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In a meta-analysis of three GWAS for susceptibility to Kawasaki disease (KD) conducted in Japan, Korea, and Taiwan and follow-up studies with a total of 11,265 subjects (3428 cases and 7837 controls), a significantly associated SNV in the immunoglobulin heavy variable gene (IGHV) cluster in 14q33.32 was identified (rs4774175; OR = 1.20, P = 6.0 × 10−9). Investigation of nonsynonymous SNVs of the IGHV cluster in 9335 Japanese subjects identified the C allele of rs6423677, located in IGHV3-66, as the most significant reproducible association (OR = 1.25, P = 6.8 × 10−10 in 3603 cases and 5731 controls). We observed highly skewed allelic usage of IGHV3-66, wherein the rs6423677 A allele was nearly abolished in the transcripts in peripheral blood mononuclear cells of both KD patients and healthy adults. Association of the high-expression allele with KD strongly indicates some active roles of B-cells or endogenous immunoglobulins in the disease pathogenesis. Considering that significant association of SNVs in the IGHV region with disease susceptibility was previously known only for rheumatic heart disease (RHD), a complication of acute rheumatic fever (ARF), these observations suggest that common B-cell related mechanisms may mediate the symptomology of KD and ARF as well as RHD.

Kawasaki disease (KD) is an acute, self-limited vasculitis, mainly affecting children younger than 5 years old, with accompanying fever and signs of mucocutaneous inflammation. Intravenous immunoglobulin (IVIG) is the standard treatment for KD; however, ~15% of patients are resistant to IVIG treatment. To identify protein coding genetic variants influencing IVIG resistance, we re-analyzed our previous genome-wide association study (GWAS) data from 296 patients with KD, including 101 IVIG non-responders and 195 IVIG responders. Five nonsynonymous SNPs (nsSNPs) in five immune-related genes, including a previously reported SAMD9L nsSNP (rs10488532; p.Val266Ile), were associated with IVIG non-response (odds ratio [OR] = 1.89–3.46, P = 0.0109–0.0035). In a replication study of the four newly-identified nsSNPs, only one in the interleukin 16 (IL16) gene (rs11556218, p.Asn1147Lys) showed a trend of association with IVIG non-response (OR = 1.54, P = 0.0078). The same IL16 nsSNP was more significantly associated with IVIG non-response in combined analysis of all data (OR = 1.64, P = 1.25 × 10−4). Furthermore, risk allele combination of the IL16 CT and SAMD9L TT nsSNP genotypes exhibited a very strong effect size (OR = 9.19, P = 3.63 × 10−4). These results implicate IL16 as involved in the mechanism of IVIG resistance in KD.

Kawasaki disease (KD) is a systemic vasculitis affecting infants and children; it manifests as fever and signs of mucocutaneous inflammation. Intravenous immunoglobulin (IVIG) treatment effectively attenuates the fever and systemic inflammation. However, 10–20% patients are unresponsive to IVIG. To identify genetic variants influencing IVIG non-response in KD, a genome-wide association study (GWAS) and a replication study were performed using a total of 148 IVIG non-responders and 845 IVIG-responders in a Korean population. rs28662 in the sterile alpha motif domain-containing protein 9-like (SAMD9L) locus showed the most significant result in the joint analysis of GWAS and replication samples (odds ratio (OR) = 3.47, P = 1.39 × 10−5). The same SNP in the SAMD9L locus was tested in the Japanese population, and it revealed a more significant association in a meta-analysis with Japanese data (OR = 4.30, P = 5.30 × 10−6). These results provide new insights into the mechanism of IVIG response in KD.

Background and objectives Patients with Kawasaki disease (KD) are clinically heterogeneous because its diagnosis is based solely on clinical observation and there are no definitive biomarkers. We dissected the clinical heterogeneity of KD patients using the KD-associated genetic variants. Methods We performed a genetic association analysis in several KD subgroups categorized by clinical characteristics using the KD-associated variants of the B lymphoid tyrosine kinase (BLK; rs6993775) and Fc gamma receptor II a (FCGR2A; rs1801274) in a large number of case (n=1,011) and control (n=4,533) samples. Results BLK and FCGR2A were very significantly associated with KD in Korean KD patients (odds ratio [OR],1.48; p=4.63×10⁻¹¹ for BLK, and OR, 1.26; p=1.42×10⁻⁴ for FCGR2A). However, in KD subgroup analysis, we found that neither BLK nor FCGR2A were associated with either incomplete Kawasaki disease (iKD) type patients or those older than 5 years of age (p>0.2), suggesting that patients with iKD or those older than 5 years of age are a unique subgroup of KD. In genetic association analysis after excluding iKD patients and those older than 5 years old, we found that BLK was associated with all KD subgroups, whereas FCGR2A was specifically associated with male KD patients younger than 1 year of age (OR, 2.22; p=2.35×10⁻⁵). Conclusions KD is a clinically and genetically heterogeneous disease. These findings will provide new insights into the clinical and genetic heterogeneity of KD.

