Development Of Coronary Artery Lesions Research Articles

Clinical significance of serum soluble TNF receptor II level and soluble TNF receptor II/I ratio as indicators of coronary artery lesion development in Kawasaki disease

To investigate the clinical significance of serum soluble tumor necrosis factor receptor (sTNFR) II level and sTNFR II/I ratio as indicators of the development of coronary artery lesions (CALs) in Kawasaki disease (KD), we measured levels of serum sTNFR I and II, interleukin (IL)-6, IL-18, and neopterin in 63 patients with KD, including nine patients with CALs and 20 healthy controls. At the time of diagnosis of KD before intravenous immunoglobulin (IVIG) treatment, serum sTNFR I and II levels were found to be significantly higher in non-responders to IVIG treatment than in responders. On the contrary, serum sTNFR II levels and sTNFR II/I ratio were significantly higher in patients with KD having CALs than in those without CALs. Longitudinal observation in a patient with KD who is unresponsive to IVIG revealed sustained elevation of serum sTNFR II level, and elevated sTNFR II/I ratio was linked to the CALs development. Increase in serum sTNFR II level and elevated sTNFR II/I ratio may be promising indicators of the development of CALs in KD.

Calcineurin inhibitors exacerbate coronary arteritis via the MyD88 signalling pathway in a murine model of Kawasaki disease.

Calcineurin inhibitors (CNIs) have been used off-label for the treatment of refractory Kawasaki disease (KD). However, it remains unknown whether CNIs show protective effects against the development of coronary artery lesions in KD patients. To investigate the effects of CNIs on coronary arteries and the mechanisms of their actions on coronary arteritis in a mouse model of KD, we performed experiments with FK565, a ligand of nucleotide-binding oligomerization domain-containing protein 1 (NOD1) in wild-type, severe combined immunodeficiency (SCID), caspase-associated recruitment domain 9 (CARD9)-/- and myeloid differentiation primary response gene 88 (MyD88)-/- mice. We also performed in-vitro studies with vascular and monocytic cells and vascular tissues. A histopathological analysis showed that both cyclosporin A and tacrolimus exacerbated the NOD1-mediated coronary arteritis in a dose-dependent manner. Cyclosporin A induced the exacerbation of coronary arteritis in mice only in high doses, while tacrolimus exacerbated it within the therapeutic range in humans. Similar effects were obtained in SCID and CARD9-/- mice but not in MyD88-/- mice. CNIs enhanced the expression of adhesion molecules by endothelial cells and the cytokine secretion by monocytic cells in our KD model. These data indicated that both vascular and monocytic cells were involved in the exacerbation of coronary arteritis. Activation of MyD88-dependent inflammatory signals in both vascular cells and macrophages appears to contribute to their adverse effects. Particular attention should be paid to the development of coronary artery lesions when using CNIs to treat refractory KD.

Retrospective analysis of risk factors associated with Kawasaki disease in China.

In order to provide early intervention for coronary artery lesion (CAL) caused by Kawasaki Disease (KD), we analyzed clinical characteristics of typical and incomplete KD cases from 1998 to 2008 in Northwest and Central China. A total of 383 patients included 298 cases of typical KD and 85 cases of incomplete KD. The morbidity of incomplete KD was 28.5%, a percentage significantly lower than that of typical KD. The occurrence of bulbar conjunctiva congestion, erythra, crissum red, film-like decrustation, lip red, rhagades, raspberry tongue, bilateral toe-end decrustation, limb sclerosis, cervical lymph nodes enlargement, agitation and irritability in incomplete KD group was lower than that in the group of typical KD (p < 0.05); however, the occurrence of unilateral toe-end decrustation, scar reappearance erythema, malaise, fatigue, liver incidence was significant higher in incomplete KD group (p < 0.05). Based on lab assays and inspection index comparisons, the incomplete KD cases whose C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) were significantly increased, had significantly higher reduction in blood platelet (PLT). Interestingly, the KD patients with CPR higher than 30 mg/L, ESR higher than 40 mm/h, hepatomegaly and IVIG ineffectiveness, had higher incidence of CAL development. Altogether, our data have indicated differential clinical characteristics between incomplete KD and typical KD, and have identified several high risk factors of KD for CAL, such as hepatomegaly.

