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Background:Kawasaki disease is an acute vasculitis of childhood that leads to coronary artery aneurysms in ≈25% of untreated cases. It has been reported worldwide and is the leading cause of acquired heart disease in children in developed countries.Methods and Results:To revise the previous American Heart Association guidelines, a multidisciplinary writing group of experts was convened to review and appraise available evidence and practice-based opinion, as well as to provide updated recommendations for diagnosis, treatment of the acute illness, and long-term management. Although the cause remains unknown, discussion sections highlight new insights into the epidemiology, genetics, pathogenesis, pathology, natural history, and long-term outcomes. Prompt diagnosis is essential, and an updated algorithm defines supplemental information to be used to assist the diagnosis when classic clinical criteria are incomplete. Although intravenous immune globulin is the mainstay of initial treatment, the role for additional primary therapy in selected patients is discussed. Approximately 10% to 20% of patients do not respond to initial intravenous immune globulin, and recommendations for additional therapies are provided. Careful initial management of evolving coronary artery abnormalities is essential, necessitating an increased frequency of assessments and escalation of thromboprophylaxis. Risk stratification for long-term management is based primarily on maximal coronary artery luminal dimensions, normalized asZscores, and is calibrated to both past and current involvement. Patients with aneurysms require life-long and uninterrupted cardiology follow-up.Conclusions:These recommendations provide updated and best evidence-based guidance to healthcare providers who diagnose and manage Kawasaki disease, but clinical decision making should be individualized to specific patient circumstances.

Background— Markedly activated neutrophils or higher plasma levels of neutrophil elastase are involved in the poor response to intravenous immunoglobulin (IVIG) and the formation of coronary artery lesions (CAL) in patients with acute Kawasaki disease. We hypothesized that ulinastatin (UTI), by both direct and indirect suppression of neutrophils, would reduce the occurrence of CAL. Methods and Results— We retrospectively analyzed the clinical records of patients with Kawasaki disease between 1998 and 2009. Three hundred sixty-nine patients were treated with a combination of UTI, aspirin, and IVIG as an initial treatment (UTI group), and 1178 were treated with a conventional initial treatment, and IVIG with aspirin (control group). The baseline characteristics did not demonstrate notable differences between the two groups. The occurrence of CAL was significantly lower in the UTI group than in the control group (3% versus 7%; crude odds ratio [OR], 0.46; 95% confidence interval [CI], 0.25–0.86; P =0.01). The OR adjusted for sex, Gunma score (the predictive score for IVIG unresponsiveness), and dosage of initial IVIG (1 or 2 g/kg) was 0.32 (95% CI, 0.17–0.60; P P P Conclusions— UTI was associated with fewer patients requiring additional rescue treatment and reduction of CAL in this retrospective study.

Introduction: The severity of coronary artery aneurysms (CAA) in patients with Kawasaki disease (KD) has been recently classified according to the z-score. However, it is not known whether this classification can predict coronary events such as stenosis, obstruction, and thrombosis. Methods: In this multicenter retrospective study, data on height, weight, CAA diameter measured by echocardiography in the acute phase, and the clinical course in KD patients 18 years of age or younger who received a coronary angiography between 1992 and 2011 were collected. Time-dependent occurrence of coronary events was analyzed by Kaplan-Meier method according to small (z-score, < 5.0), medium (≥ 5.0 to < 10.0), and large (≥ 10.0) CAA using a 5 increment scale scheduled to be included in the new American Heart Association criteria. Cox regression analysis was used to identify risk factors for coronary events. The occurrence rate of major cardiac events such as angina pectoris, myocardial infarction, and cardiac death was also analyzed. Results: Data were analyzed for 1,002 patients from 44 institutions. Both the body surface area and CAA diameters were available in 741 cases for the right coronary artery (RCA) and 609 cases for the left anterior descending artery (LAD). Coronary events occurred in 83 (11.2%) of the RCA group and 57 (9.4%) of the LAD group, while major events occurred in 30 cases (3.0%). The 10-year event-free survival rate for coronary events for small, medium, and large aneurysms was 100, 95.5, and 64.9% in the RCA group, and 100, 94.4, and 63.5% for aneurysms in the LAD group, respectively. The rate of major cardiac events was 98.5, 98.1, and 87.6% for the RCA group, and 100, 97.5, and 86.8% for the LAD group, respectively. Cox regression analyses showed that the z-score of the CAA diameter was an independent risk factor for coronary events for the RCA [large versus medium aneurysm; hazard ratio (HR) 2.8, 95% confidence interval (CI) 1.5 to 5.3, p = 0.002] and the LAD [HR 3.2, 95% CI 1.6 to 6.5, p = 0.015] groups. Conclusions: The severity assessment of CAA using the 5-increment z-score for coronary arterial diameter can predict the time-dependent occurrence of coronary events in patients with KD.

