Treatment of Kawasaki Disease using the Intravenous Aspirin Anti-inflammatory Effect of Salicylate

Serum salicylate concentrations were measured in 60 patients with acute phase Kawasaki disease (KD), who were treated with intravenous aspirin (IVASP), to evaluate its antiinflammatory effect in the treatment of KD. Patients with serum salicylate concentrations ± 150μg/ml showed shorter durations of fever (7.1 ± 2.0 vs 10.4 ± 6.6 days; P < 0.05), shorter durations of positive serum C-reactive protein (14.6 ± 4.5 vs 22.3 ± 10.6 days; P < 0.01) and lower incidences of coronary arterial involvements (0/10 vs 6/24; P < 0.05) than did patients with serum salicylate concentrations < 150μg/ml. Significant linear correlations were recognized between daily IVASP dosage and serum salicylate concentrations ( r = 0.73; P < 0.01), and between serum salicylate concentrations and serum free salicylate concentrations ( r = 0.82; P < 0.01). These correlations did not differ between the presence and absence of coronary arterial involvements. Based on these findings we concluded that a beneficial anti-inflammatory effect in the treatment of KD is achieved when the serum salicylate concentration is 150μg/ml, and that such concentrations could be achieved by increasing the daily IVASP dosage to 100 mg/kg per day or more.     

Accelerated Thrombotic Occlusion of a Medium-Sized Coronary Aneurysm in Kawasaki Disease by the Inhibitory Effect of Ibuprofen on Aspirin

The fate of coronary artery aneurysms (CAAs) caused by Kawasaki disease depends mainly on their initial size and shape. Small to medium-sized CAAs are known to regress to normal size or decrease in size, with a good outcome. A patient with Kawasaki disease is reported who had a medium-sized CAA prematurely occluded with thrombi during regression, resulting in myocardial ischemia. This event was probably due to simultaneous use of aspirin and ibuprofen. Thus, the concomitant use of ibuprofen should be avoided when aspirin is given as an antiplatelet agent because ibuprofen blocks the platelet inhibition induced by aspirin.     

Effect of Intravenous γ-Globulin on Neutrophil Function in Kawasaki Disease

The effect of intravenous γ-globulin (IVGG) on the neutrophil count and neutrophil chemiluminescence (CL) of patients with Kawasaki Disease (KD) was investigated. Forty patients with KD were enrolled in the study. Ten patients were treated with 100 mg/kg/day of γ-globulin for five days (GG 100 group) and 14 patients were treated with 400 mg/kg/day of γ-globulin (GG 400 group) for five days. These patients also took aspirin. Sixteen patients were treated with aspirin alone (ASA group). The neutrophil counts were significantly lower in the GG 400 and GG 100 groups than in the ASA group, three days, and one and two weeks after the start of treatment. Neutrophil CL of the GG 400 and GG 100 groups was significantly lower than in the ASA group one and two weeks after the start of treatment. In the in vitro study, γ-globulin had a dose-dependent suppressive effect on the neutrophil CL in the early stage. Albumin had similar effects. The suppressive effect of γ-globulin on CL was not specific. These findings suggest that IVGG is effective in reducing the production of active oxygen which is considered responsible for the vascular damage in the early stage of KD.     

细胞免疫功能在川崎病发病机制中的作用

目的探讨川崎病患儿细胞免疫功能。方法分别采用碱性磷酸酶抗碱性磷酸酶法(APAAP)、ELISA法和双抗体夹心酶联免疫吸附法测定川崎病60例患儿外周血T细胞亚群、血清白细胞介素-2(IL-2)及可溶性白细胞介素-2受体(sIL-2R)水平。结果与对照组比较,川崎病患儿急性期外周血CD3 及CD8 百分率明显下降,CD4 百分率、CD4 /CD8 、血清IL-2及sIL-2R水平明显升高,以上免疫学指标变化在并冠状动脉病变者更为显著。结论川崎病患儿急性期存在细胞免疫功能过度活化及免疫调节功能紊乱。     

B-Cell Function in Kawasaki Disease and the Effect of High-Dose Gamma-Globulin Therapy

We studied in vino B-cell function in Kawasaki disease (KD). By plaque-forming assay, IgG-, IgA- and IgM-secreting cells in the first week of KD were markedly increased, and recovered to a normal level in the second week in many cases. Lymphocyte blast formation with Staphylococcus aureus Cowan I (SAC), a B-cell-specific mitogen, was suppressed in the acute phase, and recovered to a nod level in the convalescent phase. By flow cytometry, HLA-DR- and HLA-DQ-positive cells were increased in the acute phase of KD. CD3-and CD4-positive cells were also decreased. CD8-positive cells showed no significant change. In five patients, CD4-positive cells with HLA-DR positivity neither increased in the acute phase nor changed during the course of illness. From our results, it can be considered that pathogenic microorganisms or toxins activate B cells directly in KD without the association of T cells. We also studied the effect of high-dose gamma-globulin therapy on B-cell function in KD. However, the results indicated that this form of therapy had no significant effect on B-cell functions.     

