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Initial intravenous immunoglobulin (IVIG)-refractory status and prolonged fever are established risk factors for the development of coronary artery abnormalities (CAAs) among patients with acute-phase Kawasaki disease (KD). However, whether different risk factors exist for initial unresponsiveness to IVIG and CAA development remains unclear.To evaluate whether different risk factors exist for initial unresponsiveness to IVIG and CAA development among patients with KD (stratified by age at disease onset).This retrospective cohort study included a consecutive sample of 2414 patients from a database of patients with KD from October 1, 1999, to September 30, 2019. The data were based on annual surveys (response rate, 100%) using hospital medical records across Wakayama Prefecture, Japan. Data were analyzed from March 6 to March 26, 2022.The patient's age and diagnosis of KD by board-certified pediatricians using the criteria established by the Japan KD Research Committee.Initial unresponsiveness to IVIG, defined as treatment with optional or advanced therapies, and development of CAAs. Echocardiograms performed 1 month after KD onset using the Japanese Ministry of Health criteria evaluated the presence or absence of CAAs. Odds ratios (ORs) with 95% CIs of patient age at KD onset for unresponsiveness to IVIG and developing CAAs were calculated using multivariable logistic regression models.A total of 2414 patients (1403 male patients [58.1%]; median age at onset of KD, 25 months [range, 1-212 months]) were included in the study: 550 younger than 12 months, 1342 aged 12 to 47 months, and 522 older than 47 months. A total of 535 patients (22.2%) received optional or advanced treatment and 68 patients (2.8%) developed CAAs 1 month after disease onset. The sex-adjusted OR among patients younger than 12 months for unresponsiveness to IVIG was 0.77 (95% CI, 0.59-0.99) and for development of CAAs was 1.94 (95% CI, 1.07-3.52); among those older than 47 months, the OR for unresponsiveness to IVIG was 1.32 (95% CI, 1.05-1.67) and for development of CAAs was 2.47 (95% CI, 1.39-4.39). After adjusting for IVIG administration, ORs among boys older than 47 months for unresponsiveness to IVIG was 1.14 (95% CI, 0.84-1.56) and for development of CAAs was 2.15 (95% CI, 1.08-4.30); among girls younger than 12 months, the OR for unresponsiveness to IVIG was 1.02 (95% CI, 0.65-1.60) and for development of CAAs was 3.79 (95% CI, 1.21-11.90).The results of this study suggest that risks of unresponsiveness to IVIG and the development of CAAs differ between infants with KD and older patients with KD. Residual risk factors for KD-related CAAs other than initial unresponsiveness to IVIG should be addressed, particularly in infants.

Background: Epidemiological studies show a U-shaped tendency in Kawasaki disease (KD)-related coronary artery abnormalities (CAAs) across age categories. Since studies suggest seasonal variations in KD onset, this study aimed to clarify the epidemiologic features of CAAs, considering the seasons of KD-occurrence. Methods: We analyzed 2,106 (males = 1,215, females = 891) consecutive KD cases from October 1999 through September 2017 using our electronic database of annual surveys, targeting all hospitals with pediatric departments across Wakayama, Japan. The primary outcome was the presence/absence of CAAs measured by echocardiography 1 month after KD onset. Odds ratios (ORs) and 95% confidence intervals (CIs) of combined patient age and sex for CAAs were calculated using logistic regression models adjusted for four seasons. Results: The median age was 25 (range, 1–212) months. The proportion of males decreased with increasing age. The youngest age group (1.0) in KD-occurrence. CAAs were observed in 2.8% of cases (males = 3.4%, females = 2.1%), which significantly lessened in summer than in other seasons. Moreover, 50% (n = 4/8) of cases with giant aneurysms experienced KD in autumn. Adjusted ORs for CAAs among males aged ≥60 months (3.0; 95%, CI 1.2–7.5) and females aged