Expression of Fc < gamma > Rs on monocytes among Kawasaki disease patients with coronary artery lesions

ObjectiveTo study expression of Fc gamma receptors (Fc<gamma>Rs) on monocytes in Kawasaki disease (KD) patients with coronary artery lesions (CAL). Methods160 newly diagnosed KD patients and 80 health children were enrolled in this study. All patients were scheduled to receive both aspirin and intravenous immunoglobulin (IVIG). Serial blood samples were obtained before and 3days after completing IVIG therapy. The first two-dimensional echocardiographic examination was performed for all KD patients within 10days, and was repeated at 3weeks. CAL was defined by coronary artery Z-scores≥2.5 by echocardiography. Expression of inhibitory and activating Fc<gamma>Rs on CD14+ monocytes (MCs) was assessed by flow cytometry. Cytokine expression in MC was evaluated by PCR. ResultsOf the 160KD patients enrolled in this study, 36 had coronary artery lesions (KD-CAL+ group), while 124 did not (KD-CAL− group). There was no significant difference in Fc<gamma>RI expression on MCs from KD patients and that of Ctrls. Although Fc<gamma>RIII and Fc<gamma>RIIa levels were significantly higher in KD patients compared with those in Ctrls, there were no significant differences between the KD-CAL+ and KD-CAL− groups. Fc<gamma>RIIb expression in the KD patients was lower than that of Ctrls, meanwhile expression in the KD-CAL+ group was lower than that in the KD-CAL− group. After IVIG therapy, Fc<gamma>RIIb expression increased in KD-CAL+, but did not reach the normal range. A negative correlation was observed between the levels of IL-6, TNF-α and Fc<gamma>RIIb expression. ConclusionDecreased Fc<gamma>RIIb expression on MCs may contribute to the development of coronary artery lesions in patients with KD.

Relationship between IL-27 and coronary arterial lesions in children with Kawasaki disease.

Kawasaki disease (KD) arises due to the disorder of the inflammation response and faulty immune regulation. Interleukin-27 (IL-27) is a novel cytokine with both pro-inflammatory and anti-inflammatory effects. This study investigated the relationship between serum levels of IL-27, Interleukin-17A (IL-17A), Interleukin-10 (IL-10), Interleukin-6 (IL-6), Interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α) and coronary artery lesions (CALs) in patients with KD. We obtained blood samples from 81 children with KD before intravenous immunoglobulin (IVIG) therapy. Levels of IL-27, IL-17A, IL-10, IL-6, IL-1β and TNF-α were measured in 251 cases, including 4 groups: the normal control group, NC (n=90), febrile control, FC (n=80), KD without coronary arteries (n=41) and KD with coronary arterial lesions (n=40). White blood cells counts (WBC), red blood cells counts (RBC), hemoglobin, C-reactive protein (CRP), erythrocyte sedimentation rate and procalcitonin (PCT) were tested in all subjects. Levels of IL-27, IL-10, IL-17A, IL-6, IL-1β and TNF-α were significantly elevated, and RBC and hemoglobin significantly decreased in the group of KD group compared with febrile and control groups. IL-27, IL-6, IL-1β and TNF-α serum levels are even higher in KD children with CALs. There was positive relationship between serum levels of IL-27 and WBC, CRP, PCT, IL-10, IL-17A, IL-6 and TNF-α in children with KD. The up-regulation of IL-27 may be closely linked to up-regulation of systemic pro-inflammatory markers in acute KD. Morover, IL-27 may be involved in the development of CALs in acute KD.

Association of PECAM-1 Gene Polymorphisms with Kawasaki Disease in Chinese Children.

Kawasaki disease (KD) is an acute systemic vasculitis complicated by development of coronary artery lesions. PECAM-1 is a kind of cell adhesion molecule, which plays an important role in coronary artery disease. The relationship between PECAM-1 gene polymorphisms and their susceptibility to Kawasaki diseases (KD) is still unclear. In our study, we examined the PECAM-1 gene polymorphisms in 44 KD patients and 59 healthy children and revealed the correlation of PECAM-1 gene polymorphisms in KD children with and without coronary artery lesions (CAL).

Association of Toll-like receptor 2-positive monocytes with coronary artery lesions and treatment nonresponse in Kawasaki disease.

