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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. [ABSTRACT FROM AUTHOR]

The purpose of this study is to determine whether adding intravenous methylprednisolone pulse (IVMP) to primary adjunctive prednisolone with intravenous immunoglobulin (IVIG) improves treatment resistance and coronary artery aneurysms (CAA) in patients with Kawasaki disease (KD) with a high risk of treatment resistance. This multicenter, prospective, observational study was conducted at 28 hospitals in Japan from October 2016 to June 2020. For patients predicted to be resistant to treatment based on a Kobayashi score ≥ 5 and total bilirubin ≥ 1.0 mg/dL, each hospital independently decided to add IVMP followed by prednisolone, prednisolone alone, or nothing to the primary IVIG therapy. In total, 2856 consecutive KD patients were enrolled; of these, 399 (14.0%) were predicted to be treatment resistant. Patients who were resistant to the primary treatment and required additional treatment comprised 59%, 20%, and 26% of the IVIG-alone group, IVIG-plus-prednisolone group, and IVIG-plus-IVMP group, respectively (P <.0001). The CAA incidence (Z score ≥ 2.5) at month 1 was similar among the treatment groups (6.7%, 4.8%, and 7.3%, respectively; P =.66). CAA occurred more frequently in patients who needed third- or later-line therapy. Conclusions: Primary adjunctive corticosteroid therapy improved the treatment response and suppressed inflammation. However, the study found no benefit of adding IVMP to prednisolone therapy. Patients receiving IVIG alone achieved coronary outcomes comparable to those of patients receiving primary adjunctive corticosteroid therapy although they were more likely to require additional rescue treatment. KD inflammation should be resolved no later than the third line of additional treatment to reduce the risk of CAA. Trial registration: University Hospital Medical Information Network Clinical Trials Registry in Japan (https://www.umin.ac.jp/ctr/index.htm) under code UMIN000024937. What is Known: • Children with Kawasaki disease (KD) who are resistant to standard intravenous immunoglobulin (IVIG) therapy have a high risk of developing coronary artery aneurysms (CAA). • Although primary adjunctive corticosteroid therapy reportedly reduced CAA development, the appropriate dosage and method are unknown. • Patients may experience treatment resistance and CAA development despite receiving timely treatment. What is New: • Primary adjunctive corticosteroid therapy with IVIG significantly improved the treatment response and suppressed inflammation. • The study found no benefit in adding methylprednisolone pulse to prednisolone therapy in KD patients with a high risk of treatment resistance. • Patients receiving primary IVIG alone achieved comparable coronary outcomes to those receiving adjunctive corticosteroid therapy although they were more likely to require additional rescue treatments. • Inflammation related to KD should be resolved no later than the third line of additional rescue treatment to prevent CAA development. [ABSTRACT FROM AUTHOR]

While Kawasaki disease (KD) induced coronary artery aneurysms (KD CAAs) in children are well studied, the features and prognosis of non-KD induced CAAs (non-KD CAAs) in the pediatric population are poorly documented. This case series study is to analyze the etiology and prognosis of non-KD CAAs in children and compare the characteristics of non-KD CAAs and KD CAAs. Non-KD CAA and KD CAA cases at our department from January 2022 to December 2023 were retrospectively collected. Etiologies and prognosis of non-KD CAAs were analyzed. Furthermore, demographic data, biochemical parameters and outcomes between children with Non-KD CAAs and children with KD CAAs were comparatively studied. Fifteen children with non-KD CAAs with a median age of 6 years and 117 children with KD CAAs with a median age of 2.0 years (p = 0.022) were included in this study. The causes of non-KD CAAs include: unknown etiologies (2 cases), coronary artery structural abnormalities (4), Takayasu arteritis (2), virus infection (2), cardiomyopathy (2), aplastic anemia with agranulocytosis (1), ANCA-associated vasculitis (1), and mucopolysaccharidosis (1). In the non-KD CAA group, there were a total of 19 CAAs with 3 being giant, 5 medium, and 11 small; 4 patients had complete CAA regression; an infant with a fistula between the right coronary artery and the coronary sinus complicated with cardiac enlargement died of heart failure. The KD group had significantly higher levels of CRP, white cells counts and ESR with zero mortality. Non-KD CAA cases had a significantly lower regression rate than KD-CAA cases (26.7% vs 66.7%, p = 0.004), and the probability of CAA regression in non-KD patients was 0.341 of that in KD patients (p = 0.006, OR = 0.341, 95% CI: 0.179–0.647). Conclusions: Various etiologies for Non-KD CAAs are identified. Patients with Non-KD CAAs were observed to have lower inflammatory indexes but poorer recovery than patients with KD CAAs. Therapeutic strategies different than those for KD may be needed for non-KD CAAs. What is Known: • Coronary artery aneurysm (CAA) in children is most commonly induced by Kawasaki disease (KD CAA), with a 50 ~ 70% regression rate in 1 to 2 years. • CAA induced by diseases other than KD (non-KD CAA) in children is rare and its prognosis remains largely unknown. What is New: • Most non-KD CAA cases are caused by coronary artery structural malformations. • Non-KD CAA in children has poorer prognosis and lower regression rate compared with KD CAA. • In addition to guideline directed anti-platelet and anti-coagulant therapies, treatments targeting the causal factor are necessary for non-KD CAA. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

This study aimed to identify the appropriate dose of aspirin to be prescribed to patients with acute Kawasaki disease (KD). Using a Japanese national inpatient database, we identified patients with KD treated with intravenous immunoglobulin between 2010 and 2021.The outcomes included the occurrence of coronary artery abnormalities and intravenous immunoglobulin resistance, length of hospital stay, and medical costs. Restricted cubic spline functions were performed to examine the association between aspirin dose and the outcomes. Data of 82,109 patients were extracted from the database. Non-linear associations were observed between aspirin dose and the outcomes. In comparison with an aspirin dose of 30 mg/kg/day, the odds ratio (95% confidence interval) for coronary artery abnormalities was 1.40 (1.13–1.75) at 5 mg/kg/day. An aspirin dose of ≥ 30 mg/kg/day did not significantly change the odds ratio for coronary artery abnormalities. Intravenous immunoglobulin resistance was significantly lower at a dose of 60 mg/kg/day or higher. Conclusion: The results showed no significant association between aspirin escalation over standard-dose and coronary artery abnormalities in patients with acute KD. High-dose aspirin showed the potential to reduce hospital stay and medical costs without increasing complications. What is Known: • Aspirin is used as a standard treatment together with intravenous immunoglobulin for acute Kawasaki disease (KD). However, few studies have shown the most effective dosage of aspirin to prevent coronary artery abnormalities (CAAs). What is New: • There was no significant association between aspirin dose escalation and CAAs in patients with acute KD. [ABSTRACT FROM AUTHOR]

Purpose: Due to its link with the 2019 coronavirus, the multisystem inflammatory syndrome in children (MISC) has garnered considerable international interest. The aim of this study, in which MISC patients were evaluated multicenter, and the data of the third period of the Turk-MISC study group, to compare the clinical and laboratory characteristics and outcomes of MISC patients who did and did not require admission to an intensive care unit (ICU). Methods: This retrospective multicenter observational study was carried out between June 11, 2021, and January 01, 2022. The demographics, complaints, laboratory results, system involvements, and outcomes of the patients were documented. Results: A total of 601 patients were enrolled; 157 patients (26.1%) required hospitalization in the intensive care unit (ICU). Median age was 8 years (interquartile range (IQR) 4.5–11.3 years. The proportion of Kawasaki disease-like features in the ICU group was significantly higher than in the non-ICU group (56.1% vs. 43.2% p = 0.006). The ICU group had considerably lower counts of both lymphocytes and platelets (lymphocyte count 900 vs. 1280 cells × μL, platelet count 153 vs. 212 cells × 103/ μL, all for p< 0.001). C-reactive protein, procalcitonin, and ferritin levels were significantly higher in the ICU group (CRP 164 vs. 129 mg/L, procalcitonin 9.2 vs. 2.2 μg/L, ferritin 644 vs. 334 μg/L, all for p< 0.001). Being between ages 5–12 and older than 12 increased the likelihood of hospitalization in the ICU by four [95% confidence intervals (CI)1.971–8.627] and six times (95% CI 2.575–14.654), respectively, compared to being between the ages 0–5. A one-unit increase in log d-dimer (µg/L) and log troponin (ng/L) was also demonstrated to increase the need for intensive care by 1.8 (95% CI 1.079–3.233) and 1.4 times (95% CI 1.133–1.789), respectively. Conclusion: By comparing this study to our other studies, we found that the median age of MISC patients has been rising. Patients requiring an ICU stay had considerably higher levels of procalcitonin, CRP, and ferritin but significantly lower levels of lymphocyte and thrombocyte. In particular, high levels of procalcitonin in the serum might serve as a valuable laboratory marker for anticipating the need for intensive care. What is Known: • Lymphopenia and thrombocytopenia were an independent predictor factors in patients with MISC who needed to stay in intensive care unit. • The possibility of the need to stay in the intensive care unit in patients with MISC who had Kawasaki disease-like findings was controversial compared with those who did not. What is New: • A one-unit increase log D dimer and log troponin was demonstrated to require for intensive care unit by 1.8 and 1.4 times, respectively. • Serum procalcitonin levels had the best performance to predict stay in the intensive care unit stay. [ABSTRACT FROM AUTHOR]