Kawasaki disease (KD) is an acute pediatric vasculitis that affects genetically susceptible infants and children. To identify coding variants that influence susceptibility to KD, we conducted whole exome sequencing of 159 patients with KD and 902 controls, and performed a replication study in an independent 586 cases and 732 controls. We identified five rare coding variants in five genes (FCRLA, PTGER4, IL17F, CARD11, and SIGLEC10) associated with KD (odds ratio [OR], 1.18–4.41; p = 0.0027–0.031). We also performed association analysis in 26 KD patients with coronary artery aneurysms (CAAs; diameter > 5 mm) and 124 patients without CAAs (diameter < 3 mm), and identified another five rare coding variants in five genes (FGFR4, IL31RA, FNDC1, MMP8, and FOXN1), which may be associated with CAA (OR, 3.89–37.3; p = 0.0058–0.0261). These results provide insights into new candidate genes and genetic variants potentially involved in the development of KD and CAA.

Background and Objectives Kawasaki disease (KD) is an acute systemic vasculitis that affects the coronary arteries. Abnormal immune reactions are thought to contribute to disease pathogenesis. The effect of immunoglobulin (Ig) isotype (IgG, IgA, IgM, and IgE) on inflammatory data and clinical outcomes of patients with KD was examined. Methods Ig levels in 241 patients with KD were measured during the acute, subacute, convalescent, and normal phases of the disease. Results Compared with reference Ig values, IgG, IgA, and IgM levels were significantly higher in the subacute phase, while IgE levels were elevated in 73.9% (178/241) of patients with KD in all clinical phases. However, high IgE levels were not associated with clinical outcomes, including intravenous immunoglobulin unresponsiveness and coronary artery lesions (CALs). Significantly more CALs were observed in the high IgA group than in the normal IgA group (44.7% vs. 20.8%, respectively; p

Kawasaki disease (KD) is a self-limited systemic vasculitis of an unknown pathogenesis mainly affecting children

Purpose Incomplete Kawasaki disease (KD) is frequently associated with delayed diagnosis and treatment. Delayed diagnosis leads to increasing risk of coronary artery aneurysm. Anterior uveitis is an important ocular sign of KD. The purpose of this study was to assess differences in laboratory findings, including echocardiographic measurements, clinical characteristics such as fever duration and treatment responses between KD patients with and those without uveitis. Methods We conducted a prospective study with 110 KD patients from January 2008 to June 2013. The study group (n=32, KD with uveitis) was compared with the control group (n=78, KD without uveitis). Laboratory data were obtained from each patient including complete blood count (CBC), erythrocyte sedimentation rate (ESR), platelet count, and level of alanine aminotransferase, aspartate aminotransferase, serum total protein, albumin, C-reactive protein (CRP), and N-terminal probrain natriuretic peptide (NT-pro BNP). Echocardiographic measurements and intravenous immunoglobulin responses were compared between the two groups. Results The incidence of uveitis was 29.0%. Neutrophil counts and patient age were higher in the uveitis group than in the control group. ESR and CRP level were slightly increased in the uveitis group compared with the control group, but the difference between the two groups was not significant. No significant differences in coronary arterial complication and treatment responses were observed between the two groups. Conclusion Uveitis is an important ocular sign in the diagnosis of incomplete KD. It is significantly associated with patient age and neutrophil count.

Kawasaki disease (KD), a systemic vasculitis of infants and children, manifests as fever and mucocutaneous inflammation. Although its etiology is largely unknown, the epidemiological data suggest that genetic factors are important in KD susceptibility. To identify genetic variants influencing KD susceptibility, we performed a genome-wide association study (GWAS) and replication study using a total of 915 children with KD and 4553 controls in the Korean population. Six single-nucleotide polymorphisms (SNPs) in three loci were associated significantly with KD susceptibility (P

Kawasaki disease (KD) is an acute systemic vasculitis that can potentially cause coronary artery aneurysms in some children. KD occurs approximately 1.5 times more frequently in males than in females. To identify sex-specific genetic variants that are involved in KD pathogenesis in children, we performed a sex-stratified genome-wide association study (GWAS), using the Illumina HumanOmni1-Quad BeadChip data (249 cases and 1,000 controls) and a replication study for the 34 sex-specific candidate SNPs in an independent sample set (671 cases and 3,553 controls). Male-specific associations were detected in three common variants: rs1801274 in FCGR2A [odds ratio (OR) = 1.40, P = 9.31 × 10−5], rs12516652 in SEMA6A (OR = 1.87, P = 3.12 × 10−4), and rs5771303 near IL17REL (OR = 1.57, P = 2.53 × 10−5). The male-specific association of FCGR2A, but not SEMA6A and IL17REL, was also replicated in a Japanese population (OR = 1.74, P = 1.04 × 10−4 in males vs. OR = 1.22, P = 0.191 in females). In a meta-analysis with 1,461 cases and 5,302 controls, a very strong association of KD with the nonsynonymous SNP rs1801274 (p.His167Arg, previously assigned as p.His131Arg) in FCGR2A was confirmed in males (OR = 1.48, P = 1.43 × 10−7), but not in the females (OR = 1.17, P = 0.055). The present study demonstrates that p.His167Arg, a KD-associated FCGR2A variant, acts as a susceptibility gene in males only. Overall, the gender differences associated with FCGR2A in KD provide a new insight into KD susceptibility.