PurposeActivation of Toll-like receptor 2 (TLR2) present on circulating monocytes in patients with Kawasaki disease (KD) can lead to the production of proinflammatory cytokines and interleukin-10 (IL-10). We aimed to determine the association of the frequency of circulating TLR2+/CD14+ monocytes (FTLR2%) with the outcomes of KD, as well as to compare FTLR2% to the usefulness of sIL-10.MethodsThe FTLR2% in patients with KD was measured by flow cytometry. Serum levels of IL-10 (sIL-10) were determined in 31 patients with KD before the initial treatment with intravenous immunoglobulin (IVIG) and in 21 febrile controls by using enzyme-linked immunosorbent assay. Patients were classified as having coronary artery lesions (CALs) based on the maximal internal diameters of the proximal right coronary artery and proximal left anterior descending coronary artery one month after the initial diagnosis.ResultsWe found that FTLR2% greater than 92.62% predicted CALs with 80% sensitivity and 68.4% specificity, whereas FTLR2% more than 94.61% predicted IVIG resistance with 66.7% sensitivity and 71.4% specificity. Moreover, sIL-10 more than 15.52 pg/mL predicted CALs and IVIG resistance with 40% and 66.7% sensitivity, respectively, and 73.7% and 76.2% specificity, respectively.ConclusionWe showed that measuring FTLR2% before the initial treatment could be useful in predicting CAL development with better sensitivity than sIL-10 and with results comparable to sIL-10 results for the prediction of IVIG resistance in patients with KD. However, further studies are necessary to validate FTLR2% as a marker of prognosis and severity of KD.

A Study of the Association between Enabled Homolog Gene Polymorphisms and Kawasaki Disease in Korean Children

Objective: The etiology of the Kawasaki disease (KD) remains unknown despite of extensive studies but infection, immunity, and genetics were suggested as causes. There have been attempted to link susceptibility to KD to allelic variations to search related gene. The enabled homolog (Enah) gene on the human chromosome 1q42.12 encodes enabled/vasodilator-stimulated phosphoprotein (Ena/VASP). Ena/VASP is a regulator of actin cytoskeleton, exists in cytoplasm, and maintains homeostasis such as immune response, blood vessel preservation, and hemostasis. The aim of this study was to investigate polymorphisms of the Enah gene as a risk factor for KD and coronary artery lesions (CALs) as a complication. Methods: In the Enah gene region, 15 single nucleotide polymorphisms (SNPs) were selected using human SNP websites (http://www.hapmap.org/, genome build). Three hundred and six healthy controls and 106 KD subjects were recruited. SNP genotyping was performed using the Golden Gate assay on an Illumina BeadStation 500 GX (Illumina Inc., San Diego, CA, USA). Frequencies of allele were obtained and the genetic association between of the Enah gene polymorphisms and susceptibility to KD and CALs was analyzed by SNPstats, Haploview software ver. 4.1 (Broad Institute, Cambridge, MA, USA). Multiple logistic regression analysis with adjustment for gender was performed. Results: One SNP (rs1891000) among total fifteen SNPs was associated with KD. Moreover, we found a significant association between rs487591, rs576861, rs7555139, rs10799319, and the development of CALs in KD patients. Conclusion: These results suggest that the polymorphism of Enah gene may be associated with the occurrence of KD and development of CALs as a complication. Key words: Mucocutaneous lymph node syndrome; Coronary artery; Enah protein; Single nucleotide polymorphism

Prediction of nonresponsiveness to medium-dose intravenous immunoglobulin (1 g/kg) treatment: an effective and safe schedule of acute treatment for Kawasaki disease.

PurposeMedium-dose (1 g/kg) intravenous immunoglobulin (IVIG) is effective in the majority of patients with Kawasaki disease (KD) but some patients who do not respond to medium-dose IVIG are at high risk for the development of coronary artery lesions (CALs). The purpose of this study was to identify the clinical predictors associated with unresponsiveness to medium-dose IVIG and the development of CALs.MethodsA retrospective study was performed in 91 children with KD who were treated with medium-dose IVIG at our institution from January 2004 to December 2013. We classified the patients into responders (group 1; n=68) and nonresponders (group 2; n=23). We compared demographic, laboratory, and echocardiographic data between the 2 groups.ResultsMultivariate logistic regression analysis identified 6 variables as predictors for resistance to medium-dose IVIG. We generated a predictive scoring system assigning 1 point each for percentage of neutrophils ≥65%, C-reactive protein≥100 mg/L, aspartate aminotransferase≥100 IU/L, and alanine aminotransferase≥100 IU/L, as well as 2 points for less than 5 days of illness, and serum sodium level≤136 mmol/L. Using a cutoff point of ≥4 with this scoring system, we could predict nonresponsiveness to medium-dose IVIG with 74% sensitivity and 71% specificity.ConclusionIf a patient has a low-risk score in this system, medium-dose IVIG can be recommended as the initial treatment. Through this process, we can minimize the adverse effects of high-dose IVIG and incidence of CALs.