Children with Kawasaki disease (KD), Multisystem Inflammatory Syndrome in Children (MIS-C), and Adenovirus infections (AI) of the upper respiratory tract show overlapping features. This study aims to develop a scoring system based on clinical or laboratory parameters to differentiate KD or MIS-C from AI patients. Ninety pediatric patients diagnosed with KD (n = 30), MIS-C (n = 26), and AI (n = 34) admitted to the Pediatric Emergency Unit of S.Orsola University Hospital in Bologna, Italy, from April 2018 to December 2021 were enrolled. Demographic, clinical, and laboratory data were recorded. A multivariable logistic regression analysis was performed, and a scoring system was subsequently developed. A simple model (clinical score), including five clinical parameters, and a complex model (clinic-lab score), resulting from the addition of one laboratory parameter, were developed and yielded 100% sensitivity and 80% specificity with a score ≥2 and 98.3% sensitivity and 83.3% specificity with a score ≥3, respectively, for MIS-C and KD diagnosis, as compared to AI. Conclusion: This scoring system, intended for both outpatients and inpatients, might limit overtesting, contribute to a more effective use of resources, and help the clinician not underestimate the true risk of KD or MIS-C among patients with an incidental Adenovirus detection. What is Known: • Kawasaki Disease (KD), Multisystem Inflammatory Syndrome in Children (MIS-C) and adenoviral infections share overlapping clinical presentation in persistently febrile children, making differential diagnosis challenging. • Scoring systems have been developed to identify high-risk KD patients and discriminate KD from MIS-C patients. What is New: • This is the first scoring model based on clinical criteria to distinguish adenoviral infection from KD and MIS-C. • The score might be used by general pediatricians before referring febrile children to the emergency department. [ABSTRACT FROM AUTHOR]

We aimed to investigate the predictive validity of monocyte to high-density lipoprotein cholesterol ratio (MHR) for coronary artery lesions (CALs) and intravenous immunoglobulin (IVIG) resistance in complete Kawasaki disease (KD). MHR values of a total of 207 complete KD patients were calculated and analyzed with regard to their clinical characteristics and outcomes. We compared the differences in clinical data and laboratory parameters between CAL+ group and CAL- group as well as between IVIG-resistant group and IVIG-responsive group. Spearman's correlation analysis was applied to evaluate the correlation between C-reactive protein (CRP) and MHR. Multivariate logistic regression was used to identify risk factors of CALs and IVIG resistance. Receiver operating characteristic (ROC) curve analysis was chosen to determine the optimal cut-off value of MHR and its validity in predicting CALs and IVIG resistance. The MHR level was significantly higher in the CAL+ group, with cut-off value of 1.30 g/L, yielding a sensitivity of 0.753 and specificity of 0.805, as well as in IVIG-resistant group, with cut-off value of 1.03 g/L, yielding a sensitivity of 0.97 and specificity of 0.485. Multivariate logistic regression showed that MHR was an independent risk factor for CALs but not for IVIG resistance. According to the Spearman's correlation analysis, CRP was positively correlated with the MHR. Conclusions: As a practical, cost-effective inflammatory biomarker, MHR has a significantly predictive value in complete KD children complicated with CALs and IVIG-resistance. Paying more attention to the changes of MHR in KD children may contribute to better understanding of KD development and prognosis in clinical practice. What is Known: • CALs are the most prevalent serious sequela of KD, and approximately 10%~20% of patients do not respond to IVIG therapy. • MHR could be a convenient biomarker to predict the development and progression of CVDs. It has been reported that the MHR is a new prognostic biomarker in several CVDs. What is New: • MHR has a significantly predictive value in KD children complicated with CALs and IVIG-resistance. • Compared with the molecular and immunological biomarkers that have been reported, MHR has the characteristics of practical, cost-effective, higher sensitivity and specificity, which can be used as a predictive indicator in complete KD patients. [ABSTRACT FROM AUTHOR]

To investigate the clinical characteristics of Kawasaki disease (KD) presenting with abdominal manifestation as the first manifestation. Our findings may help improve the cognition of KD with abdominal complications, and avoid misdiagnosis and missed diagnosis. A retrospective analysis was conducted of 1490 KD patients admitted to Shengjing Hospital between January 2019 and March 2022. Clinical characteristics, related factors, and prognosis of KD with abdominal manifestation as first manifestation were analyzed. Based on the presenting symptoms, patients were divided into gastrointestinal symptom group (n = 141), liver dysfunction group (n = 55), and control group (n = 1294). In the gastrointestinal group, diarrhea [100 cases (70.9%)], vomiting [55 cases (39.0%)], and abdominal pain [34 cases (24.1%)] were the most common symptoms at onset. 8 cases (5.7%) were complicated with pseudo-intestinal obstruction, 6 cases (4.3%) with ischemic colitis, 5 cases (3.5%) with pancreatitis, 2 cases (1.4%) with appendicitis, and 1 case (0.7%) with cholecystitis. Comparied to ordinary gastroenteritis caused by infection, gastroenteritis with KD has longer fever duration before treatment, higher WBC, PLT, CRP, AST levels and lower albumin levels. All patients in the liver dysfunction group had elevated transaminases, and 19 patients (34.5%) presented with jaundice. In the gastrointestinal group, the average hospital stay was 10.3 days, and the incidence of IVIG unresponsiveness and coronary artery lesion were 18.4% and 19.9%, respectively, which were significantly higher than that in the control group. In the liver dysfunction group, the average hospital stay (11.18 days), incidence of IVIG unresponsiveness (25.5%), and incidence of coronary artery lesion (29.1%) were significantly higher than that in the control group. On multivariate logistic regression analysis, gastrointestinal involvement, fever duration, ALT, PLT, and CRP were identified as risk factors for CAL, younger age, gastrointestinal involvement and fever duration were risk factors for IVIG unresponsiveness. Conclusion: KD with gastrointestinal involvement is associated with a higher risk of IVIG unresponsiveness and coronary artery lesion. KD should be considered in the differential diagnosis of children with acute fever, especially those with gastrointestinal involvement and liver dysfunction. What is Known: • Fever duration, PLT, and CRP were identified as risk factors for CAL. Timely diagnosis and application of IVIG treatment can avoid exploratory laparotomy for ileus, appendectomy for misdiagnosed appendicitis, colonoscopy for misdiagnosed inflammatory bowel disease, and reduce the complications of CAL and IVIG unresponsiveness. What is New: • Abdominal symptoms as the first manifestation can be an independent risk factor for CAL and IVIG unresponsiveness. KD should be considered in the differential diagnosis of children with acute fever, especially those with gastrointestinal symptoms or liver dysfunction. • Gastroenteritis in KD group had longer fever duration before treatment, accompanied with higher WBC, PLT, CRP, AST levels and lower albumin levels than those gastroenteritis caused by infection. Therefore, high attention should be paid to the possibility of KD when gastroenteritis accompanied by along fever duration, high WBC, PLT, CRP, AST level or lowalbumin level. [ABSTRACT FROM AUTHOR]