Kawasaki disease (KD) is the most common cause of acquired heart disease in children. Intravenous immunoglobulin (IVIG) is the standard therapy for KD, but more than 10% of KD patients do not respond to IVIG and are at high risk for the development of coronary artery lesions (CALs). To identify clinical and genetic risk factors associated with CAL development and IVIG nonresponsiveness, this study analyzed the clinical data for 478 Korean KD patients. Multivariate logistic regression analysis showed that incomplete KD, IVIG nonresponse, fever duration of 7 days or longer, and the CC/AC genotypes of the rs7604693 single nucleotide polymorphism (SNP) in the PELI1 gene were significantly associated with the development of CALs, with odds ratios (ORs) ranging from 2.06 to 3.04. The risk of CAL formation was synergistically increased by the addition of individual risk factors, particularly the genetic variant in the PELI1 gene. Multivariate analysis also showed that a serum albumin level of 3.6 g/dl or lower was significantly associated with nonresponsiveness to IVIG [OR, 2.76; 95% confidence interval (CI), 1.34-5.68; P = 0.006]. Conclusively, incomplete KD, IVIG nonresponsiveness, long febrile days, and the rs7604693 genetic variant in the PELI1 gene are major risk factors for the development of CALs, whereas low serum albumin concentration is an independent risk factor for IVIG nonresponsiveness.

Kawasaki disease is a systemic vasculitis of unknown etiology, with clinical observations suggesting a substantial genetic contribution to disease susceptibility. We conducted a genome-wide association study and replication analysis in 2,173 individuals with Kawasaki disease and 9,383 controls from five independent sample collections. Two loci exceeded the formal threshold for genome-wide significance. The first locus is a functional polymorphism in the IgG receptor gene FCGR2A (encoding an H131R substitution) (rs1801274; P = 7.35 × 10(-11), odds ratio (OR) = 1.32), with the A allele (coding for histadine) conferring elevated disease risk. The second locus is at 19q13, (P = 2.51 × 10(-9), OR = 1.42 for the rs2233152 SNP near MIA and RAB4B; P = 1.68 × 10(-12), OR = 1.52 for rs28493229 in ITPKC), which confirms previous findings(1). The involvement of the FCGR2A locus may have implications for understanding immune activation in Kawasaki disease pathogenesis and the mechanism of response to intravenous immunoglobulin, the only proven therapy for this disease.

Background and Objectives: We sought to determine parameters to guide the decision of retreatment in patients with Kawasaki disease (KD) who remained febrile after initial intravenous immunoglobulin (IVIG). Subjects and Methods: A total of 129 children with KD were studied prospectively. Patients were treated with IVIG 2 to 9 days after the onset of disease. Laboratory measures, such as white blood cell (WBC), percentage of neutrophils, C-reactive protein (CRP), and N-terminal pro-brain natriuretic peptide (NT-proBNP), were determined before and 48 to 72 hours after IVIG treatment. Patients were classified into IVIG-responsive and IVIG-resistant groups, based on the response to IVIG. Results: Of a total of 129 patients, 107 patients (83%) completely responded to a single IVIG therapy and only 22 patients (17%) required retreatment: 14 had persistent fever and 8 had recrudescent fever. There was no significant difference between the groups in age, gender distri bution, and duration of fever to IVIG initiation, but coronary artery lesions developed significantly more often in the resis tant group than in the responsive group (31.8% vs. 2.8%, p=0.000). Compared with pre-IVIG data, post-IVIG levels of WBC, percentage of neutrophils, CRP, and NT-proBNP decreased to within the normal range in the responsive group, whereas they remained high in the resistant group. Multivariate logistic regression indicated that neutrophil counts, CRP, and NT-proBNP were independent parameters of retreatment. Conclusion: Additional therapy at an early stage of the disease should be administered for febrile patients who have high values of CRP, NT-proBNP, and/or neutrophil counts after IVIG therapy. (Ko

It is difficult to predict the prognosis or clinical course of secondary hemophagocytic lymphohistiocytosis (HLH) due to the various underlying causes. The authors analyzed the clinical and laboratory findings and outcomes in patients with HLH who had initially been diagnosed with Kawasaki disease (KD), and evaluated the clinical significance of each factor. Among the 21 patients with HLH, 5 had initially been diagnosed with KD and 16 had other etiologies. A comparative analysis was performed for fever duration, presence of cytopenia, serum ferritin, aspartate aminotransferase (AST), alanine aminotransferase (ALT), triglyceride, fibrinogen, hyponatremia, reactivation, and survival rate in those HLH patients associated with KD (group I) and other causes (group II). In patients in group I, a higher level of reactivation (20%), a lower survival rate (P = .001), higher AST (P = .031) and ferritin (P = .005), and frequent hyponatremia (P = .000) were found compared to patients in group II. Interestingly, patients in group I was older than the average of age of most KD patients. A high index of suspicion on the progression from KD to HLH would be mandatory when the KD patients show elevated AST and ferritin and the presence of hyponatremia, and especially so if the patient is of older age.

Background: The aim of this study was to estimate the incidence and describe the epidemiological characteristics of Kawasaki disease among children in Korea. Methods: Questionnaires for surveying the epidemiology of Kawasaki disease were distributed to a total of 101 hospitals that conduct pediatric residency programs. Then, we retrospectively obtained the data, which covered a three-year period (2006–2008) and analyzed them. Results: During the three-year study period, a total of 9039 cases of Kawasaki disease were reported from 84 hospitals (response rate, 83.2%), comprising 5375 boys and 3664 girls (male : female ratio, 1.47:1). The outbreak rate per 100 000 children