Clinical outcome of patients with refractory Kawasaki disease based on treatment modalities.

PurposeAlthough a significant number of reports on new therapeutic options for refractory Kawasaki disease (KD) such as steroid, infliximab, or repeated intravenous immunoglobulin (IVIG) are available, their effectiveness in reducing the prevalence of coronary artery lesions (CAL) remains controversial. This study aimed to define the clinical characteristics of patients with refractory KD and to assess the effects of adjuvant therapy on patient outcomes.MethodsWe performed a retrospective study of 38 refractory KD patients from January 2012 to March 2015. We divided these patients into 2 groups: group 1 received more than 3 IVIG administration+ steroid therapy, (n=7, 18.4%), and group 2 patients were unresponsive to initial IVIG and required steroid therapy or second IVIG (n=31, 81.6%). We compared the clinical manifestations, laboratory results, and echocardiographic findings between the groups and examined the clinical utility of additional therapies in both groups.ResultsA significant difference was found in the total duration of fever between the groups (13.0±4.04 days in group 1 vs. 8.87±2.30 days in group 2; P=0.035). At the end of the follow-up, all cases in group 1 showed suppressed CAL. In group 2, coronary artery aneurysm occurred in 2 patients (6.4 %). All the patients treated with intravenous corticosteroids without additional IVIG developed CALs including coronary artery aneurysms.ConclusionNo statistical difference was found in the development of CAL between the groups. Prospective, randomized, clinical studies are needed to elucidate the effects of adjunctive therapy in refractory KD patients.

Predictive factors of resistance to intravenous immunoglobulin and coronary artery lesions in Kawasaki disease.

PurposeWe conducted a study to determine which factors may be useful as predictive markers in identifying Kawasaki disease (KD) patients with a high risk of resistance to intravenous immunoglobulin (IVIG) and developing coronary artery lesions (CAL).MethodsWe enrolled 287 patients in acute phase of KD at a single center. The demographic, clinical and laboratory data were collected retrospectively.ResultsThere were 34 patients in the IVIG resistant group. The IVIG resistant group had significantly higher serum N-terminal-pro-brain natriuretic protein (NT-proBNP) levels (P<0.01) and polymorphonuclear neutrophil (PMN) percentage (P<0.01) in comparison to the IVIG responders. The results yielded sensitivity (78.8%, 60.6%), specificity (58.2%, 90%) and cutoff value (628.6 pg/mL, 80.3%) of NT-proBNP and PMN respectively, in predicting IVIG resistance. Despite IVIG administration, 13 of the 287 patients developed CAL. The patients in the CAL group had higher NT-proBNP levels (P<0.01) and higher PMN percentage (P<0.01). In these patients, the results yielded sensitivity (73.3%, 56.7%), specificity (67.9%, 88.9%) and cutoff value (853.4 pg/mL, 80.3%) of NT-proBNP and PMN respectively, for predicting CAL. The area under the curve (AUC) for predicting resistance to IVIG was NT-proBNP 0.712, PMN 0.802. The AUC for predicting CAL was NT-proBNP 0.739, and PMN 0.773.ConclusionSerum NT-proBNP levels and PMN percentage were significantly elevated in patients with KD with IVIG resistance and CAL. Thus, they may be useful predicting markers for IVIG resistance and development of CAL in KD patients.

Age-adjusted plasma N-terminal pro-brain natriuretic peptide level in Kawasaki disease.

