobulin, currently the most effective treatment of KD, although numerous patients are resistant. Protein–protein interaction analysis identified ten hub genes (IL1R1, SOCS3, IL1R2, TLR8, IL1RN, CCR1, IL1B, IL4R, IL10RB, and IFNGR1) among the IRGs. In addition, the expressions of IL1R1, SOCS3, CCR1, IL1B, and IL10RB were validated in Chinese KD patients using the real-time reverse transcriptase-polymerase chain reaction. Finally, we found that the neutrophil/lymphocyte ratio could be used as a biomarker to predict responsiveness to intravenous immunoglobulin in KD. In conclusion, our data highlight the importance of innate immunity in KD pathogenesis and its potential in predicting treatment response.

NFIL3 aggravates human coronary artery endothelial cell injury by promoting ITGAM transcription in Kawasaki disease

ABSTRACTObjectiveHigh expression of nuclear factor interleukin-3 (NFIL3) and integrin Alpha M (ITGAM) was found in serum samples from Kawasaki disease (KD) patients through bioinformatics analysis. Hence, this study aimed to explore the biological functions of NFIL3 and ITGAM in KD serum-stimulated human coronary artery endothelial cells (HCAECs).MethodsThe differentially-expressed genes in KD were analyzed through bioinformatics analysis. Serum samples were obtained from 18 KD patients and 18 healthy volunteers, followed by detection of NFIL3 and ITGAM levels in KD serum. After HCAECs were transfected with sh-NFIL3, sh-ITGAM, or sh-NFIL3 + oe-ITGAM and underwent 24-h KD serum stimulation, cell viability and apoptosis and the levels of inflammation-related factors were measured. The binding between NFIL3 and ITGAM was validated by dual-luciferase and chromatin immunoprecipitation (ChIP) assays.ResultsNFIL3 and ITGAM were up-regulated in serum from KD patients and KD serum-stimulated HCAECs. Down-regulation of NFIL3 or ITGAM inhibited KD serum-induced cell apoptosis and inflammatory response of HCAECs and promoted cell viability. Mechanistically, NFIL3 promoted ITGAM transcription level. Up-regulation of ITGAM reversed the improvement of NFIL3 down-regulation on KD serum-induced HCAEC injury.ConclusionNFIL3 aggravated KD serum-induced HCAEC injury by promoting ITGAM transcription, which provided new insights into the treatment of KD.

Single-Cell Meta-Analysis of Neutrophil Activation in Kawasaki Disease and Multisystem Inflammatory Syndrome in Children Reveals Potential Shared Immunological Drivers.

Kawasaki disease (KD) and multisystem inflammatory syndrome in children (MIS-C) share similar clinical manifestations, including cardiovascular complications, suggesting similar underlying immunopathogenic processes. Aberrant neutrophil activation may play a crucial role in the shared pathologies of KD and MIS-C; however, the associated pathogenic mechanisms and molecular drivers remain unknown. We performed a single-cell meta-analysis of neutrophil activation with 103 pediatric single-cell transcriptomic peripheral blood mononuclear cell data across 9 cohorts, including healthy controls, KD, MIS-C, compared with dengue virus infection, juvenile idiopathic arthritis, and pediatric celiac disease. We used a series of computational analyses to investigate the shared neutrophil transcriptional programs of KD and MIS-C that are linked to systemic damage and cardiac pathologies, and suggested Food and Drug Administration-approved drugs to consider as KD and MIS-C treatment. We meta-analyzed 521 950 high-quality cells. We found that blood signatures associated with risks of cardiovascular events are enriched in neutrophils of KD and MIS-C. We revealed the expansion of CD177+ neutrophils harboring hyperactivated effector functions in both KD and MIS-C, but not in healthy controls or in other viral-, inflammatory-, or immune-related pediatric diseases. KD and MIS-C CD177+ neutrophils had highly similar transcriptomes, marked by conserved signatures and pathways related to molecular damage. We found the induction of a shared neutrophil expression program, potentially regulated by SPI1 (Spi-1 proto-oncogene), which confers enhanced effector functions, especially neutrophil degranulation. CD177 and shared neutrophil expression program expressions were associated with acute stages and attenuated during KD intravenous immunoglobulin treatment and MIS-C recovery. Network analysis identified hub genes that correlated with the high activation of CD177+ neutrophils. Disease-gene association analysis revealed that the KD and MIS-C CD177+ neutrophils' shared expression program was associated with the development of coronary and myocardial disorders. Last, we identified and validated TSPO (translocator protein) and S100A12 (S100 calcium-binding protein A12) as main molecular targets, for which the Food and Drug Administration-approved drugs methotrexate, zaleplon, metronidazole, lorazepam, clonazepam, temazepam, and zolpidem, among others, are primary candidates for drug repurposing. Our findings indicate that CD177+ neutrophils may exert systemic pathological damage contributing to the shared morbidities in KD and MIS-C. We uncovered potential regulatory drivers of CD177+ neutrophil hyperactivation and pathogenicity that may be targeted as a single therapeutic strategy for either KD or MIS-C.