Kawasaki disease (KD) is an acute self-limited vasculitis of infants and children that manifests as fever and signs of mucocutaneous inflammation. Coronary artery aneurysms develop in approximately 15-25% of untreated children. Although the etiology of KD is largely unknown, epidemiologic data suggest the importance of genetic factors in the susceptibility to KD. In order to identify genetic variants that influence KD susceptibility, we performed a genome-wide association study (GWAS) using Affymetrix SNP array 6.0 in 186 Korean KD patients and 600 healthy controls; 18 and 26 genomic regions with one or more sequence variants were associated with KD and KD with coronary artery lesions (CALs), respectively (p

Purpose : Adiponectin is an endogenous modulator of vascular remodeling that suppresses vascular inflammation. However, the role of adiponectin in Kawasaki disease (KD) has not been elucidated. The purpose of this study is to investigate the correlation between serum adiponectin level and several parameters, such as interleukin (IL)-6, tumor necrosis factor (TNF)-α, lipid profile, and C reactive protein (CRP), and to clarify the association between adiponectin and cardiac function. Methods : Twenty-two KD patients (22 patients in acute phase and 20 patients in subacute phase) were enrolled in the study group. The control group consisted of 31 subjects (13 febrile patients and 18 healthy children). Both groups underwent blood sampling and tissue Doppler imaging (TDI). Results : CRP was significantly increased in the KD group compared with the control group. There were no significant differences in serum TNF-α, IL-6, and adiponectin levels between groups. However, a negative correlation was found between adiponectin level and CRP level or platelet count. Systolic myocardial velocity and A myocardial velocity measured by TDI were decreased significantly in the acute KD group compared with the subacute KD group and control group. Positive correlations were found between adiponectin level and systolic myocardial velocity or A myocardial velocity. Conclusion : In acute KD patients, low adiponectin level was related to severe inflammatory reactions and decreased left ventricular functions. (Korean J Pediatr 2010;53:41-47)

Background and Objectives: Kawasaki disease (KD) is an acute inflammatory process affecting the arterial walls that results in panvasculitis. Recent studies have shown that even after resolution of the disease, endothelial dysfunction persists and may progress to atherosclerosis. The pulse wave velocity (PWV) and the ankle-brachial index (ABI) are simple and non-invasive methods for evaluating the degree of atherosclerosis, and are known as the predictors of cardiovascular disease in adults. Carotid intima-media thickness (cIMT) is also known as a predictor of cardiovascular disease. We conducted this study to determine the change in arterial stiffness by measuring the PWV, ABI, and cIMT in children who have recovered from KD. Subjects and Methods: Twenty-five patients with KD and coronary aneurysm were recruited. They all recovered from KD and were normal for more than 8 years. Fifty-five healthy children were evaluated as the control group. Their height, weight, body mass index, and blood pressure (systolic, diastolic, and the mean) were measured. The PWV, ABI, ejection time (ET), and pre-ejection period (PEP) were measured by ultrasonography. The cIMT was measured by ultrasonography. Results: The left brachial ankle PWV was significantly higher in the KD group (1020.6±146.5 cm/sec) than the control group (984.0±96.5 cm/sec). The ABI did not differ between the two groups. There was no difference in PEP/ET and cIMT. Conclusion: The PWV in children who recovered from KD was higher than the control group. Long-term follow up is necessary in children after recovery from KD even if there is no abnormality in echocardiography. (Korean Circ J 2009;39:264-269)

Kawasaki disease is an acute, self-limited vasculitis of infants and children, manifest as fever and signs of mucocutaneous inflammation. Treatment with high-dose immunoglobulin reduces systemic inflammation and prevents coronary artery lesions in Kawasaki disease. In this study, we investigated the possible association of the major histocompatibililty complex (MHC) region for the susceptibility to Kawasaki disease using an MHC panel of 2360 single nucleotide polymorphism (SNP) markers. Analysis of data obtained from screening MHC-specific SNP chips with 48 case and 90 control subjects revealed five candidate loci with significance levels of uncorrected p0.01. However, only one candidate locus (HLA-G) was confirmed to have a significant association with Kawasaki disease (rs2523790, odds ratio [OR] = 3.00, 95% confidence interval [95% CI] = 1.14-7.91, uncorrected p = 0.0263) in the replication study using 44 new case subjects and the previous 90 controls. In the fine mapping of the HLA-G locus, in particular, a nonsynonymous SNP (C/A) of the HLA-G gene (rs12722477, Leu134Ile) was significantly associated with Kawasaki disease (OR = 3.23, 95% CI = 1.12-9.32). A subgroup analysis showed that this association was more apparent in patients with coronary artery aneurysms (OR = 4.02, 95% CI = 1.23-13.19). Therefore, our results indicate that HLA-G may play a crucial role for the susceptibility to Kawasaki disease.

Forty-three patients with Kawasaki disease who were resistant to initial intravenous immunoglobulin (IVIG) were randomized to receive either a second dose of IVIG (n = 32) or an infliximab (n = 11). With IVIG retreatment 21 patients (65.6%) responded, and with infliximab 10 patients (90.9%) responded. The infliximab group had shorter duration of fever and fewer days of hospitalization. Coronary artery outcomes and adverse events were similar.