PurposeRecent reports showed that plasma N-terminal pro-brain natriuretic peptide (NT-proBNP) could be a useful biomarker of intravenous immunoglobulin (IVIG) unresponsiveness and coronary artery lesion (CAL) development in Kawasaki disease (KD). The levels of these peptides are critically influenced by age; hence, the normal range and upper limits for infants and children are different. We performed an age-adjusted analysis of plasma NT-proBNP level to validate its clinical use in the diagnosis of KD.MethodsThe data of 131 patients with KD were retrospectively analyzed. The patients were divided into 2 groups—group I (high NT-proBNP group) and group II (normal NT-proBNP group)—comprising patients with NT-proBNP concentrations higher and lower than the 95th percentile of the reference value, respectively. We compared the laboratory data, responsiveness to IVIG, and the risk of CAL in both groups.ResultsGroup I showed significantly higher white blood cell count, absolute neutrophil count, C-reactive protein level, aspartate aminotransferase level, and troponin-I level than group II (P<0.05). The risk of CAL was also significantly higher in group I (odds ratio, 5.78; P=0.012). IVIG unresponsiveness in group I was three times that in group II (odds ratio, 3.35; P= 0.005).ConclusionAge-adjusted analysis of plasma NT-proBNP level could be helpful in predicting IVIG unresponsiveness and risk of CAL development in patients with KD.

Epidemiologic Features of Kawasaki Disease in Shanghai From 2008 Through 2012.

This study was to investigate the epidemiologic trends of Kawasaki disease (KD) and coronary arterial lesions (CALs) in Shanghai from 2008 through 2012. Data were collected by using the network of the KD research group established during the first survey in Shanghai to conduct the third survey, covering the period from 2008 through 2012. Clinical records of 2304 patients with acute KD were retrospectively reviewed. Epidemiologic features of KD were investigated. Univariate and multivariate analyses were performed to identify the risk factors for CAL in patients with KD. The data were compared with the previous 2 surveys covering the periods from 1998 to 2002 and 2003 to 2007, respectively. The average incidence of KD was 30.3 to 71.9 per 100,000 children aged 0-4 years from 2008 through 2012. Age at onset ranged from 32 days to 11.7 years (median: 2.3 years). The occurrence of KD was more common in summer and spring. A total of 365 (15.9%) cases developed CAL defined as ectasia or aneurysm. Male, age ≤ 1 year, intravenous immunoglobulin (IVIG) unresponsiveness, a smaller administrative dosage and the delayed administration of IVIG (>10 days) were independent risk factors for CAL. The occurrence of CAL seemed less frequent in patients who received IVIG within 5 days after onset of illness. The incidence of KD in children has increased over time, and the development of CAL decreased in the past 5 years in Shanghai. Earlier treatment with IVIG (<5 days) was associated with reduced CAL among patients with KD.

Development of coronary artery lesions in indolent kawasaki disease following initial spontaneous defervescence: a retrospective cohort study

BackgroundNo standard treatment protocol exists for Kawasaki disease (KD) after spontaneous defervescence that does not use intravenous immunoglobulin (IVIG). Moreover, some cases present an indolent course and later develop coronary artery lesions (CALs). We aimed herein to assess the short-term prognosis of KD after defervescence and to clarify the characteristics of indolent KD.Study designThe present report is the culmination of a 10-year retrospective cohort study of KD at two Japanese tertiary pediatric centers. Cases of spontaneously defervesced KD ≤ 7 days of illness without IVIG which were afebrile for ≥ 3 days were classified as ‘defervesced KD’ (dKD). Of these, cases which developed CALs, or received IVIG for ongoing systemic inflammation were sub-classified into the indolent KD group (iKD). The primary outcome was the prevalence of CALs.ResultsAmong 968 KD patients, 7.3 % (71/968) fell into the dKD, and 11.2 % (8/71) into the iKD, groups. No difference in CAL prevalence was observed between the dKD group and the KD group treated with IVIG (9.9 % vs. 7.6 %, p value = 0.49). Six of the 8 iKD cases developed CALs between Days 11 and 23 (median 16) of illness. All iKD cases presented recurrent fever or re-elevated CRP; however, there were generally fewer persistent KD symptoms than at diagnosis.ConclusionsThe prognosis of spontaneously defervesced KD was relatively benign. However, indolent cases with ongoing, systemic inflammation developed CALs. In some cases, immediate IVIG use can be withheld as long as recurrent fever and re-elevation of CRP are monitored and supplementary echocardiogram are conducted.