The long-term prognosis of patients with Kawasaki disease (KD) complicated by coronary artery aneurysms (CAA) is still unclear. The present, multicenter registry study aimed to study the factors associated with coronary events (CE) and determine an appropriate management method for patients with KD complicated with CAA. Patients with KD with onset after 2015 and with a medium-sized or large CAA having an actual diameter ≥ 4 mm or a Z-score ≥ 5.0 at 30 days and later after KD onset were included in the annual survey. The primary endpoint was the time-dependent incidence of CE. Associated factors were also examined. In total, 179 patients from 53 centers were enrolled and followed up for a median of 501 days. The median age at KD onset was 2.2 years, 137 patients were male (77%), 47 had incomplete KD (26%), and 36 had large CAA (20%). CE occurred in 13 patients (7%; 95% confidence interval: 4–12%); eight (62%) experienced CE within 1 year, and all the patients experienced a CE within 2 years. All but one patient received antiplatelet drugs and warfarin. Patients with a large CAA had significantly more CAA (2.8 vs. 1.7, p < 0.001), more cases of warfarin use (86% vs. 43%, p < 0.001), and were more likely to have CE (28% vs. 2%, p < 0.001) than those with a medium-sized CAA. On univariate Cox regression analysis, the factors significantly associated with CE were large CAA (hazard ratio (HR): 17.0), three or more CAA (HR: 23.3), and beaded CAA (HR: 15.9). Multivariable Cox regression analysis revealed that the only associated factor was a large CAA. Conclusion: Patients with a large CAA were more likely to have a CE within 2 years. Antithrombotic therapy with warfarin did not eliminate the CE risk, and better therapies are desirable. What is Known: • Coronary artery aneurysms are a serious complication of Kawasaki disease, and coronary events are sometimes fatal. • In previous, retrospective studies in Japan, large aneurysms, male sex, and refractoriness to initial immunoglobulin therapy were considered risk factors for coronary events. What is New: • Of 179 patients with a medium sized or large aneurysm, 13 (7%) experienced coronary events, all of which occurred within 2 years of onset. Factors significantly associated with coronary events were large aneurysms, three or more aneurysms, and beaded aneurysms. [ABSTRACT FROM AUTHOR]

The most effective dosage of intravenous immunoglobulin (IVIG) to prevent coronary artery abnormalities (CAAs) in patients with acute Kawasaki disease (KD) remains unknown. This study aimed to identify the appropriate dose of IVIG to be administered to patients with acute KD, using a national inpatient database in Japan. We used the Diagnostic Procedure Combination database to identify KD patients treated with IVIG between 2010 and 2020. The primary outcome was the proportion of CAAs upon discharge. Secondary outcomes included IVIG resistance, length of stay, and medical costs. Data from 88,223 patients were extracted from the database. We found a U-shaped association between IVIG dose and the proportion of CAA, with the bottom of the curve at approximately 2.0 g/kg; the odds ratio (95% confidence interval [CI]) was 1.34 (1.26-1.43) for 1.8 g/kg and 1.80 (1.29-2.51) for 2.4 g/kg with reference to 2.0 g/kg for CAA. Similarly, IVIG dose had a U-shaped association with the proportion of IVIG resistance, with the bottom of the curve at approximately 2.0 g/kg; the odds ratio (95% CI) was 1.39 (1.36-1.42) for 1.8 g/kg and 8.95 (8.15-9.83) for 2.4 g/kg with reference to 2.0 g/kg for IVIG resistance. Additionally, IVIG dosage was found to have U-shaped associations with the length of stay and medical costs, with the bottom of the curve at approximately 2 g/kg.   Conclusions: IVIG with a dose of 2 g/kg was considered appropriate for the initial treatment of KD. What is Known: • For treatments of acute Kawasaki Disease (KD), IVIG has been the most recommended to reduce fever early and prevent complications of CAAs. Few studies have shown the most effective dosage of IVIG to be administered to prevent CAAs. What is New: • 2 g/kg intravenous immunoglobulin was considered appropriate for the initial treatment of Kawasaki disease. [ABSTRACT FROM AUTHOR]

The purpose of this study is to clarify the relationship between neonatal sepsis and future development of Kawasaki disease (KD). We analyzed data from the National Hospital Organization Neonatal Intensive Care Unit (NHO-NICU) registry study in Japan. Participants in this study were children with a history of hospitalization in the NICU at the participating institutions from 2010 to 2014. A questionnaire was administered at age 3 years to obtain information about the patient's history of KD. There were 8275 infants who were eligible for this study. At 3 years of age, parents of 2161 children responded to the follow-up survey (follow-up rate, 26.1%). Multivariate logistic regression analysis adjusted for preterm birth, sex, use of antibiotics in the NICU, parity, and maternal smoking showed that children with neonatal sepsis were more likely to have a history of KD at 3 years of age (adjusted odds ratio [aOR]: 11.67, 95% confidence interval [CI]: 2.84–47.96). Conclusions: Among infants admitted to the NICU, neonatal sepsis might be associated with development of KD later in life. Further large studies are needed to elucidate the relationship between neonatal infections and KD development. What is Known: • Preterm birth is known to be a risk factor for Kawasaki disease. •It is not yet known which factors related to preterm birth increase the risk of developing Kawasaki disease. What is New: •Neonatal sepsis is associated with an increased risk of subsequent development of Kawasaki disease. •Antibiotic use in the neonatal intensive care unit may also be an independent risk factor for subsequent development of Kawasaki disease. [ABSTRACT FROM AUTHOR]

Key aspects of the medical management of Kawasaki disease (KD) are not yet supported by a high evidence level, thus making room for individual recommendations. We performed a structured comparison of existing international KD guidelines to analyze potential differences in the implementation of evidence-based KD recommendations regarding diagnosis and therapy. To identify country-specific guidelines, we took a multilateral approach including a comprehensive PubMed literature, online research, and directly contacting national pediatric associations. We then ran a structured guidelines' analysis and evaluated the diagnostic and therapeutic differences in the context of evidence-based medicine. In this structured guideline analysis, we identified nine national and one European guidelines. According to them all, the diagnosis of KD still relies on its clinical presentation with no reliable biomarker recommended. First-line treatment consistently involves only intravenous immunoglobulin (IVIG) therapy. Recommendations in terms of acetylsalicylic acid, corticosteroids, and additional therapeutic options vary considerably. Conclusion: According to all guidelines, KD is diagnosed clinically with some variance in defining incomplete KD and being a non-responder to treatment. First-line treatment consistently includes IVIG. Recommendations for additional therapeutic strategies are more heterogeneous. What is Known: • The diagnosis of KD relies on the clinical presentation, entailing challenges in timely diagnosis. • Other treatment options then IVIG are not supported by a high evidence level, making room for individual recommendations. What is New: • Definition of incomplete KD and being non-responsive to an initial treatment vary to some extent between the national guidelines. • Only IVIG is consistently proposed throughout all guidelines, further therapeutic recommendations vary between the national recommendations. [ABSTRACT FROM AUTHOR]

Multisystemic inflammatory syndrome (MIS-C) diagnosis remains difficult because the clinical features overlap with Kawasaki disease (KD). The study aims to highlight the clinical and laboratory features and outcomes of patients with MISC whose clinical manifestations overlap with or without KD. This study is a retrospective analysis of a case series designed for patients aged 1 month to 18 years in 28 hospitals between November 1, 2020, and June 9, 2021. Patient demographics, complaints, laboratory results, echocardiographic results, system involvement, and outcomes were recorded. A total of 614 patients were enrolled; the median age was 7.4 years (interquartile range (IQR) 3.9–12 years). A total of 277 (45.1%) patients with MIS-C had manifestations that overlapped with KD, including 92 (33.3%) patients with complete KD and 185 (66.7%) with incomplete KD. Lymphocyte and platelet counts were significantly lower in patients with MISC, overlapped with KD (lymphocyte count 1080 vs. 1280 cells × μL, p = 0.028; platelet count 166 vs. 216 cells × 103/μL, p < 0.001). The median serum procalcitonin levels were statistically higher in patients overlapped with KD (3.18 vs. 1.68 µg/L, p = 0.001). Coronary artery dilatation was statistically significant in patients with overlap with KD (13.4% vs. 6.8%, p = 0.007), while myocarditis was significantly more common in patients without overlap with KD features (2.6% vs 7.4%, p = 0.009). The association between clinical and laboratory findings and overlap with KD was investigated. Age > 12 years reduced the risk of overlap with KD by 66% (p < 0.001, 95% CI 0.217–0.550), lethargy increased the risk of overlap with KD by 2.6-fold (p = 0.011, 95% CI 1.244–5.439), and each unit more albumin (g/dl) reduced the risk of overlap with KD by 60% (p < 0.001, 95% CI 0.298–0.559). Conclusion: Almost half of the patients with MISC had clinical features that overlapped with KD; in particular, incomplete KD was present. The median age was lower in patients with KD-like features. Lymphocyte and platelet counts were lower, and ferritin and procalcitonin levels were significantly higher in patients with overlap with KD. What is Known: • In some cases of MIS-C, the clinical symptoms overlap with Kawasaki disease. • Compared to Kawasaki disease, lymphopenia was an independent predictor of MIS-C. What is New: • Half of the patients had clinical features that overlapped with Kawasaki disease. • In patients whose clinical features overlapped with KD, procalcitonin levels were almost 15 times higher than normal. • Lethargy increased the risk of overlap with KD by 2.6-fold in MIS-C patients. • Transient bradycardia was noted in approximately 10% of our patients after initiation of treatment. [ABSTRACT FROM AUTHOR]

