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Importance: Few studies with sufficient statistical power have shown the association of the z score of the coronary arterial internal diameter with coronary events (CE) in patients with Kawasaki disease (KD) with coronary artery aneurysms (CAA)., Objective: To clarify the association of the z score with time-dependent CE occurrence in patients with KD with CAA., Design, Setting, and Participants: This multicenter, collaborative retrospective cohort study of 44 participating institutions included 1006 patients with KD younger than 19 years who received a coronary angiography between 1992 and 2011., Main Outcomes and Measures: The time-dependent occurrence of CE, including thrombosis, stenosis, obstruction, acute ischemic events, and coronary interventions, was analyzed for small (z score, <5), medium (z score, ≥5 to <10; actual internal diameter, <8 mm), and large (z score, ≥10 or ≥8 mm) CAA by the Kaplan-Meier method. The Cox proportional hazard regression model was used to identify risk factors for CE after adjusting for age, sex, size, morphology, number of CAA, resistance to initial intravenous immunoglobulin (IVIG) therapy, and antithrombotic medications., Results: Of 1006 patients, 714 (71%) were male, 341 (34%) received a diagnosis before age 1 year, 501 (50%) received a diagnosis between age 1 and 5 years, and 157 (16%) received a diagnosis at age 5 years or older. The 10-year event-free survival rate for CE was 100%, 94%, and 52% in men (P < .001) and 100%, 100%, and 75% in women (P < .001) for small, medium, and large CAA, respectively. The CE-free rate was 100%, 96%, and 79% in patients who were not resistant to IVIG therapy (P < .001) and 100%, 96%, and 51% in patients who were resistant to IVIG therapy (P < .001), respectively. Cox regression analysis revealed that large CAA (hazard ratio, 8.9; 95% CI, 5.1-15.4), male sex (hazard ratio, 2.8; 95% CI, 1.7-4.8), and resistance to IVIG therapy (hazard ratio, 2.2; 95% CI, 1.4-3.6) were significantly associated with CE., Conclusions and Relevance: Classification using the internal diameter z score is useful for assessing the severity of CAA in relation to the time-dependent occurrence of CE and associated factors in patients with KD. Careful management of CE is necessary for all patients with KD with CAA, especially men and IVIG-resistant patients with a large CAA.

Background: A Japanese nationwide survey has reported that Down syndrome (DS) is a less-frequently occurring comorbidity in Kawasaki disease (KD). Although altered immune responses are frequently observed in DS, no studies have focused on the treatment response and risk for coronary artery abnormalities (CAA) in DS patients with KD. The aim of this study was therefore to evaluate the clinical manifestations, treatment response and prevalence of CAA in DS with KD., Methods: We retrospectively reviewed the medical records of DS patients with KD from 2005 through 2012. The survey questionnaires were sent to facilities nationwide, and clinical data regarding KD in DS were collected. A control group consisted of non-DS patients with KD who were managed at Toho University., Results: Of the 94 233 children diagnosed with acute KD from 2005 to 2012, 16 children with acute KD also had DS (0.017%). The DS-KD patients were significantly older than the non-DS patients (median, 8 years vs 1 year, P < 0.05, respectively). Half of the DS patients had incomplete KD. Although 50% of the DS children were at high risk of immunoglobulin resistance, all children responded to initial treatment and none had CAA., Conclusions: All DS-KD patients responded to initial i.v. immunoglobulin (IVIG) or aspirin despite having a high risk of IVIG resistance, and none of the DS patients had CAA. This suggests that the risk of treatment resistance and development of CAA may be not higher in DS patients with acute KD., (© 2017 Japan Pediatric Society.)

Objective: To assess the clinical utility and safety of a strategy for refractory Kawasaki disease, defined by Egami score ≥3., Study Design: First-line treatment was with intravenous methylprednisolone (30 mg/kg, 2 hours, 1 dose) plus intravenous immunoglobulin (2 g/kg, 24 hours) treatment. Patients resistant to first-line treatment received additional intravenous immunoglobulin as a second-line treatment. Patients resistant to second-line treatment who had received Bacillus Calmette-Guérin vaccination 6 months earlier were treated with infliximab; otherwise, plasma exchange was performed. A total of 71 refractory patients with Kawasaki disease (median age: 2.4 years) of 365 patients with Kawasaki disease were treated according to our strategy from April 2007 to April 2016. Treatment resistance was defined as a persistent fever at 36 hours after treatment. We evaluated coronary artery lesions at the time of the diagnosis, at 1 month, and at 1 year after the diagnosis in accordance with the American Heart Association guidelines and the criteria of the Japanese Ministry of Health, Labour, and Welfare., Results: First-line therapy was effective for 58 of 71 patients (81.6%), and second-line therapy was effective for 9 of 13 patients (69.2%). At third line, 3 patients were treated by infliximab, and 1 was treated with plasma exchange. Of the 18 patients with coronary artery abnormalities at diagnosis, 13 patients at 1 month and 6 patients at 1 year had coronary artery dilatation (median z score 3.0, 2.6, and 1.4, respectively). There were no patients with coronary artery aneurysm (CAA)., Conclusions: Our strategy for refractory Kawasaki disease was safe and effective in preventing CAA., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: Infliximab (IFX), a known monoclonal antibody against tumor necrosis factor-α (TNF-α), is used to treat Kawasaki disease (KD) patients with intravenous immunoglobulin (IVIG) resistance. The transcriptional modulation of inflammation following IFX therapy has not been reported in KD patients., Methods: We investigated the transcript abundance profiles in whole blood obtained from eight IVIG-resistant KD subjects treated with IFX therapy using microarray platforms and compared them with those in initially IVIG-responsive subjects. A pathway analysis was performed using WikiPathways to search for the biological pathways of the transcript profiles. Four transcripts changed by IFX therapy were subsequently validated using quantitative real-time polymerase chain reaction., Results: The pathway analysis showed the reduced abundance of transcripts in the nucleotide-binding oligomerization domain, matrix metalloproteinase (MMP), and inflammatory cytokine pathways and the increased abundance of transcripts in the T-cell receptor, apoptosis, TGF-β, and interleukin-2 pathways. Additionally, the levels of four transcripts (peptidase inhibitor-3, MMP-8, chemokine receptor-2, and pentraxin-3) related to KD vasculitis and IVIG resistance decreased after IFX therapy., Conclusion: The administration of IFX was associated with both the signaling pathways of KD inflammation and several transcripts related to IVIG resistance factors. These findings provide strong theoretical support for the use of IFX in KD patients with IVIG resistance.