Background Coronary artery aneurysm (CAA) is an important complication of Kawasaki disease (KD) that is associated with arterial structure damage. However, few studies have examined structural changes in coronary arteries that are not associated with CAA. Methods We examined coronary arteries in KD patients with CAAs who underwent follow-up coronary angiography (CAG) and optical coherence tomography (OCT). Coronary arterial branches with no abnormal findings during the most recent CAG were classified into two groups. Arteries with an acute-phase CAA that later regressed were classified as group R; arteries with no abnormal findings on either acute or convalescent phase CAG were classified as group N. Coronary arterial wall structural changes were compared between groups using OCT. Results Fifty-seven coronary arterial branches in 23 patients were evaluated by OCT. Thirty-six branches showed no abnormality during the most recent CAG. Both groups R and N comprised 18 branches. Maximum intimal thicknesses in groups R and N were 475 and 355 µm, respectively (p = 0.007). The incidences of media disruption were 100% and 67%, respectively (p = 0.02). Calcification, macrophage accumulation, and thrombus were not found in either group. Conclusions Intimal thickening and disruption of the media occur in coronary arteries with acute phase CAAs that later regress in the convalescent phase, as well as in arteries with normal CAG findings in the acute and convalescent phases.

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

Kawasaki disease (KD) is an acute systemic vasculitis occurring in medium-sized arteries, especially coronary arteries. Patients with KD who fail to respond to standard therapy with intravenous immunoglobulin (IVIG) face a higher risk of developing coronary artery lesions. Cyclosporin A (CsA) is one treatment option for IVIG-resistant KD. However, the mechanism of its suppression of inflammation in patients with KD remains unknown.We analyzed time-line profiles of multiple inflammatory cytokines in sera of 19 patients treated with CsA (4 mg/kg/day, p.o., 14 days) after additional IVIG. Trough concentration of CsA in blood was maintained between 60 and 200 ng/ml. We examined serum samples before, on day 7, and at the end (day 14) of CsA treatment. Assays were conducted using a Milliplex kit®. Fourteen patients responded to CsA and became afebrile within 5 days (Responders), although five patients were regarded as Non-responders. Serum transitional levels of IL-6 (p0.001), sIL-2R (p0.001), sTNFRII (p0.001), and G-CSF (p0.001) reflect disease severity. In Non-responders, average levels of IL-6 at day 7 (43.5 vs. 13.8 pg/ml, p0.001) and average levels of sIL-2R at day 14 (21.3 vs. 3.31 pg/ml, p=0.014) were significantly higher than those in Responders.CsA treatment effectively reduced the persisting serum inflammatory cytokines in most of the IVIG-resistant KD patients. Soluble IL-2R suppression implies a mechanism explaining the effects of CsA.

We performed a genome-wide association study (GWAS) of Kawasaki disease in Japanese subjects using data from 428 individuals with Kawasaki disease (cases) and 3,379 controls genotyped at 473,803 SNPs. We validated the association results in two independent replication panels totaling 754 cases and 947 controls. We observed significant associations in the FAM167A-BLK region at 8p22-23 (rs2254546, P = 8.2 × 10(-21)), in the human leukocyte antigen (HLA) region at 6p21.3 (rs2857151, P = 4.6 × 10(-11)) and in the CD40 region at 20q13 (rs4813003, P = 4.8 × 10(-8)). We also replicated the association of a functional SNP of FCGR2A (rs1801274, P = 1.6 × 10(-6)) identified in a recently reported GWAS of Kawasaki disease. Our findings provide new insights into the pathogenesis and pathophysiology of Kawasaki disease.