This study aimed to explore the incidence and clinical characteristics of multiple complications in children with Kawasaki disease (KD). All patients were diagnosed in our hospital between January 2016 and December 2020. A total of 640 cases were included, 43 patients had coronary artery aneurysm, 51 patients had coronary artery dilation, and 546 patients had no coronary artery damage. The patients were divided into three subgroups based on age: < 1 year old, 1–5 years old, and > 5 years old. The multiple complications of all the KD children and the correlation between extracardiac complications and cardiovascular complications were analyzed. Among the 640 KD children, most were 1–5 years old (415/640, 64.8%). Children < 1 year old (31.6%) and > 5 years old (28.3%) were more likely to have cardiovascular complications. The incidence of respiratory complications was highest in 1–5 year olds (57.1%). Involvement of the digestive and the hematological systems gradually decreased with age, whereas involvement of the nervous system, the urinary system, and the joints gradually increased with age. The incidence of cardiovascular injury with extracardiac complications (22.3%) was higher than that without extracardiac complications (16.3%), although the difference was not statistically significant (p > 0.05). Conclusions: KD can be complicated by multiple-organ injury but there was no significant relationship between the occurrence of extracardiac complications and cardiovascular complications. What is Known: • Cardiovascular disease is generally believed to be the most common and serious complication of Kawasaki disease (KD). • Over recent years, we have found that extracardiovascular complications of KD are more common than generally supposed and, because they have some effect on prognosis, we believe that more attention should be paid to these complications. What is New: • There was no significant relationship between the occurrence of extracardiac complications and cardiovascular complications. [ABSTRACT FROM AUTHOR]

A retrospective study that compared children younger than 6 months versus older children of a Spanish cohort of patients diagnosed with Kawasaki disease between 2011 and 2016 (Kawa-Race study). From the 598 patients recruited, 42 patients were younger than 6 months (7%) and presented more frequently with an incomplete diagnosis of Kawasaki disease (52.4 vs 27.9%, p = 0.001). Cardiac abnormalities detected by echocardiography were more common in younger patients (52.4 vs 30%, p = 0.002). These younger patients presented with a higher proportion of coronary aneurysms as well (19 vs 8.6%, p < 0.001). Shock at diagnosis (9.5 vs 1.9%, p = 0.016) and admission to intensive care units (17.7 vs 4.1%, p = 0.003) were more frequent in patients younger than 6 months. There were no statistically significant differences in relation to infections, non-response to IVIG, or mid- or long-term outcomes. Conclusion: Data of the Spanish cohort are consistent with other American and Asian studies, although Spanish children younger than 6 months had a lower rate of non-response to IVIG and better clinical outcomes. A high index of suspicion should be considered for this population due to a higher risk of coronary abnormalities, presentation of shock, and admission to the intensive care unit. What is Known: •Children below 6 months of age with Kawasaki disease (KD) have different features compared to older. •Younger patients usually have an incomplete form of KD and coronary artery abnormalities. What is New: •Younger than 6 months with KD presented with shock and required admission to PICU more frequently compared to older. •Infections play a similar role in KD despite the age of the patients. [ABSTRACT FROM AUTHOR]

Kawasaki disease (KD) is an acute systemic vasculitis that most commonly causes acquired cardiac disease in children in developed countries. The most highly recommended treatment for KD is 2 g/kg intravenous immunoglobulin (IVIG). There are two types of IVIG, sodium-containing (high-Na) and sodium-trace (low-Na) preparations. However, few studies have compared the effects of these two preparations for superiority. The purpose of this study was to compare outcomes between high and low-Na IVIG preparations in KD children using a national inpatient database in Japan. We used the Diagnostic Procedure Combination database to identify KD patients treated with IVIG between 2010 and 2017. We identified those receiving high and low-Na preparations of IVIG as an initial treatment. Outcomes included proportion of coronary artery abnormalities (CAA), IVIG resistance, adverse effects, length of stay, and medical cost. Propensity score–matched analyses were conducted to compare the outcomes between the two groups. Instrumental variable analyses were performed to confirm the results. We identified 42,345 patients with KD. There were significant differences in proportions of CAA (2.8% vs. 3.2%; p = 0.031) and IVIG resistance (17% vs. 18%, p = 0.001) between the two groups. However, there were no significant differences in length of stay or medical cost. The instrumental variable analysis confirmed the same results as the propensity score analysis. Conclusion: The present study suggests that high-Na IVIG is potentially effective for reducing the proportion of CAA in KD patients. Prospective studies are warranted to confirm the effectiveness observed in this study. What is Known: • For treatments of Kawasaki Disease in acute phase, intravenous immunoglobulin have been the most recommended to reduce fever early and prevent complications of coronary artery abnormalities. There are two types of IVIG preparations, sodium-containing IVIG and sodium-trace IVIG. However, few studies have performed comparisons to determine which preparation of IVIG is superior. What is New: • The present findings suggest that high-Na IVIG is associated with reductions in the proportions of CAAs and IVIG resistance in KD patients. [ABSTRACT FROM AUTHOR]

Risk factors for coronary artery lesion (CAL) development in patients with Kawasaki disease (KD) include male sex, age < 12 months, intravenous immunoglobulin (IVIG) resistance, and delayed diagnosis.. We aimed to explore the relationship between CAL development and Z-score. We enrolled 281 patients with KD who were treated with our protocol. Echocardiography was performed in three phases: pre-treatment (P1), post-treatment (P2), and 4 weeks after onset (P3). The highest Z-score of the right, left main, left anterior descending, and left circumflex coronary arteries was expressed as Zmax at each phase. P3-Zmax ≥ 2.5 represented CAL development. Clinical parameters, such as laboratory data and Z-scores, were retrospectively compared between patients with and without CAL development. Sixty-seven patients (23.8%) showed a P1-Zmax ≥ 2.0, and CAL development occurred in 21 patients (7.5%). Independent risk factors associated with CAL development were P1-Zmax, a ΔZmax (P2-Zmax − P1-Zmax) ≥ 1, male sex, < 12 months of age, and resistant to the first intravenous immunoglobulin (IVIG) administration (adjusted odds ratio [95% confidence interval]: 198 [1.01–3.92], 4.04 [1.11–14.7], 6.62 [1.33–33.04], 4.71 [1.51–14.68], 5.26 [1.62–17.13], respectively). Using receiver operating characteristic curve analysis, a P1-Zmax ≥ 1.43 detected CAL development with an area under the curve of 0.64 (sensitivity = 81.0%; specificity = 48.1%). Conclusion: Our results suggest that P1-Zmax and a ΔZmax (P2-Zmax − P1-Zmax) ≥ 1 may predict CAL development. What is Known: • KD is an acute vasculitis predominantly affecting the coronary artery of young children. • Although P1 Z-max ≥ 2.0 has been a predictor of CAL development, it has not yet been shown in Japan. What is New: • P1-Zmax and a ΔZmax ≥ 1 are presumably associated with CAL development. • In the ROC curve analysis, P1-Zmax ≥ 1.43 detected CAL development, a sensitivity (81%) and a specificity (48%). We need to consider intensified initial therapy for patients with these risk factors. [ABSTRACT FROM AUTHOR]