Background: Sporadic cases of acute coronary syndrome (ACS) have been reported in adults with coronary sequelae presumably due to Kawasaki disease (KD). However, ACS in adults with a confirmed (whether followed-up or lost to follow-up) as well as unconfirmed history of KD is poorly characterized. Methods: To investigate ACS in such adults after KD during 2000-10, a nationwide survey was conducted in Japan. Results: A total of 67 patients (median age 35 yo, male 76%) were recruited. A diagnosis of KD was made in 32 during acute illness (Group A), in which 17 were lost to follow up. A KD diagnosis was made retrospectively in the other 35 patients from coronary imaging at ACS (Group B). Overall, 67 patients were characterized by demonstrable thrombosis (74%) as well as the presence of giant aneurysms (GAN) (≥8mm) (38%), severe stenosis (>75%) (38%) and IVUS-derived calcification (92%) in culprit lesions. Group A represented younger age at ACS (26.5 yo vs. 40 yo in group B, p

Backgrounds and Objectives: RAISE protocol demonstrated that IVIG plus prednisolone (PSL) therapy reduced the incidence of coronary artery abnormalities (CAAs) in children with high risk of refractory Kawasaki disease (KD). However, this protocol has longer hospital stay because PSL is tapered over the next 15 days when CRP was under 5mg/L. We proposed modified RAISE protocol which PSL is tapered over 9 days. The aim of this study was to evaluate clinical utility of modified RAISE protocol. Methods: This is a retrospective study to evaluate clinical data from KD between May, 2012 and August, 2014. Composite outcomes included incidence of relapse and coronary arterial abnormalities. Using Kobayashi score, children were divided into high and low risk group. Results: We enrolled 36 KD patients with high risk group in total 147 patients with KD. Median of age was 33 months (range 2-83 months), 13 males. Median days of illness were 4.0 (range 2-7) and Kobayashi score was 6.0 (range 5-9). Overall, 31 children (86.1%) were responders, whereas 5 children were non-responders (resistance; 1 (2.8%) relapse; 4 (11.1%)). Among 5 non-responders, 4 patients received methylprednisolone pulse therapy (mPSL) and the remaining one patient administrated two times mPSL and infliximab. During follow-up (1-29 months), 3 children (8.3%) had CAAs (dilatation: 3 patients). Modified RAISE protocol was not inferior to conventional RAISE protocol (CAAs 3.3%, p=0.68, responder 84.3%, p=1.0, resistance 5.0%, p=0.92, relapse 10.7%, p= 0.66). Conclusions: Clinical safety and efficacy of modified RAISE protocol (3days х3) were similar to conventional RASIE protocol(5days х3).