Kawasaki disease(KD) is an acute, self-limited vasculitis of unknown etiology that predominantly affects infants and children. Coronary artery(CA) aneurysms, the most severe complication, occur in 25 % of untreated children and may lead to ischemic heart disease, myocardial infarction, or sudden death. While a single high dose of intravenous immunoglobulin (IVIG) terminates the fever and acute inflammation in most subjects and dramatically reduces the incidence of CA aneurysms, 10 to 20 % of KD patients are IVIG- resistant and these subjects are at higher risk of developing CA abnormalities. Several mechanisms have been reported for the anti-inflammatory activity of IVIG in different disease states. In this review, we describe the clinical utility and these mechanisms of IVIG in KD.

Objective: It has been claimed that the aneurysm rate for Kawasaki disease (KD) patients in Japan is lower than in the U.S. However it has been difficult to compare coronary artery (CA) outcomes between the two countries because of different definitions for CA abnormalities. Therefore, we compared CA internal diameters between Japanese and U.S. KD patients using standard definitions and methods., Study Design: We retrospectively reviewed CA outcomes in 1082 KD patients from 2 centers in the U.S. and 3 centers in Japan and compared Z-max scores (maximum internal diameter for the left anterior descending or right coronary artery expressed as standard deviation units from the mean (Z-score) normalized for body surface area) obtained within 12 weeks after onset and calculated using two different regression equations from Canada (Dallaire) and Japan (Fuse). We defined a Z-max of < 2.5 as normal and a Z-max of ≥ 10 as giant aneurysm., Result: The median Z-max for the U.S. and Japanese subjects was 1.9 and 2.3 SD units, respectively (p < 0.001). There was no significant difference in rates of patients with Z-max ≥ 5.0 between the countries. In a multivariable model adjusting for age, sex, and treatment response, being Japanese was still associated with a higher Z-max score., Conclusion: Previously reported differences in aneurysm rates between Japan and the U.S. likely resulted from use of different definitions and nomenclature. Adoption of Z-scores as a standard for reporting CA internal diameters will allow meaningful comparisons among different countries and will facilitate international, collaborative clinical trials., (© 2013. Published by Elsevier Ireland Ltd. All rights reserved.)

Objective: To evaluate the effectiveness of intravenous immunoglobulin (IVIG) treatment of Kawasaki disease ≥10 days after illness onset., Methods: We selected patients initially treated with IVIG on days 11 to 20 in the database of the 20th nationwide survey in Japan. We then selected pair-matched control subjects of the same gender and age, who were initially treated with IVIG on days 4 to 8 with the same dose at the same institutions. We compared the proportions of additional treatments and coronary artery lesions (CALs) between the groups. We also compared fractional changes in various laboratory data before and after IVIG. Fractional change was defined as follows: (Y - X)/X, in which X represents the data before treatment and Y the data after treatment., Results: One hundred fifty patients (75 pairs) were studied. The proportion of patients who received additional treatments among those given initial IVIG after days 10 was slightly lower than those treated earlier (12% vs 16%). The fractional changes in the white blood cell count, % neutrophils, and C-reactive protein were similar. Among all patients, the proportions of CALs during the convalescent phase were significantly higher in the late than in the early group (27% vs 1%). Among patients who had not developed CALs before initial treatment, the proportions with CALs during the acute phase were similar (8% vs 8%)., Conclusions: IVIG treatment ≥10 days after illness onset achieves resolution of inflammation but was found to be insufficient for preventing CALs.