Functional single-nucleotide polymorphisms (SNPs) in inositol 1,4,5-trisphosphate 3-kinase C (ITPKC) (rs28493229) and caspase-3 (CASP3) (rs113420705; formerly rs72689236) are associated with susceptibility to Kawasaki's disease (KD). To evaluate the involvement of these 2 SNPs in the risk for intravenous immunoglobulin (IVIG) unresponsiveness, we investigated 204 Japanese KD patients who received a single IVIG dose of 2 g kg(-1) (n=70) or 1 g kg(-1) daily for 2 days (n=134). The susceptibility allele of both SNPs showed a trend of overrepresentation in IVIG non-responders and, in combined analysis of these SNPs, patients with at least 1 susceptible allele at both loci had a higher risk for IVIG unresponsiveness (P=0.0014). In 335 prospectively collected KD patients who were treated with IVIG (2 g kg(-1)), this 2-locus model showed a more significant association with resistance to initial and additional IVIG (P=0.011) compared with individual SNPs. We observed a significant association when all KD patients with coronary artery lesions were analyzed with the 2-locus model (P=0.0031). Our findings strongly suggest the existence of genetic factors affecting patients' responses to treatment and the risk for cardiac complications, and provide clues toward understanding the pathophysiology of KD inflammation.

Background: The aim of this study was to investigate whether T-cell activation is involved in the pathogenesis of Kawasaki disease (KD) resistant to intravenous immunoglobulin (IVIG) treatment. Methods: Serum samples were obtained from 27 patients who fulfilled the diagnostic criteria for KD. These 27 patients were divided into three groups according to their responses to IVIG: Group A, nine patients who showed no response to either initial IVIG or additional IVIG; Group B, six patients who did not respond to initial IVIG but did respond to additional IVIG; Group C, 12 patients who responded to initial IVIG. Serum samples were obtained before and after initial IVIG. Using a commercial chemiluminescence enzyme immunoassay, we examined the serum levels of two cytokines related to T-cell activation and the severity of inflammation: soluble interleukin-2 receptor and interleukin-6. Results: There were no significant differences in the serum levels of the two cytokines before initial IVIG among the three groups, but significant intergroup differences were evident after initial IVIG in the serum levels of soluble interleukin-2 receptor (P C) and interleukin-6 (P B > C). Conclusions: Our results show that marker of T-cell activation is elevated most markedly in KD patients resistant to both initial and additional IVIG, and suggest that T cells may be activated in refractory KD.

Kawasaki disease (KD; OMIM 611775) is an acute vasculitis syndrome which predominantly affects small- and medium-sized arteries of infants and children. Epidemiological data suggest that host genetics underlie the disease pathogenesis. Here we report that multiple variants in the caspase-3 gene (CASP3) that are in linkage disequilibrium confer susceptibility to KD in both Japanese and US subjects of European ancestry. We found that a G to A substitution of one commonly associated SNP located in the 5' untranslated region of CASP3 (rs72689236; P = 4.2 x 10(-8) in the Japanese and P = 3.7 x 10(-3) in the European Americans) abolished binding of nuclear factor of activated T cells to the DNA sequence surrounding the SNP. Our findings suggest that altered CASP3 expression in immune effecter cells influences susceptibility to KD.

Objectives To investigate whether superantigens (SAgs) are involved in the development of Kawasaki disease (KD) by examining SAg genes in the stool of patients with KD. Study design Stool specimens were obtained from 60 patients with KD and 62 age-matched children (36 children with acute illness and 26 healthy children). Total DNA was extracted from these stool samples. Using polymerase chain reaction, we examined genes of 5 SAgs: streptococcal pyrogenic exotoxin-A (SPE-A), SPE-C, SPE-G, SPE-J, and toxic shock syndrome toxin-1. Results At least 1 of the 5 SAg genes was detected in 42 (70%) specimens from patients with KD, 14 (38.9%) from the febrile group, and 7 (26.9%) from the healthy group. The detection rate between subjects with and without KD was of at least 1 of the 5 SAg genes ( P P = .002). Conclusions SAg may be involved in the development of KD; data suggest that multiple SAgs may trigger KD.