Background: In Japan, 2 guidelines are published, the clinical guidelines for medical treatment of acute stage Kawasaki disease(KD)(2012) and guidelines for diagnosis and management of cardiovascular sequelae in KD(2013). Patient Condition Adaptive Path System (PCAPS) is a technique to structure clinical knowledge. It places “patient condition” as a core, to which multiple “target conditions” are linked. On the other hand, patients of KD ware focused the severity of the disease and therapeutic strategy influences the improvement. Purpose: The purpose is confirming the PCAPS KD contents, which complied two Japanese Guidelines and to evaluate adaption of the contents. Methods: PCAPS content is composed of Clinical Process Chart (CPC) and Unit Sheet (US).CPC is an overhead view of clinical path consisting of a chain of units. CPC was made according the guidelines, and coronary evaluation, CHF, cardiac catheterization and ACS unit can activate on time. CPC stratify the patient’s severity. US are composed of specific healthcare tasks in a unit. Results: We confirm PCAPS KD contents on the base of 2 guidelines. We can evaluate diagnostic process and severity of KD by route analysis using CPC (figure). We can visualize relationship between treatments and severity by US. US are effective to support the decision on treatment and examinations. From the analysis, there are no lack of the unit and route, and confirm the advice to decision making. Conclusions: PCAPS can easily analyze the severity and clinical process from CPC route analysis because PCAPS is electrical path which can automatically store the data of each hospital. From US data, there are possibilities to find new severity score.

Background: Although RAISE study demonstrated that intravenous immunoglobulins (IVIG) plus prednisolone (PSL) therapy for refractory Kawasaki disease (KD) reduced coronary artery aneurysm, the study population included a few incomplete KD. The aim of study was to evaluate the efficacy of RAISE protocol for incomplete KD. Methods: Children with incomplete KD which have 4 or less major symptoms of KD were enrolled. Using Kobayashi score, children were divided into low and high risk for IVIG resistance. Children with low risk group received IVIG monotherapy, whereas IVIG plus PSL therapy administrated for high risk group. Retrospectively, we assessed initial treatment response and coronary artery abnormalities (CAAs). Results: Overall, 63 incomplete KD (age; median and range 17 months (1-115 months), sex ratio; boys:girls 37:26) were enrolled. Median day of illness at diagnosis was 5 day of illness (2-10 days). Low risk group included 52 cases (83%) and the remaining 11 cases were high risk group. In low risk group, 87% of children (45 cases) were initial treatment responders. All 7 non-responders were responded to additional methylprednisolone steroid pulse therapy. All 11 children with high risk group were responders to the initial treatment. Five cases have equal to greater than 2.5 of Z-Score, which were all low risk group. All CAAs regressed to normal coronary diameter within 1 month. Conclusions: RAISE protocol was useful for the treatment of incomplete KD without any CAAs.

Kawasaki disease (KD; MIM611775) is a systemic vasculitis syndrome with unknown etiology which predominantly affects infants and children. Recent findings of susceptibility genes for KD have suggested up-regulation of Ca2+/NFAT pathway as one of the main pathophysiological processes in KD. In this study, we focused on ORAI1, a gene for a channel involved in store operated Ca2+ entry located on 12q24 where positive linkage signal was seen in our previous sib pair study of KD, and conducted a genetic association study. By re-sequencing 17.4kb of ORAI1 region for 94 subjects, we identified 37 variants with minor allele frequencies larger than 0.05. After selecting 9 tagging SNPs which represent 37 variants we performed an association study using 730 KD cases and 1315 controls. As a result, one tagging SNP located within exon2 showed nominal association (rs3741596; OR = 1.19, 95%CI 1.02~1.40, P = 0.028). The same trend of association was observed in an independent case control panel (1813 KD cases and 1097 controls, OR=1.22, 95% CI 1.06-1.40, P = 0.0056) and a significant P value was observed in a meta-analysis (OR = 1.21, 95%CI 1.09~1.34, P = 0.00041). Furthermore, we also found a rare 6 base-pair insertion polymorphism which cause elongation of proline repeat within N-terminal cytoplasmic domain of the ORAI1 protein was overrepresented in KD cases (rs78448924; OR = 3.91, 95%CI 1.30~11.80, P=0.010). These data indicate altered ORAI1 function confers susceptibility of KD and further highlight importance of the Ca2+/NFAT pathway in the disease pathogenesis.