Objective: This study examined the clinical efficacy and safety of intravenous methylprednisolone-pulse plus intravenous immunoglobulin (IVIG) combination therapy (IVMP+IVIG) for the initial treatment of patients predicted to have refractory Kawasaki disease (KD)., Methods: One hundred twenty-two patients with KD were studied at Kitasato University. Refractory KD was predicted at diagnosis using the Egami score, and the patients were randomly divided to receive either IVMP+IVIG or IVIG alone. The Egami score is used to predict refractory KD patients before treatment using the patient's age, days of illness, platelet count, C-reactive protein, and alanine aminotransferase level (cutoff: ≥3 points; 78% sensitivity and 76% specificity)., Results: Forty-eight patients (39.3%) were predicted to have refractory KD on the basis of the Egami score. The predicted IVIG responders (n = 74) received the standard therapy. The 48 predicted refractory KD patients were randomly assigned to a single-IVIG group (n = 26) or an IVMP+IVIG group (n = 22). Nineteen of the 22 patients (86.4%) in the IVMP+IVIG group had a prompt defervescence compared with 6 of the 26 patients (23.1%) in the single-IVIG group. The number of patients who had a z score ≥2.5 at 1 month was significantly higher in the single-IVIG group than in the IVMP+IVIG group. No serious adverse events were observed in either treatment group., Conclusion: This study demonstrated that IVMP+IVIG therapy is safe and effective for KD patients predicted as refractory.

Objective: To compare the long-term efficacy of percutaneous coronary intervention (PCI) and coronary artery bypass grafting (CABG) for stenotic lesions after Kawasaki disease., Study Design: Questionnaires were sent to pediatricians in Japan in hospitals with 100 or more beds. A total of 1637 questionnaires were sent, and 1347 (82%) were returned. The primary endpoints of the study were the composite of deaths from any cause and the Q-wave myocardial infarction. The secondary endpoints were the repeat-revascularization for the target vessel., Results: A total of 67 patients underwent PCI and 81 patients underwent CABG. Although the rates of the primary endpoints did not differ between the groups (hazard ratio 1.35 [95% confidence interval 0.29 to 6.32], P=.7), the rate of the secondary endpoints in the PCI group was significantly higher than that in the CABG group (hazard ratio 2.23 [95% confidence interval 1.04 to 4.76], P=.04). The benefit with CABG for the secondary endpoints was notable in patients younger than 12 years old, and who had ischemic change., Conclusions: PCI after Kawasaki disease resulted in a lower efficacy in comparison to CABG because of increased repeat-revascularization procedures., (Copyright (c) 2010 Mosby, Inc. All rights reserved.)

Objective: To investigate the health-related quality of life (HRQOL) in adolescents and young adults with Kawasaki disease (KD)., Study Design: We conducted a cross-sectional observational study. Patients were eligible for this study when they were > or =16 years of age and had received a diagnosis of KD > or =5 years before the start of this study. The patients were divided in 3 groups according to their coronary status: normal, aneurysms, and giant aneurysms/ischemia. A self-administered questionnaire (Medical Outcome Study Short Form 36) was mailed to the patients to evaluate the HRQOL., Results: Of 624 total questionnaires mailed, 377 were delivered, and 250 were returned. The response rates of the normal, aneurysm, and giant aneurysms/ischemia groups were 33%, 62%, and 72% of all eligible patients, respectively. All subscale scoress of HRQOL, except vitality and role-emotional (limitations in the usual role activities because of emotional problems) in patients with KD were significantly higher than scores from the national norms., Conclusions: The HRQOL of adolescents and young adults with a history of KD is favorable. However, long-term follow-up is necessary, because the general health perceptions of older patients tended to be lower., (Copyright 2010 Mosby, Inc. All rights reserved.)

Intravenous immunoglobulin (IVIG) treatment-resistant patients are high risk of developing coronary artery lesions with Kawasaki disease. The IVIG-responsive (Group A; n = 6) and IVIG-resistant patients (Group B) were predicted before starting the initial treatment using the Egami scoring system and randomly allocated as a single-IVIG treatment group (group B1; n = 6) or as a IVIG-plus-methylprednisolone (IVMP) combined therapy group (group B2; n = 5). We investigated the transcript abundance in the leukocytes of those patients using a microarray analysis. Five patients in group A and one patient in group B1 responded to initial IVIG treatment. All group B2 patients responded to IVIG-plus-IVMP combined therapy. Before performing these treatments, those transcripts related to IVIG resistance and to the development of coronary artery lesions, such as IL1R, IL18R, oncostatin M, suppressor of cytokine signaling-3, S100A12 protein, carcinoembryonic antigen-related cell adhesion molecule-1, matrix metallopeptidase-9, and polycythemia rubra vera-1, were more abundant in group B patients in comparison with group A patients. Moreover, those transcripts in group B2 patients were more profoundly and broadly suppressed than group B1 patients after treatment. This study elucidated the molecular mechanism of the effectiveness of IVIG-plus-IVMP combined therapy.

Background: We compared the clinical utility of additional intravenous immune globulin (IVIG) therapy with the clinical utility of steroid pulse therapy in patients with IVIG-resistant Kawasaki disease., Methods: We enrolled 164 patients with Kawasaki disease who were treated with a single dose of IVIG (2 g/kg) and aspirin (30 mg/kg per day). Twenty-seven of these patients (16%) were resistant to the initial IVIG treatment. We compared the effectiveness of treatment strategies for the initial IVIG-resistant 27 patients, 14 of these patients were treated with additional IVIG therapy, and the other 13 patients were treated with steroid pulse therapy (methylprednisolone 30 mg/kg per day for 3 days)., Results: Three patients in the group receiving additional IVIG treatment had coronary artery aneurysms (21.4%), no patients had coronary artery aneurysm in the steroid pulse therapy group; the difference in the incidence of coronary artery aneurysm was not statistically significant. The duration of high fever after additional treatment in the steroid pulse therapy group (1 ± 1.3 days) was significantly shorter than that in the additional IVIG treatment group (3 ± 2.4 days; P < 0.05). The medical costs were significantly lower in the steroid pulse therapy group than in the additional IVIG treatment group., Conclusion: Steroid pulse therapy was useful to reduce the fever duration and medical costs for patients with Kawasaki disease. Steroid pulse therapy and additional IVIG treatment were not significantly different in terms of preventing the development of coronary artery aneurysm.