Polymorphism of Angiotensin-1 Converting Enzyme Gene and Kawasaki Disease

Kawasaki disease is an acute febrile illness typically elicited by vasculitis and occurring in young children. We investigated the polymorphism of the angiotensin-1 converting enzyme (ACE) gene in children with Kawasaki disease and also in age-matched controls. A total of 107 children, with a mean age at diagnosis of 1.71 ± 1.48 years, who suffered from Kawasaki disease and who were treated with aspirin as well as intravenous immunoglobulin were enrolled in this study. Control subjects consisted of 107 children, with a mean age of 1.84 ± 1.20 years. The polymorphisms of the ACE gene, including I/D, A-240T, and G2350A, were examined using a polymerase chain reaction method for Kawasaki disease patients and also for control subjects. We noted a significant difference in the distribution of the ACE gene I/D genotype between Kawasaki disease and control groups. The ACE gene G2350A polymorphism and associated allelic frequencies demonstrated an association with Kawasaki disease. Our results revealed no evidence of any association between the ACE gene polymorphism and the frequency of coronary artery aneurysm associated with Kawasaki disease, although our results do support a role for the I/D and G2350A polymorphism of the ACE gene in determining the risk of Kawasaki disease in the population of Taiwan.     

Epidemiology of Kawasaki Disease in Japan

Three nation-wide epidemiological surveys, three case control studies and a few other epidemioligical studies on mucocutaneous lymph node syndrome have been conducted in Japan since 1970. The principal epidemiological features of the disease are (1) total numbers reported as of June 1974 being 6,537, (2) prevailing throughout the country without north-south or urban-rural differences, (3) steady increases after 1968 without distinct seasonal variation, (4) peak age at 6–11 months in male and 12–17 months in female, (5) male/female ratio in incidence: 1. 5/1, that of fatal cases 4/1, (6) family and area clustering, (7) previous history of pharyngitis and allergic reactions, (8) no specific characteristics in weight at birth, birth order, immunization history, artificial feeding, (9) temporal curves of incidence consistent with the production of certain medicines.     

Dobutamine Stress Echocardiography in the Evaluation of Young Patients with Kawasaki Disease

There has been no consistent approach to the follow-up of Kawasaki disease patients for remote coronary perfusion abnormalities. Dobutamine stress echocardiography (DSE) has become a standard method for evaluation of perfusion abnormalities in adults with coronary artery disease. In addition, DSE has been used with success in some pediatric patients. The purposes of this study were to evaluate safety and accuracy of DSE in the follow-up of patients with Kawasaki disease, to evaluate whether DSE adds any additional value to the resting echocardiogram, and to determine the association of DSE results with American Heart Association (AHA) risk level categories. DSE was performed 1 month to 13 years after acute Kawasaki disease in 47 patients (range, 3.8–22.6 years; 33 males and 16 females). Patients were stratified according to AHA risk level categories (I–V). Ischemia was defined as a new or worsening regional wall motion abnormality or >1 mm ST segment depression on the electrocardiogram during DSE. In 45/47 patients, DSE was completed successfully (i.e., achievement of target heart rate or development of ischemia). No patients in risk levels lower than V (i.e., patients without coronary artery stenoses) had positive DSE, whereas 2/4 (50%) in the risk level V category had positive DSE, both of whom had coronary occlusion >50% confirmed by angiography. Of the 2 AHA risk level V patients with negative DSE, 1 had extensive collateralization and the other had coronary obstruction <50%. DSE is a safe and feasible method for the evaluation of children with Kawasaki disease. DSE provides a confirmatory benefit and may be a useful screening alternative to cardiac catheterization during follow-up. Patients in AHA risk levels I–IV are unlikely to have dobutamine-induced coronary perfusion abnormalities. Patients in the risk level V category may or may not have positive DSE depending on the degree of both coronary obstruction and collateralization.     