Kawasaki disease (KD; MIM#61175) is a systemic vasculitis syndrome with unknown etiology which predominantly affects infants and children. Recent findings of susceptibility genes for KD suggest possible involvement of the Ca(2+)/NFAT pathway in the pathogenesis of KD. ORAI1 is a Ca(2+) release activated Ca(2+) (CRAC) channel mediating store-operated Ca(2+) entry (SOCE) on the plasma membrane. The gene for ORAI1 is located in chromosome 12q24 where a positive linkage signal was observed in our previous affected sib-pair study of KD. A common non-synonymous single nucleotide polymorphism located within exon 2 of ORAI1 (rs3741596) was significantly associated with KD (P = 0.028 in the discovery sample set (729 KD cases and 1,315 controls), P = 0.0056 in the replication sample set (1,813 KD cases vs. 1,097 controls) and P = 0.00041 in a meta-analysis by the Mantel-Haenszel method). Interestingly, frequency of the risk allele of rs3741596 is more than 20 times higher in Japanese compared to Europeans. We also found a rare 6 base-pair in-frame insertion variant associated with KD (rs141919534; 2,544 KD cases vs. 2,414 controls, P = 0.012). These data indicate that ORAI1 gene variations are associated with KD and may suggest the potential importance of the Ca(2+)/NFAT pathway in the pathogenesis of this disorder.

Background: We have reported that cyclosporin A (CsA) therapy may be a promising and safe option for patients with Kawasaki disease (KD) resistant to initial and additional intravenous immunoglobulin (IVIG). Up to now, it has been considered that CsA exerts effects on the intracellular phosphatase calcineurin, and subsequently inhibits activation of nuclear factor of activated T cells (NFAT). However, the functional mechanism of CsA therapy in KD patients has remained unclear. Methods: The KD patients enrolled in this study were treated with CsA between April 2012 and December 2013. In accordance with our treatment protocol, KD patients are initially treated with IVIG and aspirin. If there is no response, a further course of IVIG is given, and if there is no response to this additional IVIG, the patients are treated with CsA. Peripheral blood samples were obtained just before and after the initial course of IVIG, additional IVIG, and CsA therapy. To evaluate the NFAT pathway and activation of the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway, we examined the gene expression of cytokines and intracellular signal transducers using real-time RT-PCR and phospho-STAT3 (pSTAT3) and STAT5 (pSTAT5) using flow cytometry. Results: Thirty-six KD patients were divided into three groups: responsive to initial IVIG (n=19), responsive to additional IVIG (n=7), and treated with CsA group (n=10). In the CsA group, expression of mRNAs for interleukin (IL)-2, NFATc1 and NFATc2 was significantly increased, whereas the mean fluorescence intensity (MFI) of pSTAT3 (CD3+ T cell) and pSTAT3 (CD16b+ granulocyte) was decreased after CsA treatment. In the group responsive to initial IVIG, the expression of mRNAs for IL-2, IL-6, NFATc1 and NFATc2 was significantly increased, whereas that for STAT3, 5A, 5B was decreased after IVIG treatment; on the other hand, the MFI of pSTAT3 (CD3+ T cell) and pSTAT3 (CD16b+ granulocyte) was decreased, and that of pSTAT5 (CD16b+ granulocyte) was increased, after IVIG. Conclusion: In patients with refractory KD, CsA exerts effects on the activity of the NFAT and JAK-STAT pathways. However, our results suggest that in patients with immunoglobulin-resistant KD, CsA may act through a mechanism other than the NFAT pathway.