We retrospectively investigated the effect of warfarin therapy in improving the clinical outcome of Kawasaki disease (KD) patients with giant coronary aneurysms (GAs). We followed 2350 KD patients from 1973 to 2004. The GAs (> or =8 mm in diameter) were diagnosed by coronary angiography. Sixty-eight patients (54 males and 14 females) were retrospectively studied. Patients were divided into two groups. One group consisted of 19 patients with 33 branches treated with a combination of low-dose aspirin and warfarin (target international normalized ratio: 1.5 - 2.5 IU). The second group consisted of 49 patients with 102 branches treated with low-dose aspirin without warfarin. The incidence of myocardial infarction was significantly less in the combination therapy group than in patients treated with aspirin without warfarin (1 patient vs. 16 patients, p < 0.05). Sudden death occurred in seven patients taking aspirin without warfarin, but none of the patients receiving warfarin died. No major bleeding events occurred in either group. Combination therapy of warfarin with aspirin is associated with a decreased risk of myocardial infarction in KD patients with GAs.

Kawasaki disease (KD) is an acute vasculitis that affects most often in children. This is unknown etiology of KD. Therefore, KD is diagnosed by characteristic symptoms. The standard care of acute KD is high-dose intravenous immunoglobulin(IVIG) treatment and aspirin. IVIG has been observed to reduce both the duration of fever and the incidence of coronary artery aneurysms when given within a few days of the onset KD. However, despite receiving IVIG within the first 10 days of illness, 10-20% of patients are resistant to initial IVIG treatment. And approximately 5% of children with KD have subsequent coronary aneurysms. Recently, it became the problems that adequately diagnose KD and early deject resistant initial IVIG case.

Patients with coronary artery aneurysms caused by Kawasaki disease are at increased risk of coronary thrombosis and ischemia. To prevent coronary thrombosis, long-term anti-thrombosis using anti-platelet drugs, such as aspirin, dipyridamole, ticlopidine, clopidogrel, and abciximab, with or without warfarin is recommended by official guidelines. In fact, aspirin or aspirin with warfarin are the most frequently administered regimen in these patients with coronary aneurysms. However, there has been paucity of data and no randomized controlled study to determine the efficacy of these drugs. This short article attempts to summarize the efficacy and safety of these drugs based on currently available literatures and our multi-institutional experience.

Background: The aim of this study was to investigate the effect of a revision of the fever criterion for initial intravenous immunoglobulin (IVIG) treatment, and cardiovascular sequelae, in the new Japanese diagnostic criteria for Kawasaki disease., Methods and Results: Patients who were reported in the 16th and 18th nationwide surveys in Japan were analyzed. New criteria group comprised patients who received the diagnosis of Kawasaki disease in the 18th nationwide survey (n=18,789). Old criteria group was comprised patients who received their diagnosis in the 16(th) nationwide survey (n=15,017). The difference between the new and old criteria for complete cases was only 1%. The proportion of patients who were treated with IVIG within 4 days of illness onset in the new criteria group was significantly lower than in the old criteria group (27.7% vs 30.7%). Multivariate logistic regression analysis identified criteria sex, age, recurrence, diagnosis, last day of initial IVIG and additional IVIG treatment as significant independent factors for cardiovascular sequelae., Conclusions: The guideline revision improves diagnostic sensitivity somewhat, but reflects the clinical reality of the disease that approximately 30% of patients are treated with IVIG within 4 days of illness onset.

Objectives: The objective of this study was to find the predictors and generate a prediction score of resistance to intravenous immunoglobulin (IVIG) in patients with Kawasaki disease (KD)., Study Design: Patients diagnosed as having KD were sampled when they received initial high-dose IVIG treatment (2 g/kg dose) within 9 days of illness (n = 320). These patients were divided into 2 groups: the resistance (n = 41) and the responder (n = 279). The following data were obtained and compared between resistance and responder: age, sex, illness days at initial treatment, and laboratory data., Results: Multivariate logistic regression analysis identified age, illness days, platelet count, alanine aminotransferase (ALT), and C-reactive protein (CRP) as significant predictors for resistance to IVIG. We generated prediction score assigning 1 point for (1) infants less than 6 months old, (2) before 4 days of illness, (3) platelet count or= 8 mg/dL, as well as 2 points for (5) ALT >or= 80 IU/L. Using a cut-off point of 3 and more with this prediction score, we could identify the IVIG-resistant group with 78% sensitivity and 76% specificity., Conclusions: Resistance to IVIG treatment can be predicted using age, illness days, platelet count, ALT, and CRP. Randomized, multicenter clinical trials are necessary to create a new strategy to treat these high-risk patients.