Kawasaki disease (KD) is an acute systemic vasculitis in children. Coronary artery lesions (CALs) are the most serious complications in KD, but the pathogenesis is still unclear so far. Adropin, a new biopeptide, plays an important role in metabolism and cardiovascular function. The aim of this study was to explore the relationship between adropin and KD. 66 KD patients and 22 healthy controls (HCs) were included in the study. KD patients were divided into KD with coronary artery lesions (KD-CALs) group and KD without CALs (KD-NCALs) group. The levels of serum adropin were determined by enzyme-linked immunosorbent assay (ELISA). Compared with the HC group, adropin concentrations were significantly increased in the KD group (p < 0.05), and the KD-CAL group had higher levels of adropin than those in the KD-NCAL group (p < 0.05). Pct (Procalcitonin) and DD (D-dimer) were positively correlated with adropin in the KD group (p < 0.05). Moreover, adropin had positive correlations with CRP (C-reactive protein) and DD in the KD-NCAL group and positive correlations with Pct, PLR (platelet-to-lymphocyte ratio), and DD in the KD-CAL group (p < 0.05). The receiver operating characteristic (ROC) curve showed that the best threshold value of serum adropin level was more than 2.8 ng/mL, with 72.2% sensitivity and 71.4% specificity for predicting CALs in children with KD.Conclusion: Adropin might be involved in the pathogenesis of KD and CALs and can be used as an auxiliary diagnostic biomarker of KD. What is Known: • CALs in KD were mainly caused by inflammation, immune imbalance, and vascular endothelial dysfunction, and adropin is involved in metabolic diseases and cardiovascular diseases. What is New: • In this study, we have found the relationship between adropin and KD, and serum adropin level can be used as an auxiliary diagnostic biomarker to predict CALs in KD. [ABSTRACT FROM AUTHOR]

In Kawasaki disease (KD), thrombocytosis is commonly found in the subacute phase. However, the exact significance of thrombocytosis in the acute phase of KD is unclear. To evaluate serum platelet counts in patients during the acute phase of KD and assess the clinical outcomes according to the degree of thrombocytosis, we collected data of KD patients between 2009 and 2017. A total of 505 patients with KD were enrolled, and 249 (49.3%) patients had thrombocytosis, including mild (69.5%), moderate (21.7%), severe (4.8%), and extreme (4.0%) thrombocytosis. Correlation analysis revealed a positive correlation between the maximum platelet count and admission duration (r = 0.359, p < 0.001) and fever duration (r = 0.204, p < 0.001). The maximum platelet count was significantly higher in IVIG non-responders than that in IVIG responders (629 ± 201 × 109/L vs. 499 ± 154 × 109/L, p < 0.001), and in patients with coronary artery dilatation (CAD) than in those without CAD (602 ± 201 × 109/L vs. 512 ± 164 × 109/L, p < 0.001). Conclusion: Thrombocytosis in acute phase KD was associated with poor clinical outcomes such as IVIG non-responsiveness, CAD, and prolonged admission and fever durations. What is Known: • Thrombocytopenia in the acute phase of KD is related to non-responsiveness to IVIG and the risk of coronary artery dilatation. • The exact significance of thrombocytosis in the acute phase of KD as a benign phenomenon or a signal of poor outcome of KD is unclear. What is New: • Thrombocytosis in acute phase KD was associated with poor clinical outcomes such as IVIG non-responsiveness, CAD, and prolonged admission and fever durations. [ABSTRACT FROM AUTHOR]

This study was conducted to assess the clinical spectrum, management, and outcome of SARS-CoV-2-related multisystem inflammatory syndrome in children (MIS-C). We reviewed medical records of children with MIS-C diagnosis seen at the Children's Hospital of Michigan in Detroit between April and June 2020. Thirty-three children were identified including 22 who required critical care (group 1) and 11 with less intense inflammation (group 2). Children in group 1 were older (median 7.0 years) than those in group 2 (median 2.0 years). Abdominal pain was present in 68% of patients in group 1. Hypotension or shock was present in 17/22 patients in group 1. Thirteen (39.4%) had Kawasaki disease (KD)–like manifestations. Five developed coronary artery dilatation; All resolved on follow-up. Intravenous immunoglobulin (IVIG) was given to all patients in group 1 and 7/11 in group 2. Second-line therapy was needed in 13/22 (group 1) for persisting inflammation or myocardial dysfunction; 12 received infliximab. All patients recovered. Conclusion: MIS-C clinical manifestations may overlap with KD; however, MIS-C is likely a distinct inflammatory process characterized by reversible myocardial dysfunction and rarely coronary artery dilatation. Supportive care, IVIG, and second-line therapy with infliximab were associated with a favorable outcome. What is Known: • Multisystem inflammatory syndrome in children (MIS-C) manifestations include fever, gastrointestinal symptoms, shock, and occasional features of Kawasaki disease (KD). • Treatment includes immunomodulatory agents, most commonly IVIG and corticosteroids. What is New: • Spectrum of MIS-C varies from mild to severe inflammation and coronary artery dilatation occurred in 5/22 (23%) critically ill patients. • IVIG and infliximab therapy were associated with a favorable outcome including resolution of coronary dilatation; only 2/33 received corticosteroids. [ABSTRACT FROM AUTHOR]

Myocarditis and Kawasaki disease are common but usually distinct diseases in children. During the coronavirus pandemic (COVID-19), reports of a new form of myocarditis with clinical features of Kawasaki appeared. We investigated the place of this new disease in the spectrum encompassing Kawasaki disease and myocarditis. Thirty two consecutive children referred to our centre for a suspicion of Kawasaki or a diagnosis of myocarditis were included and eventually divided into four groups: 11 Kawasaki diseases, 6 Kawasaki syndromes (children with another diagnosis), 7 myocarditis without Kawasaki clinical feature and 7 myocarditis with incomplete Kawasaki clinical features. All were treated with immunoglobulins except those of the myocarditis group. The survival rate was 91%. The 7 children with myocarditis and clinical features of incomplete Kawasaki were all positive for SARS-CoV-2. They had a transient myocardial failure with a favourable course and none had coronary artery disease. Conclusion: Every COVID-19 child within our population had a mild to severe myocarditis and presented with fever plus two or three Kawasaki clinical features. Short-term evolution was good for these children. This new disease seems to fill the gap between isolated myocarditis and Kawasaki disease. What is Known: • A new paediatric disease close to Kawasaki disease appeared during the COVID-19 pandemic What is New: • In our population, children presented with fever, vivid Kawasaki clinical features (although the Kawasaki syndrome was always incomplete) and a myocarditis without coronary abnormalities. • The new disease fills the gap between paediatric myocarditis and Kawasaki disease but its prognosis is much better. [ABSTRACT FROM AUTHOR]

Kawasaki disease (KD) is an acute vasculitis predominantly affecting the small arteries of young children. Up to 25% of untreated patients suffer from coronary artery (CA) complications. Early diagnosis and treatment is mandatory in incomplete KD to reduce the risk of coronary involvement. Between 2002 and 2018, 124 patients have been diagnosed suffering from KD at the University Children's Hospital Regensburg (KUNO). We assessed luminal diameters of both CAs normalized as Z-scores by 2D-echocardiography. A total of 94 patients were analyzed. Of them, 31 (33%) were affected by an incomplete form of KD. In 24 children (26%), serial echocardiography was necessary in order to confirm diagnosis. Mean Z-scores for the left main coronary artery (LMCA), right main coronary artery (RMCA), and left anterior descending artery increased significantly between the initial (LMCA 0.79z, RMCA 0.15z, LAD 0.49z) and second (LMCA 1.69z, RMCA 0.99z, LAD 1.69z) examination (p < 0.05). Conclusion:To confirm diagnosis of KD, it might not be necessary to detect dilation or aneurysms. Our observation suggests that patients suspected having KD should be monitored with serial echocardiography in order to detect a possible enlargement of the CA diameters, even if Z-scores are within the normal range. What is Known: • Kawasaki disease (KD) is an acute vasculitis predominantly affecting the small arteries of young children. Up to 25% of untreated patients suffer from coronary artery (CA) complications. • Due to less classic clinical criteria in patients with incomplete KD, the risk for CA pathology is even higher. What is New: • A significant progression of patients' CA Z-scores in serial echocardiographic measurements may be helpful to ensure diagnosis of KD early even if Z-scores are within the normal range. • Twenty-seven patients (90%) with incomplete KD could be diagnosed within 10 days of fever, early enough to prevent significantly higher rates of CA aneurysm. [ABSTRACT FROM AUTHOR]

