Kyung Lim Yoon

Infliximab Treatment for Refractory Kawasaki Disease in Korean Children

Background and Objectives This was a multicenter study to evaluate the usefulness of the tumor necrosis factor-alpha (TNF-α) blocker infliximab for treatment of Korean pediatric patients with refractory Kawasaki disease (KD). Subjects and Methods Data from 16 patients throughout Korea who were diagnosed with refractory KD and received infliximab were collected retrospectively. Results Complete response to therapy with cessation of fever occurred in 13 of 16 patients. C-reactive protein (CRP) concentrations decreased following infliximab infusion in all 14 patients in whom it was measured before and after treatment. There were no infusion reactions or complications associated with infliximab except in 1 case with acute hepatitis occurring during treatment followed by calculous cholecystitis 4 months later. Fifteen patients had coronary artery (CA) abnormalities before infliximab therapy. Three had transient mild dilatation and 9 had CA aneurysms, with subsequent normalization in 4 patients, persistent mild dilatation in 3, persistent aneurysm in 2, and there were 3 cases (2 with CA aneurysm, 1 with mild CA dilatation) without follow-up echocardiography. Conclusion The results of this study suggest that infliximab may be useful in the treatment of refractory KD, and it appears that there is no significant further progression of CA lesions developing after infliximab treatment. Multicenter trials with larger numbers of patients and long-term follow-up are necessary to assess the clinical efficacy and safety of infliximab in refractory KD.

Risk Factors for Failure of Initial Intravenous Immunoglobulin Treatment in Kawasaki Disease

The aims of this study were to determine the occurrence and variables associated with the initial intravenous immunoglobulin (IVIG) treatment failure in Kawasaki disease (KD) and to categorize differences in clinical characteristics between responders and nonresponders to initial IVIG treatment. Patients were classified into two groups. Group A included 33 patients who received a single dose of IVIG treatment and responded. Group B included 18 patients who received more than two doses of IVIG due to failure of the initial treatment. The mean duration of fever after initial treatment in group B was significantly longer than it was in group A. In group B, we found that higher bilirubin, aspartate aminotransferase (AST), polymorphonuclear cells (PMN) (%), and lower platelet values at baseline were independent predictors of persistent or recurrent fever in patients with KD. Coronary artery abnormalities were found in 8 patients (44.4%) in group B and in two patients (6.1%) in group A. We found that abnormal liver function tests and a lower platelet count at baseline were possible predictors of nonresponders to IVIG in patients with KD. There is a need for a prospective study focused on baseline hepatobiliary parameters.

Two cases of female hydrocele of the canal of nuck

The processus vaginalis within the inguinal canal forms the canal of Nuck, which is a homolog of the processus vaginalis in women. Incomplete obliteration of the processus vaginalis causes indirect inguinal hernia or hydrocele of the canal of Nuck, a very rare condition in women. Here, we report 2 cases of hydrocele of the canal of Nuck that were diagnosed with ultrasonography in both cases and magnetic resonance imaging in 1 case to confirm the sonographic diagnosis. High ligation and hydrocelectomy were conducted in both patients. In 1 patient, 14 months later, the occurrence of contralateral inguinal hernia was suspected, but did not require surgery. The other patient had a history of surgery for left inguinal hernia 11 months before the occurrence of right hydrocele of the canal of Nuck. In both cases, the occurrence of an inguinal hernia on the contralateral side was noted.