Objective To investigate the effect of medium- or higher-dose acetylsalicylic acid (ASA) for treating acute-phase Kawasaki disease to prevent coronary artery aneurysm (CAA). Study design Among the children with acute Kawasaki disease investigated in the eighth nationwide survey in the Republic of Korea, 8456 children with adequate data were included in this study. The subjects were divided into 2 groups according to the use of medium- or higher-dose ASA (≥30 mg/kg/day), or-low dose ASA (3-5 mg/kg/day) during the acute febrile phase. Both z- score–based criteria and Japanese criteria for CAA were used. Results The prevalence of CAA based on z -score (24.8% vs 18.3%; P = .001) and on the Japanese criteria (19.0% vs 10.4%; P z -score: OR, 1.472, 95% CI, 1.169-1.854, P = .001; based on Japanese criteria: OR, 2.013, 95% CI, 1.507-2.690, P P = .003 and OR, 2.198, 95% CI, 1.563-3.092, P Conclusions The use of medium- or higher-dose ASA in acute Kawasaki disease did not prevent CAA. A future randomized controlled trial is needed to determine the optimum dose of ASA.

Kawasaki disease (KD) is an acute self-limiting form of vasculitis that afflicts infants and children and manifests as fever and signs of mucocutaneous inflammation. Children with KD show various laboratory inflammatory abnormalities, such as elevations in their white blood cell (WBC) count, C-reactive protein (CRP) level, and erythrocyte sedimentation rate (ESR). We here performed a genome-wide association study (GWAS) of 178 KD patients to identify the genetic loci that influence 10 important KD laboratory markers: WBC count, neutrophil count, platelet count, CRP, ESR, hemoglobin, aspartate aminotransferase (AST), alanine aminotransferase (ALT), albumin, and total protein. A total of 165 loci passed our arbitrary stage 1 threshold for replication (p < 1 × 10(-5)). Of these, only 2 SNPs (rs12068753 and rs4786091) demonstrated a significant association with the CRP level in replication study of 473 KD patients (p < 0.05). The SNP located at the CRP locus (rs12068753) demonstrated the most significant association with CRP in KD patients (beta = 4.73 and p = 1.20 × 10(-6) according to the stage 1 GWAS; beta = 3.65 and p = 1.35 × 10(-8) according to the replication study; beta = 3.97 and p = 1.11 × 10(-13) according to combined analysis) and explained 8.1% of the phenotypic variation observed. However, this SNP did not demonstrate any significant association with CRP in the general population (beta = 0.37 and p = 0.1732) and only explained 0.1% of the phenotypic variation in this instance. Furthermore, rs12068753 did not affect the development of coronary artery lesions or intravenous immunoglobulin resistance in KD patients. These results indicate that common variants in the CRP promoter can play an important role in the CRP levels in KD.

Background and Objectives: This study is aimed at elucidating potential temporal associations between the occurrence of Kawasaki disease (KD) and various viral infections. Subjects and Methods: We obtained monthly patterns of KD from the seventh nationwide survey and viral detection data from the Korea Centers for Disease Control and Prevention from 2009 to 2011 and evaluated temporal correlations between them for each month. The respiratory viruses detected using a multiplex real-time-polymerase chain reaction kit were influenza virus (A/H1N1, A/H3N2, A/H5N1, and B), adenovirus, parainfluenza virus (type 1, 2, 3), respiratory syncytial virus (type A, B), human rhinovirus, human coronavirus (OC43/229E, NL63), human bocavirus, and enterovirus. Results: We obtained data from a total of 13031 patients who were treated for acute KD from 87 hospitals with pediatric residence programs. During this survey, KD showed highest overall incidence in summer and winter seasons and lowest incidence in February and October. We received viral detection data for a total of 14267 patients. Viral detection was highest during winter and spring seasons. The most commonly detected virus was human rhinovirus (32.6%), followed by influenza virus (26.8%). The monthly incidence of KD showed signifi cant correlation with the monthly overall viral detection (p=0.022, r=0.382). In particular, human bocavirus and enterovirus have significant correlations with monthly patterns of KD occurrence (p=0.032 and p=0.007, respectively) and influenza virus correlated with KD occurrence with borderline significance (p=0.063). Conclusion: The temporal association between monthly occurrence of KD and viral detection suggests the etiologic importance of precedent infection in the development of KD. (Korean Circ J 2014;44(4):250-254)

To assess the recent epidemiologic features of Kawasaki disease (KD) in South Korea from the nationwide survey conducted between 2009 and 2011.We collected data regarding the incidence, symptoms, treatment and coronary complications associated with acute KD by sending questionnaires to the 100 hospitals that have pediatric residency programs from 2009 to 2011.We received complete responses from 73 hospitals and partial responses from 14 hospitals. A total of 13,031 patients of KD were reported from the 87 hospitals (3941 in 2009, 4635 in 2010 and 4455 in 2011). The male to female ratio was 1.44:1, and the median age at diagnosis was 28 months. From the questionnaires with complete responses, we noted that the incidence of KD per 100,000 children5 years of age was 115.4 in 2009, 132.9 in 2010 and 134.4 in 2011 (average rate, 127.7). KD occurred more frequently during summer (June, July and August) and during winter (December and January). The recurrence rate was 3.83%. The standard dose of intravenous immunoglobulin was administered to 93.6% of the patients, and nonresponder rate was 11.6%. Coronary aneurysm occurred in 1.9% of the patients and giant aneurysm developed in 26 patients (0.26%) over 3 years, and 2 patients had myocardial infarction. No mortality was reported.The average annual incidence of KD in South Korea has continuously increased to 134.4 per 100,000 children5 years of age in 2011, which is the second highest incidence of KD worldwide, following its incidence in Japan.