Current knowledge of TNF-α monoclonal antibody infliximab in treating Kawasaki disease: a comprehensive review.

Kawasaki disease (KD), an autoinflammatory disease primarily affecting young children, characterized by consisting of acute systemic vasculitis and coronary artery involvement in severe cases. Intravenous immunoglobulin gamma (IVIG) combined with aspirin therapy is the first-line regimen for the prevention of coronary aneurysms in the acute phase of KD. The etiology and pathogenesis of KD are unclear, but its incidence is increasing gradually, especially in the cases of IVIG-naïve KD and refractory KD. Conventional therapies for refractory KD have unsatisfactory results. At present, infliximab (IFX), a human-murine chimeric monoclonal antibody that specifically blocks tumor necrosis factor-α (TNF-α), has made great progress in the treatment of KD. This review revealed that IFX infusion (5 mg/kg) could effectively modulate fever, reduce inflammation, improve arthritis, diminish the number of plasma exchange, decrease hospitalizations, and prevent the progression of coronary artery lesions. The adverse effects of IFX administration included skin rash, arthritis, respiratory disease, infusion reaction, hepatomegaly, and vaccination-associated complications. But the incidence of these adverse effects is low. The clear optimal application protocol of the application of IFX for either initial combination therapy or salvage therapy in KD is still under investigation. In addition, there are no effective biomarkers to predict IFX resistance. Further multicenter trials with large sample size and long-term follow-up are still needed to validate the clinical efficacy and safety of IFX for IVIG-resistant KD or refractory KD.

Association of Yersinia Infection With Kawasaki Disease: A Prospective Multicenter Cohort Study.

Yersinia infection is known to present with Kawasaki disease (KD)-like symptoms although differentiating the 2 has been a challenge. The present study aimed to describe the clinical characteristics and prevalence of Yersinia infection presenting with KD-like symptoms. The present, prospective, multicenter study enrolled patients who received a diagnosis of KD between January 2021 and January 2022 at 2 hospitals in Tokyo. Stool samples were collected within 3 days of the start of KD treatment, and cultures were performed for Yersinia . Clinical history and symptoms suggestive of Yersinia infection were also evaluated. During the study period, 141 KD patients were screened and 117 patients with evaluable stool samples were registered. Only 1 patient was positive for Yersinia pseudotuberculosis , which was detected from both stool and blood cultures. The patient was refractory to KD treatment but improved after initiation of appropriate antibiotic therapy. Routine screening for Yersinia is not appropriate for patients with KD and should be limited to certain patients in high-risk areas and those who are refractory to the standard KD treatment.

Live vaccines following intravenous immunoglobulin for Kawasaki disease: Are we vaccinating appropriately?