Aim: To investigate the characteristics of patients with Kawasaki disease who needed intravenous gamma-globulin (IVGG) re-treatment., Methods: Using the database of the 17th nationwide survey in Japan, a total 11,366 patients were identified and analysed (1,855 re-treatment patients and 9,511 responders)., Results: Multivariate logistic regression analysis showed that male sex (odds ratio (OR) 1.26; 95% CI 1.14-1.40), complete cases (OR 1.39; 95% CI 1.07-1.80), recurrence (OR 1.47; 95% CI 1.15-1.88), IVGG treatment within 4 d of illness (OR 2.05; 95% CI 1.84-2.27), daily dose of initial IVGG less than 1,000 mg/Kg (OR 0.54; 95% CI 0.48-0.61), exanthema (OR 2.03; 95% CI 1.62-2.56), lips and oral lesions (OR 1.57; 95% CI 1.24-1.98), peripheral extremities changes (OR 1.85; 95% CI 1.54-2.22), and cervical lymphadenopathy (OR 1.89; 95% CI 1.66-2.16) were independent risk factors associated with the need for IVGG re-treatment., Conclusion: Male sex, recurrence, and treatment with IVGG at a dose of 1,000 mg/d or less within 4 d of illness onset are independent risk factors associated with the need for IVGG re-treatment.

The purpose of this study was to assess the hypothesis that lower serum sodium levels are associated with cardiovascular sequelae in patients with Kawasaki disease (KD). We used the database of the 16th nationwide survey of KD in Japan. We investigated the distribution of serum sodium levels and the relationship between serum sodium levels and cardiovascular sequelae. Of the reported cases, serum sodium levels were reported in 13,569 patients (89%). The proportion of patients with serum sodium levels 130 mEq/L or less, was greater in complete cases than in incomplete cases. The proportion of patients with serum sodium levels 130 mEq/L or less was increased with age. The largest proportion of patients with serum sodium levels 130 mEq/L or less was found in the category of 3-5 days since onset of illness. A serum sodium of level 135 mEq/L or less was an independent risk factor for cardiovascular sequelae (odds ratio, 1.79, 95% confidence interval, 1.42-2.26). Among patients with KD, there are significant differences in serum sodium levels between diagnostic categories, age, and days since the onset of illness. The sodium level may be a simple predictor of cardiovascular sequelae.

Diagnostic guidelines for Kawasaki Disease was revised to meet the present situation in 2002. This issue intends to explain new guidelines and their backgrounds. Major alterations are interpretation of cases with 4 or fewer febrile days shortened by early intravenous immunoglobulin treatment, and the clinical importance of atypical (incomplete, or suspected) cases.

Objectives: To clarify the characteristics of Kawasaki disease (KD) in children 6 years and older and to determine whether age is a risk factor for cardiovascular abnormalities., Methods: Patients who had KD and were reported between 1999 and 2000 in the 16th nationwide survey of KD in Japan (n = 15,314) were analyzed. Patients who were aged 6 years or older (older group) were matched with patients who were aged 6 months to 3 years and were treated at the same hospital (younger groups). The total number of analyzed patients was 1498 (749 matched pairs)., Results: The proportion of complete KD in the older group was similar to that in the younger group. Recurrent cases in the older group were significantly more common than those in the younger group (9% vs 2%). The proportion of patients who were treated with intravenous gamma-globulin in the older group was significantly lower than that in the younger group (82% vs 87%). The proportion of older group patients who were treated with intravenous gamma-globulin at or after 7 days of illness was significantly higher than that in the younger group (35% vs 14%). There was a higher prevalence of cardiovascular abnormalities in the older group than in the younger group (20% vs 15%). Multivariate logistic regression analysis showed that older age was an independent risk factor for cardiovascular sequelae (odds ratio: 1.58; 95% confidence interval: 1.01-2.46)., Conclusions: In children older than 6 years, age is an independent risk factor for cardiovascular sequelae in KD.

Objective: To determine the optimal period of intravenous gamma-globulin (IVGG) treatment, using the database from nationwide Kawasaki disease surveys in Japan., Study Design: We selected patients who first visited a doctor within 3 days of illness and received IVGG treatment within 9 days of illness. We divided these patients into 2 groups: an early group (treated on days 1-4: 4731 cases) and a conventional group (days 5-9: 4020 cases). We compared the rate of additional IVGG and prevalence of cardiac sequelae between these groups., Results: The rate of additional IVGG in the early group was significantly higher than those of the conventional group (OR, 1.12 [95% CI, 1.10-1.16]). There were no significant differences in cardiac sequelae between the two groups., Conclusions: There is no evidence that IVGG treatment on day 4 or earlier has greater efficacy in preventing cardiac sequelae than treatment on days 5 to 9. In addition, early treatment is likely to result in a greater requirement for additional IVGG. However, there is also no evidence that early treatment increases the prevalence of cardiac sequelae in a clinical practice setting, where additional IVGG can be given to those whose initial treatment fails.