Background: About 10-20% of patients with Kawasaki Disease (KD) who fail to respond to IVIG, show a high prevalence of CAL. The new guideline (2012) has proposed several options for second- and third-line therapy for patients resistant to IVIG. However, there are still no definite treatment options for refractory KD. We have reported that cyclosporin A (CsA) is a well tolerated, safe and promising option for patients resistant to IVIG. However, certain subgroups of such patients may also be resistant to CsA. In this study, we examined if a third course IVIG might be effective for patients resistant to CsA. Patients and Methods: Between April 2008 and May 2014, 42 Japanese patients who met the diagnostic criteria for KD and received CsA treatment were enrolled as study subjects. All patients were resistant to both initial (2 g/kg for 24 hours) and additional IVIG, and were then administered CsA orally (Neoral[[Unable to Display Character: Ⓡ]], oral solution, Novartis Pharma Co. Ltd., Tokyo, Japan). The initial dose of CsA was 4mg/kg/day, and it was divided into two equal daily doses every 12 hours. The dose of CsA was adjusted to between 4 and 8 mg/kg/day to maintain a trough level of 60-200 ng/ml by reference to clinical and laboratory data such as body temperature and C-reactive protein level. After the start of CsA treatment, if patients remained febrile for more than 5 days, or if fever returned after an afebrile period within 5 days, CsA treatment was judged to be ineffective, and the patients were then given a third course of IVIG. We analyzed some laboratory data between CsA effective group and CsA resistant group. Results: CsA treatment was judged to be ineffective in 14 of 42 (33%) patients. Eleven of those 14 patients received a third IVIG, and then, 8 (72.7%) patients of them became afebrile within 24hours. The other three patients became afebrile after a fourth IVIG. The serum levels of AST and soluble interleukin-2 receptor before the start of CsA treatment were significantly lower in CsA effective group than in CsA resistant group. Conclusion: A third course of IVIG is an effective option for KD patients who are resistant to CsA .

Objectives: Optical coherence tomography (OCT) is an intracoronary arterial imaging modality employing near-infrared light to create images. OCT makes it possible to distinguish the three layers of the coronary arterial wall. However, few previous studies have used OCT to evaluate coronary arterial lesions (CAL) in Kawasaki disease (KD). Here we report the use of OCT to evaluate CALs in KD. Patients and Methods: Fifteen patients aged between 11 and 29 years were admitted to undergo coronary angiography (CAG) for follow-up of KD. The male : female ratio was 11:4. Their ages at disease onset and when OCT was performed were 1m - 10y11m (median; 1y2m), and 11y1m - 29y3m (median; 16y2m), respectively. The interval between disease onset and OCT examination was 5y1m - 24y4m (median; 13y2m). Repeated CAG was performed on the basis of the criteria stipulated in the guidelines for cardiovascular sequelae in KD (JCS 2008). At the time of the latest CAG, we performed not only regular CAG but also IVUS and OCT (C7 OCT imaging system, St Jude Medical, St. Paul, MN, USA) for coronary arteries between December 2012 and August 2014. Results: We demonstrated fresh thrombus, stenosis, fibrotic intimal thickening with lamellar calcification and partial disappearance of the tunica media in CAL. Fibrotic intimal thickening and disruption of the tunica media are demonstrated in all patients. In addition, OCT demonstrated intimal thickening and disruption of the tunica media in completely regressed lesions and even in regions where CAG had shown normal coronary arterial walls in the acute phase. Conclusions: Our data suggest that fibrotic intimal thickening and disruption of the tunica media may be basic changes of coronary arterial sequelae in KD. The use of OCT for evaluation of KD vasculitis may clarify the mechanisms responsible for coronary arterial sequelae and be useful for prognostication of CAL.

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

The association between functional polymorphism of inositol 1,4,5-trisphosphate 3- kinase-C(ITPKC) and susceptibility to Kawasaki disease(KD) and formation of coronary arterial lesions was reported in 2008. Since ITPKC acts as a negative regulator of T-cell activation, activated T cells may play a pivotal role in the pathogenesis of KD. Cyclosporin A(CsA), which potently suppresses the activity of T cells through negative regulation of the nuclear factor of activated T cells(NFAT) pathway, may be a promising candidate for the treatment of refractory KD. In this review, we summarize the results of our clinical trials of CsA for refractory KD, the changes in the levels of cytokines before and after CsA treatment, and the future direction of CsA treatment for refractory KD.