川崎病患儿抗心磷脂抗体检测的意义

目的：检测川崎病(KD)患儿血清中抗心磷脂抗体(ACA),探讨ACA与KD血管损害的关系。方法：55例急性期KD患儿,采用ELISA方法检测血中ACA-IgG,IgM和IgA三种亚型。结果：55例急性期KD患儿血清ACA-IgG阳性31例,ACA-IgM阳性13例。急性期KD组ACA-IgG,IgM阳性率比对照组显著增高(P<0.01);治疗后ACA-IgG阳性率仍高于对照组(P<0.05),而ACA-IgG阳性或阴性两组的临床表现比较差异均无显著性(P>0.05),但6例伴有血栓形成者有5例ACA-IgG阳性。结论：ACA-IgG是KD常见的抗体,ACA-IgG阳性与KD血栓性血管损害关系密切,但对病情判断无作用。     

学龄儿童川崎病89例

目的 分析学龄儿童川崎病的临床及实验室特点,提高对学龄儿童川崎病的认识.方法 采用回顾性调查法分析比较6个月～5岁儿童及≥6岁确诊为川崎病患儿有关的临床资料,并进行分组对比.结果 高年龄组患儿临床表现:球结膜充血、口唇改变、指(趾)端改变、手足硬肿、皮疹、颈部淋巴结大的发生率较低年龄组低.实验室检查:高年龄组中白细胞[(5～10)×109 L-1]、CRP( ＞5 mg?L-1)、ESR[(20～80)mm?(1 h)-1]3项指标的发生率较低年龄组低;高年龄组中白细胞( ＞10 ×109 L-1)、CRP(0-5mg?L-1)、ESR[0 ～20 mm?(1 h)-1]3项指标的发生率高于低年龄组.心脏彩色多普勒:高年龄组冠状动脉瘤、心脏结构改变、心包积液的发生率较低年龄组高,差异均有统计学意义.结论 学龄儿童川崎病临床表现不典型,缺乏早期诊断特异指标,易造成漏诊及延误治疗,导致冠状动脉瘤发病率较高.对学龄期儿童发热应引起足够重视,必要时进行全面检查,心脏彩色多普勒检查是确诊川崎病心脏病变简单可行的方法.     

川崎病并冠状动脉损害的危险因素

目的探讨川崎病(KD)并冠状动脉损害(CAL)的危险因素。方法收集1999年1月-2001年12月住院的145例KD患儿的临床资料,分析无CAL93例和CAL52例患儿的实验室检查资料及治疗、随访结果。结果无CAL组发热日程(8.7±3.4)d.血沉(79.5±34.6)mm/1h,CAL组发热日程(11.5±4.8)d,血沉(91.9±36.6)mm/1h,两组比较差异有显著性(P<0.01,0.05)。发病10d内接受静脉注射人血丙种球蛋白(IVIG)治疗患儿CAL发生率为18.8%(18/96),未予IVIG治疗患儿CAL发生率为69.4%(34/49),两者比较差异有显著性(P<0.001)。随访并CAL患儿38例,冠状动脉扩张20例均恢复正常;14例冠状动脉瘤中12例恢复正常,2例缩小;4例巨大冠状动脉瘤2例缩小,另2例超过2年仍未恢复。结论KD并CAL与热程过长及血沉显著增快密切相关,病程早期未予IVIG治疗的患儿并CAL的危险性明显增高,应用IVIG治疗对防治冠状动脉损害有重要作用。     

Increased levels of urinary interleukin-6 in Kawasaki disease

Kawasaki disease (KD) often presents with abnormal urinary findings, such as aseptic pyuria, mild proteinuria and microscopic haematuria. In this study, we measured urinary interleukin-6 (IL-6) by a sensitive sandwich ELISA assay using mouse monoclonal antibodies against recombinant IL-6 to elucidate the role of IL-6 in the pathogenesis of renal lesions in KD. Serum IL-6 levels were increased in acute KD as well as in febrile controls. Importantly, urinary IL-6 levels were consistently elevated in patients with acute KD, but much lower in febrile controls. Urinary IL-6 levels returned steadily to normal during the convalescent phase. In addition to IL-6, urinary levels ofN-acetyl--d-glucosaminidase (NAG) and ₂-microglobulin (₂-mg) were also elevated during the acute phase of this disease. Eosinophils and macrophages were identifiable in urinary sediments from these patients. The increased levels of urinary IL-6 in combination with increased NAG and ₂-mg seemed to suggest the presence of certain renal parenchymal lesions with cellular infiltration during the acute phase of the disease. IL-6 may serve as clinically useful parameter for the detection and monitoring of the renal involvement in KD.     