Kawasaki disease (KD) is a rare disease that occurs predominantly in infants and young children. To identify KD susceptibility genes and to develop a diagnostic test, a specific therapy, or prevention method, collecting KD patients’ clinical and genomic data is one of the major issues. For this purpose, Kawasaki Disease Database (KDD) was developed based on the efforts of Korean Kawasaki Disease Genetics Consortium (KKDGC). KDD is a collection of 1292 clinical data and genomic samples of 1283 patients from 13 KKDGC-participating hospitals. Each sample contains the relevant clinical data, genomic DNA and plasma samples isolated from patients’ blood, omics data and KD-associated genotype data. Clinical data was collected and saved using the common data elements based on the ISO/IEC 11179 metadata standard. Two genome-wide association study data of total 482 samples and whole exome sequencing data of 12 samples were also collected. In addition, KDD includes the rare cases of KD (16 cases with family history, 46 cases with recurrence, 119 cases with intravenous immunoglobulin non-responsiveness, and 52 cases with coronary artery aneurysm). As the first public database for KD, KDD can significantly facilitate KD studies. All data in KDD can be searchable and downloadable. KDD was implemented in PHP, MySQL and Apache, with all major browsers supported. Database URL: http://www.kawasakidisease.kr

목적: 가와사끼병에서 C-반응 단백질(CRP)과 적혈구 침강속도(ESR)의 불일치 및 정맥내 면역글로불 린(IVIG) 치료 후의 변화를 보고자 하였다. 방법: 총 123명의 가와사끼병 환자의 의무기록를 후향적으로 분석하였다. 염증성 지표들을 IVIG 치료 전과 치료 후 48-72시간에 검사하였다. 불일치는 CRP ≥10 mg/dL와 ESR

Kawasaki disease (KD) is often complicated by coronary artery lesions (CALs), including aneurysms. Because of the complications associated with KD, this disorder is the leading cause of acquired heart disease in children from developed countries. To identify genetic loci that confer a higher risk of developing CALs, we performed a case-control association study using previous genome-wide association study data for samples from KD cases only (n=186) by grouping KD patients without CALs (control: n=123) vs KD patients with extremely large aneurysms (diameter5 mm) (case: n=17). Twelve loci with one or more sequence variants were found to be significantly associated with CALs (P1 × 10(-5)). Of these, an SNP (rs17136627) in the potassium intermediate/small conductance calcium-activated channel, subfamily N, member 2 (KCNN2) at 5q22.3 was validated in 32 KD patients with large aneurysms (diameter5 mm) and 191 KD patients without CALs (odds ratio (OR)=12.6, P(combined)=1.96 × 10(-8)). This result indicates that the KCNN2 gene can have an important role in the development of coronary artery aneurysms in KD.

High-dose intravenous immunoglobulin (IVIG) therapy is the highly effective and standard treatment for Kawasaki disease (KD). However, ~20 % of KD patients have persistent fever or recurrence of fever after the initial IVIG treatment, which increases the risk for coronary artery lesions (CALs). Furthermore, the mechanism of IVIG resistance in KD patients still is unknown. The number of CC chemokine ligand 3-like 1 (CCL3L1) gene copies is reported to be associated with KD and IVIG resistance in Japanese patients. In addition, the authors observed significant upregulation of the CCL3L1 gene expression after in vitro immunoglobulin treatment in B cell lines derived from KD patients. Therefore, this study of 459 KD patients and 496 healthy control subjects tested whether the number of CCL3L1 gene copies is associated with a risk of KD, CALs, and/or IVIG resistance in Korean KD patients. However, the number of CCL3L1 gene copies was not associated with KD (P = 0.18), CAL formation (P = 0.062), or the IVIG resistance (P = 0.90). Therefore, the results indicate that the number of CCL3L1 gene copies does not have a role in susceptibility to KD or CALs nor with IVIG resistance in Korean KD patients.

Kawasaki disease (KD) is an acute vasculitis syndrome of unknown etiology that frequently affects small to medium size arteries. C-C chemokine receptor 5 (CCR5) is a chemokine receptor that binds C-C chemokines. This study investigated the association of the CCR5 (-2135C/T) polymorphism with KD in Korean children.The study population consisted 189 Korean children with KD and 194 Korean children with congenital heart disease (CHD). CCR5 (-2135C/T) polymorphism genotypes were determined using the single-base extension method.The allele frequencies of the CCR5 (-2135C/T) polymorphism differed significantly between CHD children and KD children (-2135T/T, 16.75% vs. 30.05%, aOR 2.14, 95% CI 1.31-3.51). The tested laboratory parameters differed significantly between the KD and CHD groups. The development of coronary artery aneurysm in KD patients was not associated with the CCR5 polymorphism.Our findings suggest that the T allele at the CCR5 (-2135C/T) polymorphism might be associated with the development of KD in Korean children but does not appear to be associated with the development of coronary artery aneurysm.