Epidemiology and Clinical Features of Kawasaki Disease in South Korea, 2012–2014

Background: To reveal the recent epidemiologic features of Kawasaki disease (KD) in South Korea based on data from a nationwide survey. Methods: We collected data between 2012 and 2014 regarding the incidence, symptoms and signs, treatment trends and coronary complications associated with acute KD by sending questionnaires to 97 hospitals with pediatric residency programs as well as 19 community hospitals without residency training. Results: We received full and partial data from 97 and 13 hospitals, respectively (response rate: 94.8%). A total of 14,916 cases of KD were reported by these 110 hospitals (4588 in 2012, 5183 in 2013 and 5145 in 2014). The male-to-female ratio was 1.4:1, and the median age at diagnosis was 29 months. The incidence of KD per 100,000 children younger than 5 years of age were 170.9, 194.9 and 194.7 in 2012, 2013 and 2014, respectively. The recurrence rate was 4.7%. KD occurred more frequently during summer (especially June and July) and winter (December and January) seasons. Intravenous immunoglobulin was administered to 95.4% of the patients, and the nonresponder rate for the first intravenous immunoglobulin was 11.8%. Coronary aneurysm occurred in 1.7% of the patients, and giant aneurysm developed in 19 patients (0.16%) during the 3 years. One patient had myocardial infarction and 1 patient died of suspected coronary aneurysm rupture. Conclusions: The incidence of KD in South Korea increased to 194.7 per 100,000 children younger than 5 years in 2014; meanwhile, the coronary aneurysm rate decreased to 1.7%.

Transforming growth factor beta receptor II polymorphisms are associated with Kawasaki disease

Purpose Transforming growth factor beta receptor 2 (TGFBR2) is a tumor suppressor gene that plays a role in the differentiation of striated cells and remodeling of coronary arteries. Single nucleotide polymorphisms (SNPs) of this gene are associated with Marfan syndrome and sudden death in patients with coronary artery disease. Cardiovascular remodeling and T cell activation of TGFBR2 gene suggest that the TGFBR2 gene SNPs are related to the pathogenesis of Kawasaki disease (KD) and coronary artery lesion (CAL). Methods The subjects were 105 patients with KD and 500 healthy adults as controls. Mean age of KD group was 32 months age and 26.6% of those had CAL. We selected TGFBR2 gene SNPs from serum and performed direct sequencing. Results The sequences of the eleven SNPs in the TGFBR2 gene were compared between the KD group and controls. Three SNPs (rs1495592, rs6550004, rs795430) were associated with development of KD (P=0.019, P=0.026, P=0.016, respectively). One SNP (rs1495592) was associated with CAL in KD group (P=0.022). Conclusion Eleven SNPs in TGFBR2 gene were identified at that time the genome wide association. But, with the change of the data base, only six SNPs remained associated with the TGFBR2 gene. One of the six SNPs (rs6550004) was associated with development of KD. One SNP associated with CAL (rs1495592) was disassociated from the TGFBR2 gene. The other five SNPs were not functionally identified, but these SNPs are notable because the data base is changing. Further studies involving larger group of patients with KD are needed.

Medium- or Higher-Dose Acetylsalicylic Acid for Acute Kawasaki Disease and Patient Outcomes

Objective To investigate the effect of medium‐ or higher‐dose acetylsalicylic acid (ASA) for treating acute‐phase Kawasaki disease to prevent coronary artery aneurysm (CAA). Study design Among the children with acute Kawasaki disease investigated in the eighth nationwide survey in the Republic of Korea, 8456 children with adequate data were included in this study. The subjects were divided into 2 groups according to the use of medium‐ or higher‐dose ASA (≥30 mg/kg/day), or‐low dose ASA (3‐5 mg/kg/day) during the acute febrile phase. Both z‐ score–based criteria and Japanese criteria for CAA were used. Results The prevalence of CAA based on z‐score (24.8% vs 18.3%; P = .001) and on the Japanese criteria (19.0% vs 10.4%; P < .001) was higher in the 7947 patients who received medium‐ or higher‐dose ASA compared with the 509 patients who received low‐dose ASA. The use of medium‐ or higher‐dose ASA was a significant predictor of CAA based on both sets of criteria by univariate analysis (based on z‐score: OR, 1.472, 95% CI, 1.169‐1.854, P = .001; based on Japanese criteria: OR, 2.013, 95% CI, 1.507‐2.690, P < .001) and multivariate logistic regression analysis (OR, 1.527, 95% CI, 1.166‐2.0, P = .003 and OR, 2.198, 95% CI, 1.563‐3.092, P < .001, respectively). Conclusions The use of medium‐ or higher‐dose ASA in acute Kawasaki disease did not prevent CAA. A future randomized controlled trial is needed to determine the optimum dose of ASA.