Use of Intravenous γ-Globulin for Kawasaki Disease: Effects on Cardiac Sequelae

The administration of intravenous γ-globulin (IVGG) for Kawasaki disease was investigated throughout Japan in 1993 by obtaining information from pediatric departments in 2652 hospitals that had more than 100 beds. Of 11,221 reported patients, 8958 patients (79.8%) received IVGG treatment. Of all the patients to whom IVGG was administered, the most common total dose was 1000 mg/kg (36.3%) followed by 2000 mg/kg (16.9%) and 1200 mg/kg (16.8%). The treatment was started in 53.8% by day 5 of the illness and in 83.7% by day 7. The proportion of those with cardiac sequelae was higher among patients administered >2000 mg/kg or in those started on IVGG on day 9 of their illness or later. The possible reasons are (1) those who were more severely affected were treated with high-dose IVGG earlier; or (2) IVGG does not effectively prevent cardiac sequelae. We concluded that there is a risk of unfavorable effects with IVGG regarding cardiac sequelae when the IVGG dose is >2000 mg/kg or if IVGG is started on day 9 or later. We believe that only a randomized controlled trial, undertaken prospectively, can adequately address the question of the optimal use of IVGG.     

Etiological Role of Phagocytes in Kawasaki Disease

The numbers of immature neutrophils and monocytes in the peripheral blood are increased in the acute phase of Kawasaki disease. These phagocytes contain toxic granules and vacuoles in the cytoplasm. Phagocytes are primed and activated to release active oxygen species, lysosome enzymes and chemical mediators, which injure cultured endothelial cells and vascular smooth muscle cells. One of the possible factors causing cardio-vascular complications in Kawasaki disease is these activated phagocytes. Some microbial agents or their products such as toxins may activate neutrophils and monocytes, but the real cause remains unknown.     

Inhibitory Effects of High Doses of Intravenous γ-Globulin on Platelet Interaction with the Vessel Wall in Kawasaki Disease

Clinical effects of high-dose γ-globulin therapy in Kawasaki disease have been evaluated from the viewpoints of its inhibitory effects on platelet adhesion and thrombus formation on the vessel wall. Platelet adhesion to the subendothelium is the first step of thrombosis as well as platelet interaction with the vessel wall, which can be observed experimentally by Baumgartner's method. Twelve patients with Kawasaki disease treated with intact intravenous γ-globulin (IVGG) showed decreased platelet adhesion in contrast to ten patients treated with only aspirin (ASA) or flurbiprofen (FP). Addition of intact IVGG to normal blood in Baumgartner's method also resulted in decreasing platelet adhesion and thrombus formation; however, other pepsin-treated IVGG caused enhanced platelet adhesion and thrombus formation. Moreover, pretreatments of the vessel wall with both types of IVGG showed effects similar to those of addition. In conclusion, high-dose therapy with intact IVGG has inhibitory effects on platelet adhesion and thrombus formation. Although the mechanism of the effects is not yet clear, some competitive inhibition between intact IgG and adhesive protein such as von Willebrand factor is suggested, and Fc receptors of the platelet membrane and Fab and Fc receptors of the subendothelium of the vessel wall may have some role in the interaction.     

Immunological Abnormalities in Kawasaki Disease with Coronary Artery Lesions

A review of our previous immunological studies on Kawasaki disease (KD) was undertaken. The results showed that peripheral blood macrophages/monocytes, T-cells and B-cells become activated during acute KD in terms of numerical changes in immunocompetent cells, expression of activated antigens on the cell surfaces and cytokine production. Also, during acute KD with coronary artery lesions (CALs) the numbers of macrophages/monocytes are increased. In addition, both the increased levels of tumor necrosis factor-α and shed intercellular adhesion molecule-1 in serum are more evident in KD patients with CALs than in those without. Our results further suggest that the main characteristics of the pathogenesis of KD are increased numbers of peripheral blood macrophages/monocytes with the secretion of monokines by these activated cells, and the expression of adhesion molecules on immunocompetent cells. These immune responses develop more vigorously in KD patients with CALs.     