Despite intravenous immunoglobulin therapy, a certain percentage of patients with Kawasaki disease (KD) still develop coronary arterial lesions (CAL). In an effort to find new combined therapies to reduce the incidence of CAL, we focused on the oedema which can be an important sign of the increased vascular permeability in KD. A total of 127 patients with KD were included in the retrospective study. Serial weekly changes in serum sodium and albumin levels from the 1st to the 4th week of illness were examined. In addition, the maximum rate of increase in body weight from admission to the 14th day of illness was evaluated. Serum sodium levels (mEq/l) in only the 2nd week of illness were significantly lower in patients with CAL than in those without CAL (mean ± SD, 135.5±4.5 versus 138.0±2.4, P

Background To clarify the contribution of patient age to the development of coronary artery lesions (CALs) associated with Kawasaki disease (KD), epidemiologic features and prognostic factors were investigated using hospital-based complete enumeration surveys in a specific area. Methods Consecutive KD cases identified between October 1999 and September 2012 in Wakayama Prefecture, Japan, were analyzed. The primary outcome measure was the presence/absence of CALs (giant aneurysm, mid- or small-sized aneurysm, and dilatation) on echocardiography 1 month after disease onset. Demographics and medical treatment factors were compared between the patients with and without CALs. Odds ratios (ORs) and 95% confidence intervals (CIs) of explanatory variables (age, gender, and factors related to high-dose intravenous immunoglobulin treatment) for the development of CALs were determined. Results The median age of the 1415 patients (796 males, 619 females) was 25 months after excluding 2 children of foreign residents; 2.2% of the patients had a past history of KD, and 1.8% showed incomplete presentation. CALs were observed in 3.3% (4.0% of males, 2.3% of females; P = 0.080). The ORs of CALs among patients 48 months old (3.1, 95% CI 1.5–6.6) were significantly higher than values in 11- to 48-month-olds. Conclusions The effect of patient age on the development of CALs was found to be U-shaped, with the bottom at ages 11 to 48 months. This finding was based on a 13-year cohort of consecutive KD cases in a specific area with little selection bias and is consistent with previously reported results.

There are still no definite treatments for refractory Kawasaki disease (KD). In this pilot study, we evaluated the use of cyclosporin A (CyA) treatment in patients with refractory KD.We prospectively collected clinical data of CyA treatment (4-8 mg/kg/d, oral administration) for refractory KD patients using the same protocol among several hospitals. Refractory KD is defined as the persistence or recurrence of fever (37.5°C or more of an axillary temperature) at the end of the second intravenous immunoglobulin (2 g/kg) following the initial one.Subjects were enrolled out of 329 KD patients who were admitted to our 8 hospitals between January 2008 and June 2010. Among a total of 28 patients of refractory KD treated with CyA, 18 (64.3%) responded promptly to be afebrile within 3 days and had decreased C-reactive protein levels, the other 4 became afebrile within 4 to 5 days. However, 6 patients (21.4%) failed to become afebrile within 5 days after the start of CyA and/or high fever returned after becoming afebrile within 5 days. Although hyperkalemia developed in 9 patients at 3 to 7 days after the start of CyA treatment, there were no serious adverse effects such as arrhythmias. Four patients (1.2%), 2 before and the other 2 after the start of CyA treatment, developed coronary arterial lesions.CyA treatment is considered safe and well tolerated, and a promising option for patients with refractory KD. Further investigations will be needed to clarify optimal dose, safety, and timing of CyA treatment.

The aim of this study was to investigate whether T-cell activation is involved in the pathogenesis of Kawasaki disease (KD) resistant to intravenous immunoglobulin (IVIG) treatment.Serum samples were obtained from 27 patients who fulfilled the diagnostic criteria for KD. These 27 patients were divided into three groups according to their responses to IVIG: Group A, nine patients who showed no response to either initial IVIG or additional IVIG; Group B, six patients who did not respond to initial IVIG but did respond to additional IVIG; Group C, 12 patients who responded to initial IVIG. Serum samples were obtained before and after initial IVIG. Using a commercial chemiluminescence enzyme immunoassay, we examined the serum levels of two cytokines related to T-cell activation and the severity of inflammation: soluble interleukin-2 receptor and interleukin-6.There were no significant differences in the serum levels of the two cytokines before initial IVIG among the three groups, but significant intergroup differences were evident after initial IVIG in the serum levels of soluble interleukin-2 receptor (P0.01, Group AC) and interleukin-6 (P0.01, Group ABC).Our results show that marker of T-cell activation is elevated most markedly in KD patients resistant to both initial and additional IVIG, and suggest that T cells may be activated in refractory KD.