Australian and New Zealand guidelines recommend that live vaccines be postponed for 11 months after treatment of Kawasaki disease (KD) with intravenous immunoglobulin (IVIG). We aimed to describe patterns of live-vaccine administration after KD treatment, focusing on the measles-mumps-rubella/measles-mumps-rubella-varicella (MMR/MMRV) vaccines, and to compare real-world practice with current recommendations. We combined data from inpatient Electronic Health Records and the Australian Immunisation Register for all children who received IVIG for the treatment of KD under the age of 5 years at two Australian tertiary children's hospitals over a 12-year period. Children who received IVIG <11 months before a scheduled MMR/MMRV were deemed 'at risk' of breaching the guidelines, and those whose subsequent vaccination occurred <11 months after the IVIG were deemed to have 'breached' the guidelines. Of those at risk, three-quarters (76%) breached the guidelines for their first MMR/MMRV. Findings were similar (50%-80%) for the second MMR/MMRV dose. The majority of Australian children treated for KD with IVIG may not be optimally protected by MMRV vaccination. Immunisation systems should address this avoidable risk.

Cathelicidin (LL-37) causes expression of inflammatory factors in coronary artery endothelial cells of Kawasaki disease by activating TLR4-NF-κB-NLRP3 signaling.

Kawasaki disease (KD) is a type of vasculitis with an unidentified etiology. Cathelicidin (LL-37) may be involved in the development of the KD process; therefore, further research to investigate the molecular mechanism of LL-37 involvement in KD is warranted. Enzyme-linked immunosorbent assay (ELISA) was used to detect the levels of tumor necrosis factor-α (TNF-α), interleukin (IL)-1β, NLRP3, and LL-37 in the sera of healthy subjects, children with KD, and children with pneumonia. Subsequently, human recombinant LL-37 or/and toll-like receptors 4 (TLR4)-specific inhibitor TAK-242 stimulated human coronary artery endothelial cells (HCAECs), CCK-8 was used to detect cell proliferation, flow cytometry to detect apoptosis, transmission electron microscopy to observe cytoskeletal changes, Transwell to measure cell migration ability, ELISA to detect inflammatory factor levels, Western blot analysis to analyze protein levels of toll-like receptors 4 (TLR4) and NF-κB p-65, and quantitative real-time polymerase chain reaction (qRT-PCR) to determine LL-37, NLRP3 mRNA levels. In this study, we found that the level of LL-37 was highly expressed in the serum of children with KD, and after LL-37 stimulation, apoptosis was significantly increased in HCAECs, and the expression levels of TLR4, NLRP3 and inflammatory factors in cells were significantly enhanced. Intervention with the TLR4-specific inhibitor TAK-242 significantly alleviated the LL-37 effects on cellular inflammation, TLR4, NLRP3 promotion effect. Our data suggest that LL-37 induces an inflammatory response in KD coronary endothelial cells via TLR4-NF-κB-NLRP3, providing a potential target for the treatment of KD.

Characteristics of persistent arthritis with refractory Kawasaki disease: a single-center retrospective study

Arthritis is one complication of Kawasaki disease (KD); however, the clinical features of arthritis in KD have not been well clarified. We retrospectively investigated the characteristics of persistent arthritis beyond the subacute phase of KD. In this cohort, 49 of 243 patients (20%) developed arthritis, with 33 patients (14%) experiencing persistent arthritis. Among these 33 patients, 31 (94%) had complete KD. Thirty (91%) were resistant to first intravenous immunoglobulin, and 15 (45%) required additional infliximab. Five patients (15%) developed coronary artery lesions, and 24 (73%) had oligoarthritis, mainly in large lower-extremity joints. Twenty-four patients (73%) complained of arthralgia. At arthritis onset, 16 patients (48%) presented with fever, including recurrent fever in 10 patients. Serum C-reactive protein concentration in patients with active arthritis significantly increased compared with after acute KD treatment (2.4 vs. 0.7 mg/dL, p < 0.001). Serum matrix metalloproteinase-3, a biomarker of arthritis, was significantly higher in patients with active arthritis than in remission (93.7 vs. 20.3 ng/mL, p < 0.001). Thirty (91%) and 14 (42%) patients, respectively, were treated with non-steroidal anti-inflammatory drugs and prednisolone, and they completely recovered. To summarize, persistent arthritis is a common complication in refractory KD, and adequate diagnosis and treatment are necessary.