上海地区1998－2002年川崎病流行病学特征

目的 对上海地区川崎病发病情况进行调查，了解中国发达地区川崎病的流行病学特征。方法 参照日本流行病学调查方案，制作统一调查表和诊断指南，调查对象为1998年1月1日－2002年12月31日上海地区50家有儿科临床服务的二级及二级以上医院收治的所有川崎病病例。结果 调查表回收率100％，将18例不符合表格填写要求者剔除后，对768例进行分析。上海地区5岁以下儿童川崎病发病率呈逐年增高趋势， 1998年为16.79/10万，1999年为25.65/10万，2000年为28.16/10万，2001年为28.05/10万，2002年为36.76/10万。男女性别比为1.83:1；发病年龄为1个月～18.8岁（中位数1.8岁），发病年龄高峰为9.6个月；全年均可发病，但以春夏之交较多见。主要症状表现为发热持续5 d以上者最为常见（99.3％），其后依次为口唇、口腔黏膜损害（83.5％）、指（趾）端脱皮（82.9％）、皮疹（81.0％）、结膜充血（78.4％）、颈部淋巴结肿大（69.3％）、肢端充血硬肿（48.1％），45.2％的病例有肛周脱皮。心血管损害发生率24.3％，以冠状动脉扩张最为常见，占68％，其次为冠状动脉瘤，占10%。急性期病死率为0.26%，死因为冠状动脉瘤破裂和急性心力衰竭。再发率为1.82%。 结论 上海地区川崎病发病率明显低于日本，但高于西方国家。发病率呈增高趋势，性别分布和心血管损害与其他报道相似。发病季节分布与北京地区的报道相似，但与其他报道不同。     

Evaluation of the Efficacy of Treatment of Kawasaki Disease before Day 5 of Illness

We evaluated the efficacy of treating Kawasaki disease earlier than Day 5 of illness with a standard dose of immunoglobulin and aspirin. We performed a case–control study of patients with Kawasaki disease admitted to Princess Margaret Hospital from 1994 to 1999. Patients with pretreatment coronary aneurysm or those treated after day 10 of illness were excluded. All patients received immunoglobulin (2 g/kg) and aspirin (80–100 mg/kg/day) until fever subsided for 48 hours. Immunoglobulin retreatment was given for persistent fever 48 hours after the first dose of immunoglobulin or recrudescent fever. The case group consisted of 15 patients who received treatment earlier than day 5 of illness, and the control group consisted of 66 patients who were treated on or after day 5. Patients sex, age, duration of posttreatment fever, need for additional immunoglobulin, and coronary artery status were noted. Treatment efficacy was assessed by the duration of posttreatment fever and the prevalence of coronary artery aneurysms. Eighty-one patients were included in this study. There were 15 patients in the case group and 66 in the control group. No significant difference was noted in age and sex between the case and control groups. Thirty-three percent (5/15) and 8% (5/66) of the case and control groups, respectively, had persistent/ recrudescent fever 48 hours after the first dose of immunoglobulin that required retreatment (p = 0.017). Thirteen percent (2/15) and 5% (3/66) of the case and control groups, respectively, had coronary aneurysms (p = 0.158). Treatment of Kawasaki disease before day 5 of illness was associated with persistent/recrudescent fever that required retreatment. However, there was no significant increase in the prevalence of coronary aneurysm if retreatment was given. Poster presented at the third World Congress of Pediatric Cardiology and Cardiac Surgery, Toronto, Ontario, Canada, 2001     

不完全川崎病的早期诊断和临床特征

目的 探讨不完全川崎病(IKD)的早期诊断和临床特征,以提高川崎病(KD)的早期诊断率,减少KD延迟诊断及冠状动脉病变(CAL)的发生.方法 对2000年1月-2010年1月收治的42例IKD患儿和147例典型KD进行回顾性分析.分别对IKD和典型KD患儿的年龄、性别、临床特点[包括发热、淋巴结大、指(趾)端脱皮、球结膜充血、手足硬性水肿、皮疹、口腔黏膜充血、肛周脱屑、卡介苗接种处再现红斑(卡疤红肿)]、实验室特点[包括血WBC计数、Hb、PLT计数、ESR、CRP、血清清蛋白(Alb)、血清ALT、血钠]、心脏彩超及心电图等临床资料进行比较.应用SPSS 17.0软件对数据进行统计学处理.结果 IKD组与典型KD组比较发病无性别差异,但发病年龄小;IKD组诊断时发热持续时间长;IKD组急性期手足硬肿、口腔黏膜充血、球结膜充血、皮疹方面低于典型KD组,而卡疤红肿则多于典型KD组;IKD组 WBC计数及CRP较典型KD组高;2组心电图异常比较差异无统计学意义,但IKD组发生CAL高于典型KD组.结论 IKD患儿CAL发生率高,小年龄、发热时间长、卡疤红肿、WBC计数及CRP明显升高有助于IKD诊断.尽早完善相关实验室检查可减少IKD延迟诊断及CAL发生.