Little is known whether 2-g/kg IVIG is necessary for older children with Kawasaki disease (KD), because they could have more complications and financial burden. The purpose of this study was to compare outcomes between high- and low-dose IVIG in KD children with higher body weight (25 kg or more), using a national inpatient database in Japan from 2010 to 2017. We identified those receiving 2-g/kg and 1-g/kg IVIG as an initial treatment. Outcomes included the proportions of coronary artery abnormality (CAA) formation, IVIG resistance, adverse effects, length of stay, and medical costs. A propensity score matching analysis was conducted to compare the outcomes between the groups. We identified 1332 patients with KD and created 4:1 propensity score–matched pairs between high- and low-dose IVIG groups. There were no significant differences in the proportions of CAA (5.3% vs. 4.1%; p = 0.587), IVIG resistance, and length of stay. Medical costs were significantly higher in the high-dose group than in the low-dose group (p < 0.001). Conclusion: No significant difference was shown between the high- and low-dose IVIG groups in the proportions of outcomes, while medical costs were higher in the high-dose group. Further studies are needed to ascertain the appropriate IVIG dose in older patients with KD. What is Known: • For treatments of Kawasaki disease at any age in the acute phase, 2-g/kg single-dose intravenous immunoglobulin and aspirin have been the most recommended to reduce fever early and prevent complications of coronary artery abnormalities. What is New: • There was no significant difference in outcomes between children with Kawasaki disease weighing ≥ 25 kg treated with high-dose or low-dose IVIG in terms of coronary artery abnormalities, IVIG resistance, adverse effects, and length of stay, except for medical costs. [ABSTRACT FROM AUTHOR]

Kawasaki disease (KD) is associated with several musculoskeletal manifestations. Although arthritis has been reported to occur in 2.3-31% of children with KD, there is paucity of detailed studies on the subject. We report our experience on arthritis in children with KD. Data were collated from a review of records of patients diagnosed with KD and arthritis during the period January 1994-June 2019. Eight hundred sixty-five children (male:female 29:11) were diagnosed with KD during this period-of these, 40 (4.6%) had arthritis. Median day of diagnosis of KD was 17 days. Twenty-nine (72.5%), 8 (20%), and 3 (8.6%) children developed arthritis in acute, subacute, and convalescent phases of KD, respectively. Oligoarticular involvement was observed in 32 (80%) children and among these, 7 (20%) had monoarthritis. Predominant joints involved were knee (74.3%), ankle (40%), and hip (28.6%). Thirty-two children (80%) were treated with non-steroidal anti-inflammatory drugs (NSAIDs). Median duration of arthritis was 10 days (range, 2-180 days) with uneventful recovery in all cases. Three (7.5%) children had coronary artery ectasia which regressed on follow-up.Conclusion: Arthritis in KD is usually non-erosive, self-limiting, and responds well to a short course of NSAIDs.What is Known:• Arthritis has been reported to occur in 2.3-31% of children with KD.• Arthritis in KD is usually oligoarticular, non-erosive, and responds well to short course of non-steroidal anti-inflammatory drugs.What is New:• Children with KD and arthritis do not appear to be at increased risk of development of coronary artery abnormalities.• Arthritis in children with KD can result in diagnostic confusion, and diagnosis of KD may get delayed. [ABSTRACT FROM AUTHOR]

To identify the risk factors of progression and persistence of small- and medium-sized coronary artery aneurysm (CAA) in a contemporary cohort of patients with Kawasaki disease (KD) and to determine the relationship between CAA progression and persistence. A total of 89 KD patients with small- and medium-sized CAA were prospectively enrolled. All patients were followed up at least for 2 years by serial echocardiography. Multivariate logistic regression analysis was conducted to evaluate independent risk factors for CAA progression and persistence. A total of 46 (51.7%) and 73 (82.0%) patients showed echocardiographic CAA regression by 1 month and 24 months of follow-up, respectively. CAA progression was documented in 12 (13.5%) patients during follow-up. The initial aneurysm size according to CAA classification (OR 0.089, 95% CI 0.013-0.634, P = 0.016) and CAA progression (OR 42.618, 95% CI 3.740-485.6, P = 0.003) were independently associated with CAA persistence. The number of involved coronary arteries (OR 0.223, 95% CI 0.065-0.767, P = 0.015) and lymphocyte proportion (OR 1.327, 95% CI 1.019-1.727, P = 0.040) were independently associated with CAA progression.Conclusion: Patients with KD and greater initial aneurysm size, CAA progression, more involved coronary arteries, and lower lymphocyte proportion may require intensive cardiac monitoring and adjuvant therapies.What is Known:• Long-term outcomes of patients with KD and CAA are primarily driven by the consequences of CAA regression and progression.• Regression and progression occurs more frequently in patients with small- and medium-sized CAAs, and less frequently for giant CAAs.What is New:• The CAA size at diagnosis, NCAI, and the proportion of lymphocytes are presumably associated with the small- and medium-sized CAA persistence or CAA progression.• The CAA progression was associated with CAA persistence. [ABSTRACT FROM AUTHOR]

The association between breastfeeding and Kawasaki disease is not fully understood. We performed a case-control study to examine the association between breastfeeding and Kawasaki disease. In this study, 389 children diagnosed with Kawasaki disease and 426 gender- and age-matched controls were identified at Renmin Hospital of Wuhan University between November 2013 and March 2019. Demographic and clinical data were collected from a structured telephone interview and medical record database. Odds ratio and 95% confidence interval for risk of Kawasaki disease were estimated. Children who were breastfed exclusively had a decrease in developing Kawasaki disease (adjusted odds ratios and 95% confidence intervals 0.53 (0.38-0.74). Although the risk reduction was not statistically different, partial breastfeeding also provided a protective effect (adjusted odds ratios and 95% confidence intervals 0.70 (0.48-1.01). In the stratified analysis, we still observed that exclusive breastfeeding was inversely associated with the development of complete Kawasaki disease (adjusted odds ratios and 95% confidence intervals 0.52 (0.31-0.88) and incomplete Kawasaki disease (adjusted odds ratios and 95% confidence intervals 0.54 (0.38-0.77). However, there was no significant association between exclusive breastfeeding and the intravenous immunoglobulin treatment response (adjusted odds ratios and 95% confidence intervals 0.69 (0.27-1.69) and the risk of coronary artery lesions (adjusted odds ratios and 95% confidence intervals 0.79 (0.49-1.31) in Kawasaki disease.Conclusion: Our analysis suggests that exclusive breastfeeding was inversely associated with the development of Kawasaki disease and that breastfeeding might be a potential protective factor against Kawasaki diseaseWhat is known• Previous studies have demonstrated that breastfeeding has been shown to potentially confer protection against several autoimmune disorders of childhood.• The association between breastfeeding and Kawasaki disease is not fully understood.What is newThe first study to evaluate the association between breastfeeding and the development of Kawasaki disease in China with a large sample size.• Exclusive breastfeeding was inversely associated with the development of Kawasaki disease and breastfeeding might be a potential protective factor against Kawasaki disease. [ABSTRACT FROM AUTHOR]

Elevated von Willebrand factor (vWF):Antigen plasma levels have been observed in conjunction with cardiovascular diseases or vasculitis. The association of Kawasaki disease, a vascular inflammatory disease and vWF:Antigen, vWF:Collagen binding activity, and vWF multimers is unknown. We therefore investigated vWF parameters in 28 patients with acute Kawasaki disease in association with disease activity and coronary artery lesions. VWF:Antigen and vWF:Collagen binding activity were assessed via enzyme-linked immunoassay. The ratio of both (vWF:Collagen binding activity and VWF:Antigen) was calculated and vWF multimeric structure analysis performed. We analyzed the association between vWF parameters and our clinical data focusing on coronary artery outcome. VWF:Antigen and vWF:Collagen binding activity levels were significantly higher in the acute than in the disease's convalescence phase, and correlated positively with CRP levels. Neither variable was associated with coronary artery lesions. The vWF:Collagen binding activity/vWF:Antigen ratio, however, was significantly decreased in patients with a coronary artery lesion (z-score > 2; N = 10; mean ratio 0.96 vs. 0.64; p = 0.031) and even more so in those with a coronary artery aneurysm (z-score > 2.5; N = 8; mean ratio 0.94 vs. 0.55; p = 0.02). In a sub-analysis, those patients with a very low ratio in the acute phase presented a persistent coronary artery aneurysm at their 1-year follow-up.Conclusion: This study suggests that comprehensive analysis of vWF parameters may help to both monitor KD inflammation and facilitate the identification of those patients carrying an increased risk for coronary artery lesion.What is Known:• Von Willebrand factor (VWF)-parameters represent surrogate markers for vascular inflammation.• Kawasaki disease is a generalized vasculitis in children, which can be complicated by coronary artery lesions.What is New:• In those Kawasaki disease patients with coronary artery lesions, the vWF:CB/vWF:Ag ratio was significantly decreased.• VWF parameters may help to identify patients at risk for coronary artery lesions. [ABSTRACT FROM AUTHOR]