Background and Objective: Long term prognosis of Kawasaki disease (KD) with giant aneurysm is not yet well understood. We conducted a nationwide survey of KD with giant aneurysm for recent 10 years, and analyzed cardiac events of those patients. Methods: Nationwide epidemiological survey of KD has been conducted every 2 years since 1970 in Japan. We performed questionnaire survey based on 16th - 21th (1999 - 2010) nationwide epidemiological data. Results: We send questioners to 275 facilities asking about 415 patients who were reported to have giant aneurysm (>=8mm), and collected the data of 334 patients (80.5%). We excluded 84 non-giant aneurysm patients and 36 duplicated cases and difined finally 214 patients. Out of 214 patients, 13 deaths and 32 AMIs were described (6.1% and 15.0%, respectively). The first AMI attack was mostly reported within a few months from KD onset (medium 5 months (0-85 months)). AMI was occurred one time in 26 patients, and two times in 6 cases. Myocardial ischemia was observed in 80% of AMI patients, and 12 patients were received coronary artery bypass graft. Thirteen patients were reported to be dead (medium 1 month (0-23 months) from KD onset). There were 6 cardiac deaths within 1 month from KD onset (5: rupture of aneurysm, 1: AMI). The others were all caused by AMI except for 2 accidental death. Four out of 6 AMI deaths were caused by the first AMI attack. For the remaining 2 AMI deaths, the period from the first AMI to second fatal AMI was 1 month and 6 month, respectively. There were no death reported byond 2 years from KD onset. Conclusion: AMI and cardiac death of KD with giant aneurysm occurred mostly in early phase of KD onset. Coronary rupture occurs within a month after onset, and 84% AMI and all AMI death occurs within 2 years after onset. Patients survival become promising after 2 years from onset. These evidences indicate that therapeutic strategy up to 2 years after onset is extremely important for prognosis of KD with giant aneurysm.

Backgrounds: In Japan, infliximab (IFX) has been used in patients with Kawasaki disease (KD) who did not respond to initial treatment. However, nationwide surveillance of the IFX for KD patients has not been reported. The objective of the present study is to reveal epidemiological and clinical features of KD patients treated with IFX. Method: This retrospective observational study was conducted from 2007 to 2013. We sent a questionnaire to members of Japanese Society of Kawasaki disease annually and collected demographic data and clinical outcomes of KD patients treated with IFX. A total of 315 patients (208 boys and 107 girls, age at onset 37±25 months, illness days of initial treatment 4.3±1.2) from 46 hospitals were identified and analyzed in the present study. Results: No patients received IFX as initial treatment. Over 60% of the patients were treated with IFX as first or second line additional rescue treatment. After the IFX administration, 237 patients (75.7%) became afebrile within 24 hours and 82 patients (26.0%) treated additional rescue treatments subsequently. Before IFX administration, 55 patients already had coronary artery aneurysm exceeding 4mm and 69 patients were finally affected coronary artery aneurysm exceeding 4mm. Serum level of C reactive protein were significantly decreased after IFX administration (10.6±7.2 to 4.9±4.7, P Conclusions: IFX therapy for Kawasaki disease patients who did not respond to the initial treatment would be well tolerated and play a certain role to improve clinical course.

Background —Restenosis after percutaneous transluminal coronary (balloon) angioplasty (PTCA) remains a major drawback of the procedure. We previously reported that cilostazol, a platelet aggregation inhibitor, inhibited intimal proliferation after directional coronary atherectomy and reduced the restenosis rate in humans. The present study aimed to determine the effect of cilostazol on restenosis after PTCA. Methods and Results —Two hundred eleven patients with 273 lesions who underwent successful PTCA were randomly assigned to the cilostazol (200 mg/d) group or the aspirin (250 mg/d) control group. Administration of cilostazol was initiated immediately after PTCA and continued for 3 months of follow-up. Quantitative coronary angiography was performed before PTCA and after PTCA and at follow-up. Reference diameter, minimal lumen diameter, and percent diameter stenosis (DS) were measured by quantitative coronary angiography. Angiographic restenosis was defined as DS at follow-up >50%. Eligible follow-up angiography was performed in 94 patients with 123 lesions in the cilostazol group and in 99 patients with 129 lesions in the control group. The baseline characteristics and results of PTCA showed no significant difference between the 2 groups. However, minimal lumen diameter at follow-up was significantly larger (1.65±0.55 vs 1.37±0.58 mm; P P P P Conclusions —Cilostazol significantly reduces restenosis and target lesion revascularization rates after successful PTCA.