Vasa vasorum enhancement on optical coherence tomography in Kawasaki disease.

BACKGROUND: Patients with Kawasaki disease (KD) prone to develop coronary artery aneurysm (CAA) with unknown etiology. We aimed to disclose the relationship between vasa vasorum (VV) and intimal thickening using optical coherence tomography (OCT) in KD. METHODS: Forty-three coronary artery branches of 21 patients with KD were examined by OCT. The coronary arteries were classified into three groups: the CAA group (n = 9) in which CAAs remained since the acute phase, the regressed group (n = 16) in which CAAs were regressed, and the no CAA group (n = 18). The number and distribution of VV, and intimal thickening in coronary arteries were evaluated on OCT. RESULTS: Intimal thickening was significantly more severe in the CAA and regressed groups than in the no CAA group (median: 481, 474, and 218 µm, p = 0.001 and p < 0.001, respectively). The number of VV in the regressed group was significantly higher than that in the CAA and no CAA groups. The numbers of adventitial VV and internal VV were positively correlated with the intimal thickness (R = 0.64, p < 0.001; R = 0.62, p < 0.001, respectively). In the no CAA group, no internal VV were observed. CONCLUSIONS: VV enhances according to intimal thickening, suggesting that VV may have some link to the healing process, such as CAA regression and intimal thickening. IMPACT: Kawasaki disease (KD) is a vasculitis syndrome developing coronary artery aneurysm, however its etiology still remains unclear. Coronary artery imaging using optical coherence tomography (OCT) can reveal coronary arterial wall pathology, however OCT studies are limited in patients with KD. Using OCT, we disclosed the closed relationship between vasa vasorum enhancement and regressed coronary arterial lesions. Vasa vasorum enhancement is involved in the pathomechanism of the convalescent phase of KD.

Analysis of Age, Sex, Lack of Response to Intravenous Immunoglobulin, and Development of Coronary Artery Abnormalities in Children With Kawasaki Disease in Japan.

Importance: 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. Objective: 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). Design, Setting, and Participants: 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. Exposures: The patient's age and diagnosis of KD by board-certified pediatricians using the criteria established by the Japan KD Research Committee. Main Outcomes and Measures: 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. Results: 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). Conclusions and Relevance: 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.

Intimal thickening and disruption of the media occur in the arterial walls of coronary arteries not associated with coronary arterial aneurysms in patients with Kawasaki disease.

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.

Z-score is a possible predictor of the risk of coronary artery lesion development in patients with Kawasaki disease in Japan.

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.

Seasonal Variation in Epidemiology of Kawasaki Disease-Related Coronary Artery Abnormalities in Japan, 1999-2017.

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 (<6 months) showed an inverse summer/autumn to winter/spring ratio (>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 <6 months (3.6; 95%, CI 1.1-11.8) were significantly higher than those among males aged 12-35 months. CONCLUSIONS: Cumulative 18-year data of consecutive KD cases from one area suggest the influence of interactions between patient age and sex on the development of KD-related CAAs. The season of KD-occurrence may reflect the diversity of agents.

Variations in ORAI1 Gene Associated with Kawasaki Disease.

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.

[Cyclosporin A treatment for refractory Kawasaki disease].

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.

Epidemiologic features and prognostic factors of coronary artery lesions associated with Kawasaki disease based on a 13-year cohort of consecutive cases identified by complete enumeration surveys in Wakayama, Japan.

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 <11 months old (3.0, 95% CI 1.4-6.6) and those >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.

Evaluation of coronary arterial lesions due to Kawasaki disease using optical coherence tomography.

Optical coherence tomography (OCT) is a high-resolution intracoronary arterial imaging modality. We describe 2 patients who were admitted to undergo coronary angiography and OCT for follow-up of Kawasaki disease with coronary artery aneurysms. OCT clearly demonstrated thrombus, stenosis, fibrotic intimal thickening with lamellar calcification, and partial disappearance of the tunica media at the aneurysm site. In addition, focal calcification, intimal thickening, and medial irregularity were observed even in regions of coronary arterial walls that appeared to be normal using coronary angiography. OCT is useful for evaluating coronary arterial sequelae of Kawasaki disease.

Inflammatory cytokine profiles during Cyclosporin treatment for immunoglobulin-resistant Kawasaki disease.

BACKGROUND: 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. METHODS AND RESULTS: 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 (p<0.001), sIL-2R (p<0.001), sTNFRII (p<0.001), and G-CSF (p<0.001) reflect disease severity. In Non-responders, average levels of IL-6 at day 7 (43.5 vs. 13.8 pg/ml, p<0.001) 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. CONCLUSION: 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.

A genome-wide association study identifies three new risk loci for Kawasaki disease.

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.

Cyclosporin A treatment for Kawasaki disease refractory to initial and additional intravenous immunoglobulin.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Marker of T-cell activation is elevated in refractory Kawasaki disease.

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 < 0.01, Group A > C) and interleukin-6 (P < 0.01, Group A > 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.

Common variants in CASP3 confer susceptibility to Kawasaki disease.

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.

Detection of multiple superantigen genes in stools of patients with Kawasaki disease.

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 < .001), and more than 2 SAg genes were significantly different (P = .002). CONCLUSIONS: SAg may be involved in the development of KD; data suggest that multiple SAgs may trigger KD.

Water retention in the acute phase of Kawasaki disease: relationship between oedema and the development of coronary arterial lesions.

UNLABELLED: 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<0.05). Serum albumin levels in all 4 weeks were significantly lower in patients with CAL than in those without CAL ( P<0.001). The maximum rate (%) of increase in body weight from admission to the 14th day of illness was significantly higher in patients with CAL than in those without CAL (ranges and median values, 0-12.3 (7.0) versus 0-10.3 (3.2), P<0.001). CONCLUSION: these results suggest that water retention in the acute phase of Kawasaki disease may be a risk factor for CAL, and water intake of both infusion and oral intake should be kept to a minimum in order to avoid progressive oedema.

Detection of auto-antibodies against a 70 kDa protein derived from vascular smooth muscle cells in patients with Kawasaki disease.

UNLABELLED: 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<0.05) and more intensely ( P<0.005) in patients with coronary arterial lesions (CAL) than in those without CAL. Positive immunoreactivity of sera was prominent before intravenous immunoglobulin therapy and decreased dramatically thereafter. CONCLUSION: these data suggest that auto-antibodies against a 70 kDa protein from vascular smooth muscle cells may cause coronary arteritis and systemic vasculitis in KD.