Kawasaki disease (KD) is a multisystemic vasculitis that often includes coronary artery involvement. The serum levels of matrix metalloproteinase (MMP)-3 and -9 are significantly elevated in KD patients, and polymorphisms in the genes encoding MMP-3 and MMP-9 have been associated with the susceptibility, severity, and progression of atherosclerosis and aneurysm. However, the association between MMP-3 gene polymorphisms and development of aneurysm is somewhat controversial in a number of diseases. Ninety-seven children with KD and 194 children with congenital heart disease (CHD) were included in this study. Echocardiography was used to examine all children in the KD group for coronary artery aneurysm. Genotyping of the MMP-3 (-439C/G) promoter polymorphism was performed using the single-base extension method, and serum MMP-3 levels were estimated using the sandwich enzyme immunoassay method. There was no significant difference in MMP-3 (-439C/G) genotypes between KD and control groups. There was no association between this MMP-3 polymorphism and development of coronary aneurysm in KD. Serum MMP-3 levels were significantly higher in KD patients compared to control subjects. Among the KD patients, serum MMP-3 levels were higher in children with genotypes CG+GG compared to the CC group, but this difference was not significant. Although further large-scale studies will be required to fully examine the relationship between MMP-3 gene polymorphisms and coronary artery lesions (CAL) in KD, the present findings suggest that while MMP-3 may play a role in the pathogenesis of KD, there is no apparent association between CAL and the MMP-3 (-439C/G) gene polymorphism in Korean children with KD.

Kawasaki disease (KD) is an acute febrile vasculitic syndrome of unknown etiology that preferentially affects the coronary artery. Interleukin-10 (IL-10) is a key proinflammatory cytokine, and a polymorphism near the major transcriptional start site of the IL-10 gene was shown to influence IL-10 production in vitro. This study investigated the association of the IL-10 promoter polymorphism with KD and its clinical parameters in Korean children. A total of 194 children with congenital heart disease (CHD) and 95 children with KD were included in this study. IL-10 (-627 A/C) polymorphism genotypes were determined using the single-base extension method. There was no difference in the allele frequencies of IL-10 (-627 A/C) polymorphism between CHD children and KD children. KD children with one or two copies of the IL-10 (-627C) allele showed significantly lower albumin levels (p = 0.020) and higher frequencies of early coronary artery aneurysm [62.22% versus 37.78%, adjusted odds ratio (aOR) = 3.50, 95% confidence interval (CI): 1.50-8.16] compared with KD children with the common IL-10 (-627A) allele. These findings suggest that the IL-10 (-627 A/C) promoter polymorphism might be a genetic marker for the risk of early coronary artery complication in KD.

Background and Objectives Respiratory symptoms are often observed in children with Kawasaki disease (KD) during the acute phase. The association of respiratory viruses in children with KD was investigated using multiplex reverse transcriptase-polymerase chain reaction (RT-PCR) and tissue Doppler echocardiography. Subjects and Methods 138 KD patients were included from January 2010 to June 2013. We compared 3 groups (group 1: n=94, KD without respiratory symptoms; group 2: n=44, KD with respiratory symptoms; and group 3: n=50, febrile patients with respiratory symptoms). Laboratory data were obtained from each patient including N-terminal pro-brain natriuretic peptide (NT-proBNP). Echocardiographic measurements were compared between group 1 and group 2. RT-PCR was performed using nasopharyngeal secretion to screen for the presence of 14 viruses in groups 2 and 3. Results The incidence of KD with respiratory symptoms was 31.8%. The duration of fever was significantly longer, and coronary artery diameter was larger in group 2 than in group 1. Tei index was significantly higher and coronary artery diameter larger in group 2 than group 1. Coronary artery diameter, C-reactive protein levels, platelet count, alanine aminotransferase levels, and NT-pro BNP levels were significantly higher and albumin levels lower in group 2 compared with group 3. Conclusion NT-pro BNP was a valuable diagnostic tool in differentiating KD from other febrile viral respiratory infections. Some viruses were more frequently observed in KD patients than in febrile controls. Tei index using tissue Doppler imaging was increased in KD patients with respiratory symptoms.

In order to perform large-scale genetic studies of Kawasaki disease (KD) in Korea, the Korean Kawasaki Disease Genetics Consortium (KKDGC) was formed in 2008 with 10 hospitals. Since the establishment of KKDGC, there has been a collection of clinical data from a total of 1198 patients, and approximately 5 mL of blood samples per patient (for genomic deoxyribonucleic acid and plasma isolation), using a standard clinical data collection form and a nation-wide networking system for blood sample pick-up. In the clinical risk factor analysis using the collected clinical data of 478 KD patients, it was found that incomplete KD type, intravenous immunoglobulin (IVIG) non-responsiveness, and long febrile days are major risk factors for coronary artery lesions development, whereas low serum albumin concentration is an independent risk factor for IVIG non-responsiveness. In addition, we identified a KD susceptibility locus at 1p31, a coronary artery aneurysm locus (KCNN2 gene), and the causal variant in the C-reactive protein (CRP) promoter region, as determining the increased CRP levels in KD patients, by means of genome-wide association studies. Currently, this consortium is continually collecting more clinical data and genomic samples to identify the clinical and genetic risk factors via a single nucleotide polymorphism chip and exome sequencing, as well as collaborating with several international KD genetics teams. The consortium-based approach for genetic studies of KD in Korea will be a very effective way to understand the unknown etiology and causal mechanism of KD, which may be affected by multiple genes and environmental factors.