Background: The purpose of this study was to assess the sequential follow-up results of catheter intervention in Kawasaki disease by use of quantitative coronary angiography (QCA) and intravascular ultrasound imaging., Methods and Results: Catheter intervention was performed on 23 stenotic lesions in 22 patients (aged 2 to 24 years). Percutaneous balloon angioplasty (PBA) was performed in 4 patients, stent implantation in 7, percutaneous transluminal coronary rotational ablation (PTCRA) in 10, and a combination of PTCRA with stent implantation in 2. A total of 21 lesions (91%) were successfully dilated by catheter intervention without major or minor complications. One patient immediately underwent coronary artery bypass grafting (CABG) surgery because stent implantation failed to resolve his lesion. At 4 to 6 months after catheter intervention, 2 restenotic lesions (9%) were detected by QCA in 2 patients who had undergone PBA, and these patients subsequently underwent CABG surgery. In 6 months to 3 years after catheter intervention, no patients showed evidence of ischemic findings. At 3 to 4 years after catheter intervention, QCA and intravascular ultrasound studies were performed on 15 lesions in 14 patients. Two restenotic lesions (13%) were detected by QCA in 2 patients. One of the 2 had stent implantation and underwent CABG surgery, and the other had undergone PTCRA and underwent re-PTCRA. Thirteen patients demonstrated no ischemic findings at 3 to 8 years after catheter intervention., Conclusion: Catheter intervention for Kawasaki disease can be accomplished and can be effective in the short term, but the long-term efficacy should be verified by further study.

The aim of our study was to assess the ability of myocardial contrast echocardiography (MCE) with harmonic power Doppler imaging (HPDI) to identify perfusion abnormalities in patients with Kawasaki disease at rest and during pharmacological stress imaging with dipyridamole. Results were compared with those of 99mTc-tetrofosmin single-photon emission computed tomography (SPECT) imaging as the clinical reference standard. MCE with HPDI was performed on 20 patients with a history of Kawasaki disease. Images were obtained at baseline and during dipyridamole infusion (0.56 mg x kg(-1)) in the apical two- and four-chamber views. Myocardial opacification suitable for the analysis was obtained in all patients. Nine patients with stenotic lesions had a reversible defect after dipyridamole infusion detected by both MCE with HPDI and SPECT, and 3 patients with a history of myocardial infarction had a partially or completely irreversible defect detected by both methods. Three patients with coronary aneurysm without stenotic lesion, 4 patients with regressed coronary aneurysm, and 2 patients with normal coronary artery in acute phase also had normal perfusion at rest and after pharmacological stress by both methods. A 96% concordance (kappa = 0.87) was obtained when comparing the respective segmental perfusion scores using the two methods at baseline, and an 86% concordance (kappa = 0.81) was obtained at postdipyridamole infusion. After combining baseline and postdipyridamole images, each segment was labeled as having normal perfusion, irreversible defects, or reversible defects. Using these classifications, concordance for the two methods was 92% (kappa = 0.87). MCE with HPDI is a safe and feasible method by which to detect asymptomatic ischemia due to severe stenotic lesion, and it may be an important addition to the modalities used to identify patients at risk for myocardial infarction as a complication of Kawasaki disease.

Aim: To investigate the relationship between the plasma levels of soluble forms of the selectin family and the incidence of coronary artery lesions (CALs) in patients with Kawasaki disease (KD)., Methods: Thirty-three patients with KD, including group A patients (n = 22) who had no CALs and group B patients (n = 11) who had CALs, as well as age-matched febrile (n = 10) and afebrile controls (n = 11), were studied., Results: Peak plasma E-selectin levels (172.0 +/- 58.6 ng ml(-1)) occurred during the acute phase of KD, while peak plasma P-selectin levels (260.3 +/- 43.2 ng ml(-1)) occurred during the subacute phase of the illness (p<0.05). Plasma L-selectin levels (1757.3 +/- 244.3 ng ml(-1)) during the convalescent phase tended to be higher than in either the acute or the subacute phase (not significant). Before intravenous immunoglobulin treatment, the plasma levels of E- (225.1 +/- 46.8 ng ml(-1)) and P-selectin (259.4 +/- 76.2 ng ml(-1)) of patients with CALs (n = 11) were significantly higher than those of patients (n = 22) with no CALs (E-selectin, 131.6 +/- 36.9 ng ml(-1); P-selectin, 184.9 +/- 84.6 ng ml(-1); p < 0.05). When a plasma E-selectin value before immunoglobulin treatment of >184.7 ng ml(-1) was used as the cut-off point, the sensitivity and specificity for the incidence of CALs were 81.8% and 90.9%, respectively. These findings demonstrate the relationship between plasma levels of selectins and disease severity of Kawasaki vasculitis., Conclusion: Higher plasma levels of E-selectin may have potential as a predictor of the incidence of coronary artery lesions in Kawasaki disease patients.

The Research Committee of Ministry of Health, Labour and Welfare 'Study of treatment and long-term management in Kawasaki disease' reported the guidelines for catheter intervention in coronary artery lesion in Kawasaki disease in this paper. The contents include: (i) background and natural history of coronary artery lesion in Kawasaki disease; (ii) indication of catheter intervention; (iii) types of procedure, and their indication and care; (iv) institute and backup system; (v) the management after procedure, evaluation and follow up; and (vi) prospects, especially in relation to bypass surgery.

