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Hiromichi Hamada,
Hiroyuki Suzuki,
Jun Abe,
Yoichi Suzuki,
Tomohiro Suenaga, Takashi Takeuchi,
Norishige Yoshikawa,
Shoichi Shibuta,
Masakazu Miyawaki,
Ko Oishi,
Hironobu Yamaga,
Noriyuki Aoyagi,
Seiji Iwahashi,
Ritsuko Miyashita,
Takafumi Honda,
Yoshihiro Onouchi,
Masaru Terai,
Akira Hata
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ABSTRACT: 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 (4mg/kg/day, p.o., 14days) after additional IVIG. Trough concentration of CsA in blood was maintained between 60 and 200ng/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 5days (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. 13.8pg/ml, p<0.001) and average levels of sIL-2R at day 14 (21.3 vs. 3.31pg/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.
Cytokine 08/2012; · 3.02 Impact Factor
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Yoshihiro Onouchi,
Kouichi Ozaki,
Jane C Burns,
Chisato Shimizu,
Masaru Terai,
Hiromichi Hamada,
Takafumi Honda,
Hiroyuki Suzuki,
Tomohiro Suenaga, Takashi Takeuchi, [......],
Ritsuko Miyashita,
Yuji Murata,
Kumiko Sasago,
Atsushi Takahashi,
Naoyuki Kamatani,
Michiaki Kubo,
Tatsuhiko Tsunoda,
Akira Hata,
Yusuke Nakamura,
Toshihiro Tanaka
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ABSTRACT: 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.
Nature Genetics 03/2012; 44(5):517-21. · 35.53 Impact Factor
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Hiroyuki Suzuki,
Masaru Terai,
Hiromichi Hamada,
Takafumi Honda,
Tomohiro Suenaga, Takashi Takeuchi,
Norishige Yoshikawa,
Shoichi Shibuta,
Masakazu Miyawaki,
Ko Oishi,
Hironobu Yamaga,
Noriyuki Aoyagi,
Seiji Iwahashi,
Ritsuko Miyashita,
Yoshihiro Onouchi,
Kumiko Sasago,
Yoichi Suzuki,
Akira Hata
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ABSTRACT: 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 Pediatric Infectious Disease Journal 05/2011; 30(10):871-6. · 3.58 Impact Factor
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Heart and Vessels 10/2010; · 2.05 Impact Factor
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ABSTRACT: 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 (P < 0.01, Group A > C) and interleukin-6 (P < 0.01, Group A > B > C).
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.
Pediatrics International 10/2010; 52(5):785-9. · 0.63 Impact Factor
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Yoshihiro Onouchi,
Kouichi Ozaki,
Jane C Buns,
Chisato Shimizu,
Hiromichi Hamada,
Takafumi Honda,
Masaru Terai,
Akihito Honda, Takashi Takeuchi,
Shoichi Shibuta, [......],
Mayumi Yashiro,
Yoshikazu Nakamura,
Keiko Wakui,
Yoshimitsu Fukushima,
Akihiro Fujino,
Tatsuhiko Tsunoda,
Tomisaku Kawasaki,
Akira Hata,
Yusuke Nakamura,
Toshihiro Tanaka
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ABSTRACT: 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.
Human Molecular Genetics 07/2010; 19(14):2898-906. · 7.64 Impact Factor
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ABSTRACT: A 2-year-old girl with isolated unilateral absence of right pulmonary artery is described. Catheterization at 5 months demonstrated hypoplastic right pulmonary artery by pulmonary venous wedge angiography, and the patient underwent right Blalock-Taussig shunt and angioplasty of right pulmonary artery with autologous pericardial roll as an initial step. At 2 years, she underwent anastomosis of right pulmonary artery to main pulmonary artery with an autologous pericardial tube. Postoperative computed tomography showed a patent reconstructed right pulmonary artery.
Heart and Vessels 07/2010; 25(4):353-5. · 2.05 Impact Factor
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ABSTRACT: 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.
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.