Polymorphism of angiotensin converting enzyme (ACE) gene is reported to be associated with ischemic heart disease, hypertrophic cardiomyopathy, and idiopathic dilated cardiomyopathy. In this study, we investigated the relationship between Kawasaki disease and insertion/deletion polymorphism of ACE gene. Fifty five Kawasaki disease patients and 43 healthy children were enrolled. ACE genotype was evaluated from each of the subjects' DNA fragments through polymerase chain reaction (PCR). Frequencies of ACE genotypes (DD, ID, II) were 12.7%, 60.0%, 27.3% in Kawasaki group, and 41.9%, 30.2%, 27.9% in control group respectively, indicating low rate of DD and high rate of ID genotype among Kawasaki patients (p

Purpose The incidence of Kawasaki disease (KD) is rare in young infants (less than 3 months of age), who present with only a few symptoms that fulfill the clinical diagnostic criteria. The diagnosis for KD can therefore be delayed, leading to a high risk of cardiac complications. We examined the clinical characteristics and measured the serum levels of N-terminal pro-brain natriuretic peptide (NT-proBNP) levels of these patients for assessing its value in the early detection of KD. Methods We retrospectively reviewed the data of young infants diagnosed with KD from 2004 to 2012. The control group included 20 hospitalized febrile patients. Laboratory data, including NT-proBNP were obtained for each patient in both groups. Results Incomplete KD was observed in 21/24 patients (87.5%). The mean fever duration on admission was 1.36±1.0 days in the KD group. Common symptoms included erythema at the site of Bacille Calmette-Guerin inoculation (70.8%), skin rash (50.0%), changes of oropharyngeal mucosa (29.1%), and cervical lymphadenopathy (20.8%). The mean number of major diagnostic criteria fulfilled was 2.8±1.4. Five KD patients (20.8%) had only one symptom matching these criteria. The incidence of coronary artery complications was 12.5%. The mean serum NT-proBNP level in the acute phase, in the KD and control groups, were 4,159±3,714 pg/mL and 957±902 pg/mL, respectively, which decreased significantly in the convalescent phase. Conclusion Incomplete KD was observed in 87.5% patients. Serum NT-proBNP might be a valuable biomarker for the early detection of KD in febrile infants aged

Background and Objectives We sought to determine whether high-dose aspirin is necessary for the acute therapy of Kawasaki disease (KD) in the intravenous immunoglobulin (IVIG) era. Subjects and Methods Two groups of KD patients treated during the different periods were included. Study group (n=51, treated with IVIG without concomitant use of aspirin in the acute phase) was compared with control group (n=129, treated with IVIG plus high-dose aspirin) with regard to the response to IVIG, duration of fever after IVIG completion, time to C-reactive protein (CRP)

Purpose This study investigated the epidemiology of Kawasaki disease (KD) in infants ≤3-month-old. Methods To study the epidemiology of KD in Korea, data for 27,851 KD patients were collected on a 3-year basis between 2000 and 2008 in a retrospective survey. From this, data for 609 KD patients ≤3-month-old were analyzed and compared with the data for KD patients >3-month-old. Results The 609 KD patients ≤3-month-old (385 males and 224 females) constituted 2.2% of the KD patients. They included 25 infants 2- and 3-months-old. The ratio of males to females was 1.72:1. The incidence of coronary artery (CA) dilatation (19.9% vs. 18.7%) and CA aneurysms (3.4% vs. 2.6%) detected by echocardiography did not differ significantly between patients with KD younger and older than 3-month-old. Conclusion Compared with the data for the KD patients >3-month-old, the data for the 609 patients ≤3-month-old did not show a significantly higher incidence of CA dilatation or CA aneurysms.

Purpose Kawasaki disease (KD) is the main cause of acquired heart disease in children. In addition to cardiovascular involvement, many complications have been recognized in KD. However, respiratory complications have been rarely reported. We investigated the differences in clinical characteristics, laboratory findings, radiography findings, and echocardiography findings of Mycoplasma pneumoniae infection and other types of pneumonia in KD patients. Methods Among 358 patients with KD, 54 developed concurrent pneumonia. Among the 54 patients, 12 (22.2%) with high titers of anti-M. pneumoniae antibody (AMA) (>1:640) were grouped in the M. pneumoniae group and 42 were included in the control group. Serum AMA was measured in each patient. Clinical laboratory findings and total duration of fever were analyzed. Results The duration of fever, serum hemoglobin, white blood cell count, platelet count, erythrocyte sedimentation rate, C-reactive protein level, albumin level, and the incidence of coronary arterial lesions showed no statistical difference in the 2 groups. Neutrophil count was significantly higher in the M. pneumoniae group than in the control group. Among various radiography findings observed in pneumonia, consolidation and pleural effusion were more frequent in the M. pneumoniae group than in the control group. On the other hand, parahilar peribronchial opacification, diffuse interstitial lesion, and normal findings prevailed in the control group. Conclusion KD patients can have concurrent infections, especially pulmonary symptoms. The cause of KD is likely to be associated with M. pneumoniae infection. Thus, immediate treatment of M. pneumoniae infection in KD patients is very important.

Background and Objectives The pathogenesis of hyponatremia (serum sodium

Although the clinical manifestations of cardiovascular disease (CVD), such as myocardial infarction, stroke, and peripheral vascular disease, appear from middle age, the process of atherosclerosis can begin early in childhood. The early stage and progression of atherosclerosis in youth are influenced by risk factors that include obesity, hypertension, dyslipidemia, and smoking, and by the presence of specific diseases, such as diabetes mellitus and Kawasaki disease (KD). The existing evidence indicates that primary prevention of atherosclerotic disease should begin in childhood. Identification of children at risk for atherosclerosis may allow early intervention to decrease the atherosclerotic process, thereby preventing or delaying CVD. This review will describe the origin and progression of atherosclerosis in childhood, and the identification and management of known risk factors for atherosclerotic CVD in children and young adults.