The aetiology and pathogenesis of Kawasaki disease (KD) remain unknown. To investigate the pathogenesis of vasculitis in KD, we tested for the presence of auto-antibodies against a component of vascular smooth muscle cells in the sera of patients with KD. Sera from 48 patients with KD, as well as sera from 14 sick children and from 22 healthy children, were examined for reactivity to both coronary arterial wall tissues and cultured smooth muscle cells (CSMC) derived from human coronary artery, using immunofluorescence and Western immunoblot assay techniques. Sera from 16 of 48 patients with KD gave positive immunoreactions to the vascular walls of coronary artery with fluorescein isothiocyanate-labelled rabbit anti-human IgA antibodies. In Western immunoblot assays, the sera from 15 of 34 and 10 of 31 patients with KD showed positive reactions against a 70 kDa protein from CSMC with IgA and IgM antibodies, respectively. Positive immunoreactivity of sera from patients with KD, determined either by immunofluorescence studies or by Western immunoblotting, was detected more frequently (P

I) T cell receptor (TCR) usage We investigated TCR usage and antibody responses to streptococcal pyrogenic exotoxin-C (SPE-C) in order to determine whether an association exists between SPE-C and the onset of Kawasaki disease (KD). Patients and Method Fifty-four patients with KD were studied. Analysis of TCR usage was performed by adaptor-ligation PCR and microplate hybridization assay. Serum levels of antibody against SPE-C were assessed by ELISA using purified recombinant protein. Results Forty (74.1%) of the patients with KD showed significant polyclonal activation of Vβ2- and/or Vβ-6.5-bearing T cells. In 22 of 35 paired patients with KD, serum levels of anti-SPE-C antibodies (IgM) in the convalescent phase were lower than those in the acute phase. II) Detection of autoantibodies against vascular smooth muscle cells To investigate the pathogenesis of vasculitis in KD, we tested for the presence of autoantibodies against vascular smooth muscle cells in the patients. Patients and Methods Sera from 48 patients with KD were examined for reactivity with both coronary arterial wall tissues and cultured smooth muscle cells (CSMC) derived from human coronary artery, using immunofluorescence and Western immunoblotting. Results Sera from 16 of 48 patients with KD gave positive immunoreactions with the smooth muscle cells of coronary artery with anti-human IgA antibodies. Western immunoblotting revealed positive reactions of sera from 15 of 34 and 10 of 31 patients with KD against a 70-kDa protein from CSMC with IgA and IgM antibodies, respectively. Positive immunoreactivity of sera from KD patients was detected more frequently in patients with coronary arterial lesions (CAL) than in those without CAL (p

It is now clear that a high-dose intravenous immunoglobulin therapy (IVIG) in patients with Kawasaki disease (KD) is effective for reducing the incidence of coronary arterial lesions (CAL). But both the total dose and the dose regimens of IVIG are still controversial.In this study, we report two cases with CAL in KD. These two cases were treated with aspirin (30mg/kg/day) and a single high-dose IVIG (1g/kg/day) on 5th day of illness. IVIG reduced their body temperature immediately to less than 37.5°C on 6th day of illness, so we did not add IVIG. Although they did not get high fever, and both the counts of white blood cells and the levels of C-reactive protein decreased after IVIG, their coronary arteries dilated gradually. In one case, the diameter of anterior descending branch of left coronary dilated to 4.0mm. In the other case, that of left main coronary artery dilated to 5.8mm. We confirmed these changes regressed to normal by either 2DE or selective coronary angiography after three months of onset. These cases suggest that a single high-dose IVIG (1g/kg/day) can not prevent CAL in KD, even after good response to IVIG.