Background: We compared the efficacy and safety of additional intravenous immune globulin (IVIG) therapy with steroid pulse therapy in patients with IVIG-resistant Kawasaki disease., Methods: Two-hundred and sixty-two consecutive patients had been treated with a single dose of IVIG (2 g/kg) and aspirin (30 mg/kg per day). Thirty-five patients (13.4%) were not clinical responders to the initial IVIG treatment. They received an additional IVIG treatment (1 g/kg) within 48 h after the initial treatment. Seventeen patients (6.5%) did not respond to the additional IVIG treatment. We randomly divided these patients into two groups: group 1 consisted of eight patients who were treated with a single additional dose of IVIG (1 g/kg), while group 2 consisted of nine patients who were treated with steroid pulse therapy., Results: The IVIG-resistant patients had a high incidence of coronary artery lesions (CAL; 48.6%). Five patients (62.5%) in group 1 had CAL, including two patients who each had a giant aneurysm and three patients who each had a small aneurysm. Seven patients (77.8%) in group 2 had CAL, including two patients who each had a giant aneurysm, two patients who each had a small coronary aneurysm and three patients who each showed transient dilatation during steroid pulse therapy. There was no significant difference in the incidence of CAL between the two groups. The duration of high fever in group 2 (1.4~0.7 days) was significantly shorter than in group 1 (4.8~3.4 days; P<0.05). The medical costs for the treatment of patients in group 2 (113, 012 yen +/- 22,084) were significantly lower than those for group 1 (144,194 yen +/- 12,914; P<0.05)., Conclusions: Steroid pulse therapy may be useful in the treatment of patients with IVIG-resistant Kawasaki disease who experience prolonged fever. However, transient dilatation of the coronary artery is observed during steroid pulse therapy, so careful echocardiographic examination should be performed for those patients receiving steroid pulse therapy for the sake of early detection of coronary artery abnormalities.

Objective: To assess the current status of catheter intervention in Kawasaki disease and to evaluate its efficacy and outcome., Study Design: A questionnaire was sent to 55 major institutions in Japan., Results: A total of 58 procedures in 57 patients were reported. The median age at the time of intervention was 12.1 years. The procedures included percutaneous transluminal coronary angioplasty (PTCA; n = 34), percutaneous transluminal coronary rotational ablation (PTCRA; n = 13), directional coronary atherectomy (DCA; n = 4), and stent implantation (n = 7). The immediate success rate was 74% for PTCA, 100% for PTCRA, 100% for DCA, and 86% for stents. The interval from the onset of disease to intervention in successful PTCA (n = 25) was significantly shorter than that in unsuccessful PTCA (n = 9). Restenosis after PTCA was observed in 24%. Development of new coronary aneurysms was reported in 3 patients for PTCA, 2 for PTCRA, 3 for DCA, and 1 for stents. Except for the DCA, all new aneurysms were associated with the use of high-pressure balloon inflation. Two deaths were reported as acute complications., Conclusions: Catheter intervention is a promising therapeutic strategy in the management of coronary stenosis caused by Kawasaki disease. Care should be paid to avoid acute coronary arterial complications and the development of new coronary aneurysms.

Objectives: To investigate the long term consequences of regressed aneurysms after Kawasaki disease, using follow up coronary angiography; to assess the vascular wall morphology at the site of the aneurysms by intravascular ultrasound imaging; and to evaluate the function of the affected vessels using intracoronary infusions of acetylcholine and isosorbide dinitrate., Design: 33 patients were studied, 27 with previous Kawasaki disease and six with congenital heart disease. All Kawasaki disease patients were followed for more than 10 years from disease onset. The 33 patients comprised four groups: group 1 included 13 Kawasaki disease patients with a total of 23 sites of regressed large sized (>/= 4 mm) coronary aneurysms; group 2 included 13 Kawasaki disease patients with 22 sites of regressed small sized (< 4 mm) coronary aneurysms (four patients had sites of both large and small sized aneurysms); group 3 included a further five Kawasaki disease patients with 25 normal coronary angiography sites in the acute stage of Kawasaki disease; and group 4 comprised the six patients with congenital heart disease as controls, with a total of 27 normal coronary angiography sites. During coronary angiography, 15 microg of acetylcholine and 0.5 mg isosorbide dinitrate were infused into the coronary artery. The luminal diameter at the sites was measured using a cine-videodensitometric analyser, to assess the distensibility of the coronary artery wall., Results: Coronary angiography in all 22 patients in groups 1 and 2 and in all the patients in group 3 was normal, with no stenoses and no irregularity of the arterial wall. However, the intravascular ultrasound imaging in groups 1 and 2 showed various degrees of the intimal thickening. In groups 1 and 2, there was significantly more vascular constriction with acetylcholine, and poorer dilatation with isosorbide dinitrate than in groups 3 or 4 (each p < 0.05, respectively). There was no difference between group 3 and group 4 in response to either acetylcholine or isosorbide dinitrate,, Conclusions: There is evidence of persisting abnormal vascular wall morphology and vascular dysfunction at the site of regressed coronary aneurysms in patients with previous Kawasaki disease. These patients should be counselled to avoid potential risk factors for atherosclerosis, and long term follow up is needed into adult life.