Risk factors predicting intravenous immunoglobulin (IVIG) resistance in patients with Kawasaki disease (KD) were assessed according to the duration of illness prior to treatment. Of 555 KD patients included between 2008 and 2014, 362 were IVIG responders (65.2%) and 193 were IVIG non-responders (34.8%). The risk of IVIG resistance was inversely correlated with the duration of illness prior to treatment. Neutrophil dominance (≥  80%) was significantly higher in IVIG non-responders regardless of the duration of pre-IVIG illness. While there were no differences between IVIG responders and non-responders who were diagnosed at < 3 days, increasing platelet count and decreasing liver enzyme levels were seen over time in IVIG responders, but not in IVIG non-responders. Multivariable analysis showed that, in addition to neutrophil levels ≥  80%, risk factors for IVIG resistance were age ≤  12 months for patients who were diagnosed at ≤  3 days, and platelet count ≤  300 × 103/μL and aspartate aminotransferase level ≥  100 IU/L for patients who were diagnosed at ≥  6 days.Conclusion: Predictors of IVIG resistance in patients with KD differ according to the duration of pre-treatment illness. Risk assessment according to the duration of illness may improve the prediction of IVIG resistance.What is Known:• Several systems have been developed to predict IVIG resistance in patients with KD but the sensitivity and specificity of these tools are insufficient and ethnic variations have been reported.What is New:• Predictors of IVIG resistance differ depending on the duration of illness prior to treatment.• Risk assessment according to the duration of pre-treatment illness may improve the ability to predict IVIG resistance. [ABSTRACT FROM AUTHOR]

Kawasaki disease is an acute systemic vasculitis in children. Antiplatelet medicines are commonly used for Kawasaki disease to attenuate vasculitis and prevent thromboembolism; however, the mechanisms have not been elucidated. The objective of this study is to assess the effectiveness of antiplatelet medications for Kawasaki disease. We used Medline, Embase, Cochrane Central Register of Controlled Trials, and Igaku Chuo Zasshi (Ichushi) from January 1947 to August 2018. Studies describing the platelet functions of antiplatelet drugs for Kawasaki disease were included. Twenty studies met the inclusion criteria. There were no randomized controlled trials. Seven studies compared platelet aggregation ability before and after treatment. Eight studies compared platelet aggregation with that in Kawasaki disease patients without treatment. Four studies compared aggregation among different types of antiplatelet drugs or at different doses. Antiplatelet medications administered in the studies included aspirin, flurbiprofen, dipyridamole, and choline salicylate. Methods for the measurement of platelet aggregation ability varied among studies. The groups with antiplatelet treatment tended to have a decreased platelet aggregation function. The statistical analyses were impossible due to insufficient quantitative data and heterogeneity among the studies.Conclusion: The present systematic review revealed that there was insufficient evidence for the effectiveness of antiplatelet therapy for Kawasaki disease. What is Known: • Antiplatelet therapy is widely used for Kawasaki disease to mitigate cardiac complications. • The mechanisms of antiplatelet therapy for Kawasaki disease are not clarified. What is New: • This systematic review showed that the groups with antiplatelet treatment tended to have a decreased platelet aggregation function. • There is insufficient evidence for the effectiveness of antiplatelet therapy for Kawasaki disease. [ABSTRACT FROM AUTHOR]

Since resistance to intravenous immunoglobulin (IVIG) is associated with coronary lesions (CALs) in Kawasaki disease (KD), it is crucial to identify patients at risk to protect them from coronary involvement. The available risk scores to predict IVIG resistance were developed in Asian populations in whom their effectiveness has been proven, but data on non-Asian children are limited. The aim of this study is to evaluate the ability of the Kobayashi, Egami, and Formosa risk scores to predict IVIG resistance and CALs in Italian patients with KD. A multicenter retrospective analysis involving children with KD diagnosed between 2000 and 2015 was carried out: 257 patients were enrolled (57.9% boys, 89.9% Caucasian); 43 patients were IVIG resistant (16.7%). The scores have low sensitivity and specificity in predicting IVIG resistance: respectively, KS 64% and 62.5%, ES 41.4% and 77.4%, and FS 70.8% and 44.9%. The predictive value of the 3 scores for predicting CALs was also poor.Conclusion: Kobayashi, Egami, and Formosa Scores are ineffective in predicting IVIG resistance and coronary involvement in a predominantly Caucasian cohort. A specific score system for mostly Caucasian children with KD is needed enable the early identification of those at risk for CALs who could benefit from intensified treatment. What is Known: • There are several risk scores developed in the Asian population to early identify patients with KD at risk for immunoglobulin-resistance and thus for coronary lesions. • Data are scarce on their effectiveness in non-Asian children. What is New: • We present a comprehensive analysis of the ability of 3 Asian risk scores in a cohort of mostly Caucasian children to predict immunoglobulin resistance and coronary involvement. • Low sensitivity and specificity of the Asian scores for immunoglobulin-resistance and coronary lesions suggest the need for criteria specific for different ethnicities. [ABSTRACT FROM AUTHOR]

The purpose of this study was to identify the clinical features and laboratory factors that are predictive of intravenous immunoglobulin (IVIG)-resistant Kawasaki disease. Multiple databases were searched for relevant studies on IVIG-resistant Kawasaki disease published from January 2002 to April 2017. Eligible studies were retrieved by manual review of the references. Stata 12 was used for the meta-analysis. Weighted mean differences and odds ratios with 95% confidence intervals were calculated for several indices. Twenty-eight studies involving 26,260 patients comprising 4442 IVIG-resistant Kawasaki disease patients and 21,818 IVIG-sensitive Kawasaki disease patients were included. The meta-analysis showed that the erythrocyte sedimentation rate (ESR) in the IVIG-resistant group was significantly higher than that in the IVIG-sensitive group, and that platelet count and hemoglobin levels were significantly lower in the IVIG-resistant group. The patients with oral mucosa alterations, cervical lymphadenopathy, swelling of the extremities, polymorphous rash, and initial administration of IVIG ≤ 4.0 days after the onset of symptoms were more likely to be IVIG resistant.Conclusion: The initial administration of IVIG ≤ 4.0 days after the onset of symptoms increased ESR and decreased hemoglobin and platelet counts, oral mucosa alterations, cervical lymphadenopathy, swelling of the extremities, and polymorphous rash and are the risk factors for IVIG-resistant Kawasaki disease. What is Known: • Recent reports on this topic are about aspartate aminotransferase (AST), alanine aminotransferase (ALT), gammaglutamyl transferase, total bilirubin, white blood cells, platelets, erythrocyte sedimentation rate (ESR), polymorphonuclear leukocytes (PMN), C-reactive protein (CRP), pro-brain natriuretic peptide (BNP), albumin, and sodium as the risk factors in the IVIG-resistant Kawasaki disease; however, no studies have been published on clinical features as predictors of IVIG resistance. What is New: • This meta-analysis identified the clinical features, the initial administration of IVIG ≤ 4.0 days after the onset of symptoms, and much more comprehensive laboratory indicators, such as hemoglobin, as predictors of IVIG-resistant Kawasaki disease. [ABSTRACT FROM AUTHOR]

Kawasaki disease (KD) is a pediatric vasculitis with coronary artery aneurysms (CAA) as its main complication. The diagnosis is based on the presence of persistent fever and clinical features including exanthema, lymphadenopathy, conjunctival injection, and changes to the mucosae and extremities. Although the etiology remains unknown, the current consensus is that it is likely caused by an (infectious) trigger initiating an abnormal immune response in genetically predisposed children. Treatment consists of high dose intravenous immunoglobulin (IVIG) and is directed at preventing the development of CAA. Unfortunately, 10-20% of all patients fail to respond to IVIG and these children need additional anti-inflammatory treatment. Coronary artery lesions are diagnosed by echocardiography in the acute and subacute phases. Both absolute arterial diameters and z-scores, adjusted for height and weight, are used as criteria for CAA. Close monitoring of CAA is important as ischemic symptoms or myocardial infarction due to thrombosis or stenosis can occur. These complications are most likely to arise in the largest, so-called giant CAA. Apart from the presence of CAA, it is unclear whether KD causes an increased cardiovascular risk due to the vasculitis itself.Conclusion: Many aspects of KD remain unknown, although there is growing knowledge on the etiology, treatment, and development and classification of CAA. Since children with previous KD are entering adulthood, long-term follow-up is increasingly important. What is known: • Kawasaki disease (KD) is a pediatric vasculitis with coronary artery damage as its main complication. • Although KD approaches its 50th birthday since its first description, many aspects of the disease remain poorly understood. What is new: • In recent years, multiple genetic candidate pathways involved in KD have been identified, with recently promising information about the ITPKC pathway. • As increasing numbers of KD patients are reaching adulthood, increasing information is available about the long-term consequences of coronary artery damage and broader cardiovascular risk. [ABSTRACT FROM AUTHOR]