Hyponatremia May Reflect Severe Inflammation in Children with Kawasaki Disease

Purpose: The aim of the present study was to investigate the risk factors for the development of coronary artery lesions (CALs) and to determine whether hyponatremia is associated with CALs in children with Kawasaki disease (KD). Methods: We retrospectively analyzed the data of 105 children with KD who were admitted to Ilsan Hospital between January 2000 and July 2011. Results: Erythrocyte sedimentation rate (P = 0.013), total bilirubin levels (P = 0.017) were higher and serum sodium levels (P = 0.027) were lower in KD children with CALs than those without. White blood cell (WBC) counts (P = 0.006), neutrophil counts (P = 0.003) were higher and albumin levels (P = 0.009) were lower in KD children with hyponatremia than those without. On multiple logistic regression analysis, hyponatremia (P = 0.024) and intravenous immunoglobulin–resistance (P = 0.024) were independent risk factors for CALs in KD. Furthermore, serum sodium levels were correlated negatively with WBC counts (P = 0.004), neutrophil counts (P < 0.001), total bilirubin levels (P = 0.005) and positively with albumin levels (P = 0.009). Conclusion: Our study indicates that hyponatremia may reflect severe inflammation in children with KD. Key words: Kawasaki disease; hyponatremia; inflammation; cardiovascular abnormalities

Genetic epistasis between killer immunoglobulin-like receptors and human leukocyte antigens in Kawasaki disease susceptibility.

Kawasaki disease (KD) is a pediatric acute multisystemic vasculitis complicated by development of coronary artery lesions. The breakthrough theory on KD etiopathogenesis points to pathogens/environmental factors triggered by northeastern wind coming from China. Natural Killer cells and T lymphocytes express the inhibitory/activating Killer Immunoglobulin-like Receptors (KIR) to elicit an immune response against pathogens by binding to human leukocyte antigens (HLA) class I epitopes. We first report on the role of KIR/HLA genetic epistasis in a sample of 100 Italian KD children. We genotyped KIR, HLA-A, HLA-B and HLA-C polymorphisms, and compared KD data with those from 270 Italian healthy donors. The HLA-A*11 ligand for KIR2DS2/2DS4/3DL2 was a KD susceptibility marker by itself (odds ratio (OR)=3.85, confidence interval (CI)=1.55-9.53, P=0.004). Although no epistasis between HLA-A*11 and KIR2DS2/S4 emerged, HLA-A*11 also engages KIR3DL2, a framework gene encoding for a pathogen sensor of CpG-oligodeoxynucleotides (CpG-ODN), and KD blood mononuclear cells are actually prone to pathogen CpG-ODN activation in the acute phase. Moreover, carriers of KIR2DS2/HLA-C1 and KIR2DL2/HLA-C1 were more frequent among KD, in keeping with data demonstrating the involvement of these HLA/KIR couples in autoimmune endothelial damage. The highest KD risk factor was observed among carriers of KIR2DL2 and two or more HLA ligands (OR=10.24, CI=1.87-56.28; P=0.007).

Abstract 35: Common Variants in the CRP Promoter are Associated with a High C-reactive Protein Level in Kawasaki Disease

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 (Hb), aspartate aminotransferase (AST), alanine aminotransferase (ALT), albumin, and total protein. A total of 165 loci passed our arbitrary stage 1 threshold for replication ( p &lt; 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 &lt; 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.

Abstract 204: Risk factors for development of coronary artery aneurysms in Kawasaki disease in Mexican Children

Background: Kawasaki Disease (KD) is an acute febrile illness characterized by systemic vasculitis of unknown etiology. Cardiac sequelae, such as coronary artery aneurysms (CAA), are one of the most important aspects of this disease. Actually, it is the major cause of acquired heart disease in developed countries but its frequency in Mexico is still unknown. Objective: To establish the risk factors for development of coronary artery lesions in children with KD who were treated at the Instituto Nacional de Pediatria in Mexico City. Material and Methods: An observational, comparative, retrospective case-control study of all patients diagnosed with KD in our Institution from August 1995 to May 2014. We reviewed the medical records and analyzed gender, age, weight, height, clinical manifestations, time from the onset of the symptoms to diagnosis, hemoglobin, leucocyte count, platelet count, ESR, C-RP, albumin, sodium, AST ASL, treatment used and the development of coronary artery aneurysms. Results: We studied 384 cases of KD, 68% were male with a mean age at diagnosis of 39.02 ± 36.55 months. The mean duration of fever from the onset of the symptoms to diagnosis was 9.4 ± 5.79. An incomplete form of KD was diagnosed in 69 patients (19.4%). 150 patients developed CAA (39%). Multivariate analysis for CAA showed that younger age (p &lt; 0.028) prolonged time to diagnosis (p &lt; 0.001), central nervous system manifestations (p &lt; 0.008) anemia (p &lt; 0.001) leukocytosis (p &lt; 0.005), thrombocytosis (p &lt; 0.041) and elevated C-RP (p &lt; 0.022) were the most important risk factors for development of CAA in our patients. Conclusions: This is the largest series of KD in Mexico, with more cases diagnosed in recent years, so it appear that the disease is more common than initially thought. Also, the frequency of CAA is greater than the reported in the literature, but it appears that is related to a delayed diagnosis and treatment.