Background: High-dose intravenous gamma-globulin (IVGG) plus aspirin (ASA) treatment is effective in preventing coronary artery complications in acute Kawasaki disease (KD). However, gamma-globulin is very expensive, especially in Japan. Furthermore the indication for IVGG treatment and the optimal dose of gamma-globulin remain controversial., Objectives: To examine these two issues, we used Harada's scoring system to investigate whether a single 2 g/kg dose therapy has any advantage over the 5 day 400 mg/kg per day therapy., Methods: We studied 203 patients with KD who had no coronary artery complications on admission. Of these, 145 patients scored 4 or more on Harada score within the first 9 days of illness and were treated with IVGG treatment. Using a random number table, 72 patients were selected to receive a single 2 g/kg dose (2 g group), while the remaining 73 patients were treated with 400 mg/kg per day for 5 consecutive days (400 mg group). Those who had a Harada score of three or less received no IVGG (non-IVGG group) treatment (58 patients)., Results: The incidence rate of coronary artery complications in the 2 g group was significantly lower than in the 400 mg group. The duration of high fever, positive duration of C-reactive protein and the number of hospital days in the 2 g group were each significantly shorter than in the 400 mg group. The total medical expense in the 2 g group was significantly lower than in the 400 mg group. There were no coronary artery complications in the non-IVGG group., Conclusions: It was found to be clinically more effective and more cost effective to select a patient by Harada's scoring system and, where a score of four or more was obtained, to administer a single 2 g/kg intravenous dose of gamma-globulin for acute KD.

Objectives: This study sought to assess the endothelial function of long-term coronary artery lesions in patients with Kawasaki disease (KD)., Background: The vascular function of the coronary arteries in children with long-term KD remains uncertain. We report our findings of the vascular response of the coronary arteries to intracoronary injection of acetylcholine (ACh) in patients with KD., Methods: A total of 35 patients (25 patients with KD and 10 control subjects) were examined using coronary angiography. Individual arteries were divided into four groups according to the type of the coronary artery lesion: group 1 consisted of 25 sites with regressed aneurysms. These aneurysms had developed in the acute stage but had subsequently regressed and demonstrated normal findings on the follow-up coronary angiogram. Group 2 consisted of 24 sites with persistent aneurysms. Group 3 involved 60 angiographically normal sites in the same patients as those in group 1 or 2. Group 4 consisted of 30 sites in control subjects who had congenital heart disease with normal coronary arteries. During coronary angiography we infused 15 microg of ACh chloride into the coronary artery. The lumen diameters were measured using a cine videodensitometric analyzer to study the distensibility of the coronary artery wall., Results: The mean (+/-SD) change in diameter was an increase of 11.71+/-12.34% in group 3 (coronary arteries without lesions in patients with KD) and 12.21+/-9.71% in the control group, demonstrating marked vasodilation in both groups. In contrast, the changes in the regressed aneurysms of group 1 and in the persistent aneurysms of group 2 were -2.65+/-12.12% and -0.08+/-6.51%, respectively, demonstrating no change or mild vasoconstriction. The change in groups 1 and 2 was significantly less than that in group 3 or in the control group. Group 3 showed no significant difference from the control group., Conclusions: These findings suggest that long-term coronary artery lesions, even after aneurysm regression, may have impaired endothelial function. A long-term follow-up study for those patients is essential.

Background: The long-term clinical issue in Kawasaki disease (KD) concerns the coronary artery lesion. Two-dimensional echocardiography and coronary angiography are routine examinations to evaluate the coronary lesions; however, these are not adequate to assess the wall morphology of the coronary artery (CA). Intravascular ultrasound imaging (IVUS), a new technology for the evaluation of the coronary artery lumen and wall morphology in vivo, was performed for patients after KD in their long-term follow-up, and we examined the new insights it gave., Methods and Results: IVUS was performed during cardiac catheterization in 20 subjects (10 patients after KD who still had coronary aneurysms or regressed coronary aneurysms, 2 after KD who had no coronary abnormal lesion, and 8 control patients with congenital heart disease and normal CA). We evaluated the wall structure at 10 to 15 sites of the CA in each patient. IVUS was performed with a commercially available ultrasound imaging catheter. Four sites of a CA aneurysm in KD demonstrated a markedly dilated lumen without thickened intima. One site of a CA aneurysm with calcification demonstrated an asymmetrical lumen by a dense echo with acoustic shadows. Twenty-two sites of a regressed CA aneurysm demonstrated a marked symmetrical or asymmetrical thickening of the intima with a dense echo, in which the size of the lumen was similar to that at a site near a regressed aneurysm. The sites of angiographically normal CA revealed normal structures and a thin intima in many instances. Nine of 28 sites in KD with a CA abnormal lesion, particularly near a coronary aneurysm or regressed aneurysm, demonstrated a mild thickening of the intima. All the 10 sites in KD without a CA abnormal lesion and all the 25 sites in patients with congenital heart disease with normal CA demonstrated a smooth intima., Conclusions: This study demonstrated that the site of a regressed coronary aneurysm has a markedly thickened but smooth intima. The sites of angiographically normal CA after KD with or without a coronary lesion demonstrated normal IVUS findings in most instances but in some cases revealed a mild intimal thickening. IVUS is useful to evaluate the CA wall morphology and may contribute to the assessment of long-term CA sequelae and the possible development of arteriosclerotic changes in KD.