Management of Multisystem Inflammatory Syndrome in Children: Decision-Making Regarding a New Condition in the Absence of Clinical Trial Data.

Multisystem inflammatory syndrome in children (MIS-C) is a new illness that evolved during the COVID-19 pandemic with initial reports of severe disease including use of extracorporeal membrane oxygenation and death. Institutions rapidly assembled task forces to develop treatment algorithms. At the national/international levels, collaboratives and associations assembled consensus writing groups to draft guidelines. These guidelines and algorithms were initially on the basis of expert opinion and small case series. Some groups used the Delphi approach, and the resultant guidelines often mimicked those for other conditions that resembled MIS-C, like Kawasaki disease (KD). For instance, intravenous immunoglobulin (IVIG), a known effective treatment for KD, was recommended for MIS-C. Early in the pandemic many favoured IVIG over steroids as first-line therapy. As evidence evolved so did some guidelines, which now endorse the dual use of IVIG with steroids as first-line therapy. In contrast, withholding immunotherapy became an option for some MIS-C patients with mild symptoms. Herein, we review guidelines and discuss the evidence informing early recommendations, how this has evolved, the role and limitations of expert opinion and observational data, and the importance of leveraging existing research infrastructures, such as the intensive care unit collaborative (Overcoming COVID-19 surveillance registry), and the International Kawasaki Disease Registry. Finally, we discuss strategies to rapidly develop, deploy, and adapt clinical trials evaluating the treatment of such rare conditions in children, which might include alternatives to conventional clinical trial design. The emergence of MIS-C during the COVID-19 pandemic has highlighted unmet needs regarding research of a new condition.

가와사키병과 선천면역

Kawasaki disease (KD) is a self-limited febrile illness diagnosed based on various clinical manifestations, including fever. The major complication of KD is systemic vasculitis, particularly involving the coronary artery. The etiology of KD is not clear, but the pathogenesis may be related to excessive activation of the immune system. Immune modulation for KD treatment, including intravenous immunoglobulin (IVIG), is based on the control of immune hyperactivation. Many studies have reported a genetic susceptibility to KD, which is related to immune cell activation (ITPKC, CAPS3, BLK, FCGR2A, etc.). The innate immunity of humans begins to recognize and react through pattern recognition receptors against pathogen-associated molecular patterns (PAMPs) or damage-associated molecular patterns (DAMPs). Among receptors, the nucleotide-binding domain and leucine-rich repeat-containing receptor (NLRP) or NOD-like receptor (NLRs) in the cytosol contribute to inflammation as a key component. Cytosolic protein complexes called inflammasomes, assembled by NLRP, activate proinflammatory caspase 1 and 11, which ultimately produce IL-1β and IL-18 or induce cell death. IL-1 serves as an initiator for the recruitment of immune cells and the inflammatory response. Systemic vasculitis, such as Behcet disease, may be related to IL-1 polymorphism, and the expression of NLRP3. Coronary arteritis in KD is associated with an innate immune response, including IL-1. The suggested evidence of innate immunity in KD is related to increased neutrophils and monocytes, high levels of γδT cells, macrophage infiltration in coronary arteries and skin, elevated DAMPs such as S100 or HMGB1, and is sometimes associated with hyperactive innate immunity. The gene of the IL-1 pathway may be related to IVIG-resistant KD, and a clinical trial with IL-1 antagonist is currently ongoing. Adjunctive therapy in KD consists of various strategies, including second IVIG, steroids, and TNF inhibitors. The rationale for adjunctive therapy is based on immune hyperactivation with hypercytokinemia or immune modulation. Further efforts are needed to understand innate immunity and KD, especially in IVIG-resistant cases.