Abstract 217: Difference of Coronary Artery Lesions or associated Pathogens between the Two Phenotypes of Kawasaki Disease

Introduction: There are several reports that coronary artery lesions (CALs) are increased/or not increased in patients who predominantly showed arthritis in patients with Kawasaki disease (KD). Patients with eczematoid skin lesions which seem like atopic dermatitis have not been reported in association with CALs. We intended to evaluate the risk of development of CALs in patients with two different phenotypes. Materials and methods: We retrospectively reviewed the medical records in 220 patients who diagnosed as KD and received IVIG treatment in Kyung Hee University Hospital at Gangdong from August 2006 to December 2013. In both patients groups (6 patients with arthritis and 52 patients with eczematoid skin lesion), we reviewed the state of coronary artery, clinical characteristics, associated viral or bacterial infections. Results: In patients with eczematoid lesions (52/220, 23.6%), the ages of patients were significantly older, the duration of fever was longer, and the prevalence of CAL was significantly higher than that of controls ( P =.000, P =.041, P =.033, respectively). In patients with arthritis (6/220, 3%), there were higher incidence of methylprednisolone or infliximab therapy ( P =.000, P =.004, respectively), and higher incidence of viral infection like influenza A and B, rhinovirus, parainfluenza 2, metapneumovirus, and coronavirus OC43 ( P =.018). Conclusions: The incidence of CAL was higher in group of eczematoid skin lesion in KD patients than in group of patients with arthritis. Associated viral infections were higher in arthritis group, therefore, it is better to find associated pathogens aggressively that might be a certain trigger of the development of KD in this group of patients.

Abstract 65: T cell Differentiation in Human Kawasaki Disease and a Murine Model of Coronary Arteritis

The role of T cell differentiation in the immunopathogenesis of Kawasaki disease (KD) remains unclear. The aim of this study is to elucidate the role of T cell subsets in coronary artery lesion (CAL) of KD. Peripheral blood was obtained in 10 patients with acute KD before and 1 week after intravenous gamma-immunoglobulin (IVIG) treatment and in 20 patients with past history of KD for more than 5~20 years. Meanwhile, induction of coronary arteritis was performed on wild type BALB/c mice by Lactobacillus casei cell wall extract (LCWE). Human peripheral blood leukocytes were analyzed by using flow cytometric analysis and murine hearts were examined for immunofluorescence study and for RNA expression levels. Results: Compared to the febrile controls, KD patients prior to IVIG treatment had increased percentage of CD3 + /CD4 + /interferon-γ + (T helper 1, Th1) cells and CD3 + /CD4 + /interleukin-17A + (Th17) cells (mean ± SD, 1.36% ± 1.39% and 0.51% ± 0.25%, respectively) among Th cells (CD3 + /CD4 + ). Both increases declined after IVIG treatment (0.71% ± 0.74% and 0.33% ± 0.18%) despite no statistically difference by Mann-Whitney test. None of these 10 acute KD patients developed CAL after IVIG treatment. However, patients with previous KD and definite CALs (n= 11) seemed to have higher percentage of Th17 cells (0.50% ± .025% versus 0.35% ± 0.23%) but similar level of Th1 cells (0.93% ± 0.51% versus 1.05% ± 0.64%) when compared to those without CAL (n= 9). Murine cardiac tissues displayed the presence of Th1 (double-stained with CD3 and T-bet) and Th17 cells (double-stained with CD3 and RORγt) during days 7 and 14 after LCWE treatment but not in PBS-treated mice. Compatible with these, cardiac mRNA levels showed both increased levels of IFN-γ and IL17A mRNA in LCWE-treated mice. Conclusions: Our initial data suggests that specific T cell differentiation into Th1 and Th17 cells occurred in both human KD and mice stimulated with LCWE. IVIG treatment was associated with the recovery of such T cell differentiation. However, the clinical application to predict IVIG responsiveness and future CAL development by such increase in the peripheral Th17 remains unclear. Further studies to elucidate the detailed immune regulation of these T subsets on CAL are warrant by using this LCWE murine model.