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.

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.

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.