Involvement of tryptophan hydroxylase 2 (TPH2) gene polymorphisms in susceptibility to coronary artery lesions in Korean children with Kawasaki disease.

Kawasaki disease (KD) is an acute vasculitis of childhood that predominantly affects the coronary arteries. We investigated single nucleotide polymorphisms (SNPs) of the tryptophan hydroxylase 2 (TPH2) gene as risk factors for KD with coronary artery lesions (CALs) in Korean children. We genotyped two SNPs [rs7305115 (exon 7) and rs4290270 (exon 9)] using direct sequencing in 101 KD and 256 control subjects. To analyze the genetic data, SNPStats, SNPAnalyzer, and Helixtree programs were used. The genotype analysis of rs7305115 and rs4290270 showed no significant differences between KD and control groups. However, we found a statistically significant association between the two SNPs and the development of CALs in KD (p < 0.05). The minor homozygous genotype (rs7305115, AA genotype and rs42901270, AA genotype) of each SNP showed increased susceptibility to risk of CALs in KD patients. These results suggest that TPH2 may be associated with the development of KD with CALs in Korean children.

Consortium-Based Genetic Studies of Kawasaki Disease in Korea: Korean Kawasaki Disease Genetics Consortium

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

Association of Polymorphisms in the Vitamin D Receptor Promoter with Idiopathic Short Stature

The genetic alterations of vitamin D receptor (VDR) are related with the growth of long bone. There were a lot of reports regarding an association of polymorphisms in the VDR promoter with many disorders, but not with idiopathic short stature (ISS). We investigated the association of them with ISS. A total of 50 subjects, including 29 ISS patients and 21 healthy controls with their heights within the normal range was recruited. We selected two single nucleotide polymorphisms (SNPs) from VDR promoter (rs11568820 at the Cdx-2 binding site upstream of exon 1e and rs4516035 at -1012 upstream of exon 1a) as candidates, respectively. In genotype analysis, the frequency of A/A genotype at the Cdx-2 binding site locus (rs11568820) upstream of exon 1e of VDR was decreased to 6.9% in ISS patients (28.6% in controls) (P = 0.027). The genetic variation at the Cdx-2 binding site of VDR promoter can be a contributing factor of growth of height.

Coding Single-Nucleotide Polymorphisms of Interleukin-1 Gene Cluster Are Not Associated with Kawasaki Disease in the Korean Population

This study aimed to examine whether coding single-nucleotide polymorphisms (cSNPs) of the interleukin-1 gene cluster [interleukin-1-alpha (IL1α), IL1β, IL-1-receptor antagonist (IL1RN)] are genetic markers of susceptibility to Kawasaki disease (KD) in the Korean population. The study enrolled 109 KD patients and 287 healthy control subjects. Four cSNPs [rs17561 (Ala114Ser) of IL1α, rs1143634 (Phe105Phe) of IL1β, and rs419598 (Ala23Ala) and rs315952 (Ser96Ser) of IL1RN] were genotyped using the restriction fragment-length polymorphism (RFLP) and direct sequencing. The KD patients were divided into two groups according to the presence of coronary artery lesions (CALs). For genetic analysis, SNPStats, HapAnalyzer, Helixtree, and SNPAnalyzer were used. The allele and genotype frequencies of the IL1 gene cluster polymorphisms in the KD patients had a pattern similar to that in the control subjects. Furthermore, no association was observed between four cSNPs of the IL1 gene cluster and the development of CALs in KD. These results suggest that the IL1 gene cluster may not be associated with susceptibility to KD and the development of CALs in the Korean population.