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).
SAg may be involved in the development of KD; data suggest that multiple SAgs may trigger KD.
The Journal of pediatrics 06/2009; 155(2):266-70. · 4.02 Impact Factor
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ABSTRACT: We experienced a successful pediatric surgical case of partial anomalous pulmonary venous connection to the superior vena cava with cor triatriatum. Echocardiography and multidetector-row computed tomography showed partial anomalous pulmonary venous connection (right upper pulmonary vein connected to the high superior vena cava) and atypical cor triatriatum (analogue to type III-A2 of Lucas-Schmidt classification: left upper pulmonary vein had dual connection to the innominate vein via vertical vein and the accessory chamber). At 8 years of age, the male patient underwent extracardiac right atrial pedicle repair of partial anomalous pulmonary venous connection to the superior vena cava (Williams' modification) and excision of the diaphragm between the accessory chamber and the left atrium simultaneously. The postoperative course was uneventful in normal sinus rhythm and there was no stenosis of newer drainage root from right upper pulmonary vein.
Heart and Vessels 12/2008; 23(6):433-5. · 2.05 Impact Factor
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ABSTRACT: Two children, aged 1 and 14 years with methicillin-resistant Staphylococcus aureus mediastinitis after pediatric open-heart surgery, were fitted with a vacuum-assisted closure system. Complete healing was achieved in both cases, and primary wound closure could be carried out without an omental flap after 6 and 16 days.
Asian cardiovascular & thoracic annals 11/2008; 16(5):e45-6.
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ABSTRACT: We experienced a conversion case from total cavopulmonary shunt (TCPS) to the Fontan circulation with an 11-year interval in the left isomerism and an interruption of the inferior caval vein. Marked cyanosis (pulse oximetry measuring 74%) progressed 8 years after TCPS because of the prominent development of bilateral pulmonary arteriovenous fistula (PAVF), which was diminished after the Fontan conversion, and recent pulse oximetry measured 95% 22 months after the conversion. We believe that this report is a case with the longest interval from TCPS to Fontan in which PAVF was diminished and marked cyanosis was improved.
Annals of thoracic and cardiovascular surgery: official journal of the Association of Thoracic and Cardiovascular Surgeons of Asia 03/2008; 14(1):29-31. · 0.69 Impact Factor
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ABSTRACT: To investigate whether reduced levels of plasma platelet-activating factor acetylhydrolase (PAF-AH) as a result of a genetic polymorphism are involved in the pathogenesis of Kawasaki disease (KD).
The frequency of a V279F polymorphism (G/T transversion) in the PAF-AH gene was quantified in 76 Japanese children with KD and 112 healthy Japanese adults using the allele-specific polymerase chain reaction (PCR). Associations between genotype, clinical features, and resistance to intravenous immunoglobulin (IVIG) were investigated in the patients with KD. Plasma PAF-AH activity was measured by using [3H]-acetyl-PAF.
There were no significant differences in genotype frequency between patients and controls (P = .51). Compared with the GG (normal genotype) group, significantly more patients in the GT (heterozygous) +TT (homozygous deficient) group required additional IVIG (52% vs 14%, P = .001). The duration of fever and maximum serum C-reactive protein (CRP) levels also were significantly increased in the GT+TT group (P = .012 and .036, respectively), whereas plasma PAF-AH activity was significantly lower (P <.0001).
We conclude that the V279F polymorphism in the plasma PAF-AH gene and consequent enzymatic deficiency is one of the factors for IVIG nonresponse in Japanese patients with acute KD.
Journal of Pediatrics 07/2005; 147(1):78-83. · 4.11 Impact Factor
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Pediatrics International 05/2005; 47(2):217-9. · 0.63 Impact Factor
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ABSTRACT: 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.
European Journal of Pediatrics 12/2003; 162(12):856-9. · 1.88 Impact Factor
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ABSTRACT: 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.
European Journal of Pediatrics 06/2002; 161(6):324-9. · 1.88 Impact Factor