Kawasaki disease is a systemic vasculitis with an acute and self-limited course. The incidence of the disease differs widely among ethnic groups and is higher in the Asian populations. In Italy, no recent data are available. We studied the epidemiology of Kawasaki disease in the years 2008-2013 in children 0-14 years old in Italy using hospital ICD-9 discharge codes with a thorough data cleaning for duplicates in order to select the first hospital admission for the disease. The disease peaked in the first 2 years of life, with 85.5% of cases under 5 years. Male/female ratio was 1.4:1. The incidence rate was 5.7 per 100,000 children 0-14 years old and 14.7 for children younger than 5 years. The incidence rose slightly during the study period and had a seasonal distribution, with higher incidence in spring. A coronary artery aneurysm was recorded in 2.2% of the patients younger than 5 years of age.Conclusion: This is the first epidemiologic study on Kawasaki disease incidence in the country of Italy. Figures are in line but slightly higher than those reported for other European countries. What is known: • Kawasaki disease is more common in Asian populations. • European incidence data are scarce. What is new: • Epidemiological data in Italy show similar incidence, albeit slightly higher, than in other European countries. • Incidence data slightly rose in the recent past. [ABSTRACT FROM AUTHOR]

The purpose of this study was to determine whether the serum N-terminal pro-brain natriuretic peptide (NT-proBNP) level could be a useful marker for Kawasaki disease in the pediatric emergency department (PED) and in the presence of fever duration of 4 days or less (hyper-acute phase of Kawasaki disease). Medical records of patients who were 1 month to 15 years old of age and presented at the PED with suspected Kawasaki disease from January 1, 2010, to December 31, 2014, were collected retrospectively. Two hundred thirty-nine patients with a history of fever for 4 days or less were diagnosed with Kawasaki disease, as well as 111 patients with other febrile diseases, and were enrolled. The NT-proBNP level was significantly higher in patients with Kawasaki disease (Kawasaki disease vs. other febrile disease group, 444.8 (189.7-951.5) vs. 153.4 (68.9-287.6) pg/mL; p < 0.001), and a cutoff value of 244.7 pg/mL yielded a sensitivity and specificity of 68.6 and 70.3 %, respectively. The area under the curve of the NT-proBNP for predicting Kawasaki disease was 0.763 (95 % CI 0.712-0.814).Conclusion: NT-proBNP might be an adjunctive laboratory marker for hyper-acute phase of Kawasaki disease in the PED. What is Known: • N-terminal pro-brain natriuretic peptide level has been reported as a useful marker for diagnosis in patients with the acute phase of Kawasaki disease. • But, in the cases of less than 5 days of fever, the appropriate level of NT-proBNP for differentiating Kawasaki disease in PED has not been yet evaluated. What is New: • NT-proBNP might be an adjunctive laboratory marker for hyper-acute phase of Kawasaki disease. [ABSTRACT FROM AUTHOR]

Unlabelled: Kawasaki disease (KD) is a systemic vasculitis childhood disease frequently complicating coronary artery lesions (CALs). Recently, the gene encoding a disintegrin and metalloprotease 17 (ADAM17) was found to modify vascular pathology in humans by differentially regulating the transforming growth factor-β (TGF-β) signaling pathway, which affects KD/CAL susceptibility. To explore the potential role of ADAM17 in KD occurrence and outcomes, we investigated the association of 28 single nucleotide polymorphisms (SNPs) in ADAM17 and three pathway genes of TGF-β signaling with KD phenotypes in a Han Chinese population, including 392 KD patients and 421 non-KD controls. Three ADAM17 SNPs showed an association with KD risk, which was further confirmed by haplotype analysis. The effect of ADAM17 on KD was also shown by multi-variable logistic regression analysis. In two-locus model analyses with SNPs in ADAM17 and TGF-β signaling pathway genes, stronger compound effects on the risk of KD and secondary CAL formation were observed relative to comparable single SNPs.Conclusion: Our results suggest that ADAM17 contributes to the KD risk and is involved in secondary CAL formation via the TGF-β/SMAD3 signaling pathway. This further enriches our understanding of the importance of the signaling pathway in KD occurrence and outcomes.What Is Known: • The transforming growth factor (TGF)-β/SMAD3 signaling pathway greatly influences susceptibility to Kawasaki disease (KD) and secondary coronary artery lesions (CALs) and/or the treatment response of intravenous immunoglobulin. • A disintegrin and metalloprotease 17 (ADAM17) effectively reduces TGF-β signaling by cleaving TGF-β receptor type-1, while ADAM17 genetic variants modify human vascular pathology by differentially regulating this signaling although it is unknown whether ADAM17 contributes to KD phenotypes. What is New: • ADAM17 genetic variants were shown to be associated with KD risk, even when excluding the influence of TGF-β signaling pathway genes, suggesting that ADAM17 is an important KD susceptibility-related genetic locus. • The more significant compound effects of two-locus models, combining single nucleotide polymorphisms (SNPs) in ADAM17 and other TGF-β signaling pathway genes including TGFB2 and SMAD3, on KD phenotypes relative to single SNPs suggest that ADAM17 is also involved in secondary CAL formation and confers the risk of KD/CALs via the TGF-β/SMAD3 signaling pathway. [ABSTRACT FROM AUTHOR]

Kawasaki disease (KD) is associated with the development of coronary arterial lesions (CALs) in children. We aimed to test the hypothesis that circulating 25-hydroxyvitamin D [25-(OH)D] could be identified as a clinical parameter for predicting CALs secondary to KD in children. We enrolled 35 children with KD in the acute phase and measured serum 25-(OH)D levels in all of them, then followed up by echocardiography for CALs. Additionally, serum 25-(OH)D levels were obtained in 23 febrile children with respiratory tract infections and 30 healthy children. Of the 35 KD children, nine had CALs according to echocardiography and 26 did not (NCALs). Serum 25-(OH)D levels were not significantly different between NCALs and healthy children (49.2 ± 23.8 versus 44.1 ± 30.2 ng/ml; P = 0.49). Serum 25-(OH)D levels were significantly higher in children with CALs than those without CALs (83.9 ± 26.3 versus 49.2 ± 23.8 ng/ml; P = 0.001). The cutoff value of 65 ng/ml to predict subsequent CALs had a specificity of 0.73, sensitivity of 0.78, and diagnostic accuracy of 0.74. Conclusion: Serum 25-(OH)D levels were elevated dur-ing the acute phase in KD children who had subsequent CALs. Serum 25-(OH)D levels in the acute phase of KD may be used to predict subsequent CALs. [ABSTRACT FROM AUTHOR]

Pathologic studies of the heart in patients with Kawasaki disease (KD) revealed vasculitis, valvulitis, myocarditis, and pericarditis. However, there have been no studies on the quantitative determination of multi-site echogenicity of the heart in KD patients. It is also undetermined whether the degree of echogenicity of each site of the heart in patients with KD might be related to the response to intravenous immunoglobulin (IVIG) treatment. In 81 KD patients and 30 control subjects, we prospectively analyzed echogenicity of the heart. Echogenicity was measured in four sites: coronary artery wall (CAW), mitral valve (MV), papillary muscle (PM), and ascending aortic wall (AAo wall) by the calibrated integrated backscatters (cIBs). The cIB values of all measurement sites at acute phase in KD patients were significantly higher than those in control subjects (KD patients vs control subjects; CAW, 19.8 ± 6.2 dB vs 14.5 ± 2.0 dB, p < 0.05; MV, 23.3 ± 5.3 dB vs 16.0 ± 3.3 dB, p < 0.05; PM, 22.4 ± 5.1 dB vs 12.7 ± 1.9 dB, p < 0.05; AAo wall, 25.3 ± 5.6 dB vs 18.3 ± 3.4 dB, p < 0.05). The cIB values of CAW at the acute phase in IVIG nonresponders were significantly higher than those in responders. Conclusion: Echogenicity of the heart in KD patients at the acute phase increased not only in the coronary artery wall but also in other parts of the heart. Echogenicity of CAW might be helpful in determining the unresponsiveness of IVIG treatment. [ABSTRACT FROM AUTHOR]