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.     

Intravenous γ-Globulin for Kawasaki Disease

We studied the effect of γ-globulin (IVGG) and aspirin (ASA) on the development of the coronary artery lesions (CAL) of Kawasaki disease (KD) in three different protocols. Within 29 days of the onset of KD the echocardiographic evidence of CAL had developed in 39–42% of the patients in the ASA group, but only in 13.7–20.8% of the patients treated with IVGG (200 or 400 mgγkgX5). In long-term follow-up observation of CAL of these patients the evidence of CAL in both the ASA and the IVGG group regressed gradually; however, the residual rate of CAL was significantly low in the IVGG group at all times up to 24 months after onset. These facts suggest that when using IVGG for KD, we should select a dose of intact γ-globulin, 1,000 mgγkg or more in total, to prevent the occurrence of CAL. We have demonstrated not only a significant reduction in the occurrence of CAL in patients treated with IVGG but a reduction in the residual rate of CAL for two years as compared with those treated by ASA.     

Extreme thrombocytosis predicts Kawasaki disease in infants

Infants with Kawasaki disease are at high risk of developing life-threatening coronary complications, yet may elude timely diagnosis because they often lack the full complement of classic clinical features. We retrospectively studied 26,540 children 1 year of age or less who were evaluated at a tertiary care pediatric emergency department in whom a platelet count was performed. Among those infants with fever without a source identified, 8.5% with platelet counts of 800,000 cells/mm(3) or greater had Kawasaki disease compared to 0.4% with platelet counts of less than 800,000 cells/mm(3) (likelihood ratio for Kawasaki disease was 17 [95% confidence interval, 8-34]). Because many infants present atypically, Kawasaki disease should be considered in all children of 1 year or less with prolonged fever, extreme elevation of the platelet count, and no compelling alternative diagnosis.     

Prevalence of coronary artery lesions on the initial echocardiogram in Kawasaki syndrome

OBJECTIVES: To determine whether coronary artery lesions (ectasia and aneurysm) are commonly observed on the initial echocardiogram of patients with acute Kawasaki syndrome, whether coronary artery ectasia and/or aneurysms occur more frequently in patients with incomplete Kawasaki syndrome than in those patients with complete findings, and whether earlier diagnosis and treatment of Kawasaki syndrome are associated with less frequent occurrence of coronary artery ectasia and/or aneurysm. DESIGN: A retrospective medical record review. SETTING: A tertiary care pediatric hospital. PARTICIPANTS: One hundred patients treated for Kawasaki syndrome between July 1, 1998, and June 30, 2003, who were identified by a medical record search. MAIN OUTCOME MEASURE: Prevalence of coronary artery lesions (ectasia and aneurysm) on the initial and subsequent echocardiograms. RESULTS: Forty-four percent of patients had a coronary artery lesion (31% with ectasia, 13% with aneurysm) on the initial echocardiogram. Patients with incomplete Kawasaki syndrome were treated significantly later (median, 10 days) and had a significantly higher occurrence of coronary artery aneurysms over the course of their illness (37%) than those with complete Kawasaki syndrome, who were treated at a median of 7 days (P<.001) and had a 12% aneurysm occurrence (P = .009). Patients treated by day 7 of illness had a less frequent occurrence of aneurysm (6%) compared with those patients treated between days 8 and 10 of illness (27%) (P = .03). CONCLUSIONS: Coronary artery lesions are frequently detected on the initial echocardiogram of children with Kawasaki syndrome. If future studies show ectasia to have a relatively high degree of specificity for Kawasaki syndrome, the initial echocardiography may be a useful adjunctive diagnostic test.     

Leukotriene B4 and Kawasaki Disease

The role of LTB4 in Kawasaki disease as a chemo-attractant and immunomodulator is reviewed through our own experience and reports by other invenstigators. In our experiment using 19 patients, we measured calcium ionophore-stimulated LTB4 synthesis in PMNs obtained in three different stages of the illness (acute, convalescent and recovered phases). LTB4 synthesis was significantly increased in the convalescent phase of the illness. Other investigators showed increased serum-LTB4 concentration in acute as well as convalescent phases, suggesting that LTB4 participated in the inflammatory process of Kawasaki disease as an inflammatory mediator and immunomodulator. However, no difference was found in LTB4 synthetic activity in PMNs in any phases of the illness between the patients with and without coronary lesions, which indicated that LTB4 was not a parameter of coronary aneurysm formation. Therapeutic use of high-dose γ-globulin showed a tendency to decreased LTB4 synthesis in PMNs, although it is not conclusive.     

Histiocytic haemophagocytosis in a patient with Kawasaki disease: Changes in the hypercytokinaemic state

Abstract A 32-month-old Japanese boy exhibited haemophagocytic syndrome (HPS) during the recurrent course of Kawasaki disease. Despite repeated -globulin therapy, he developed cytopenia with marked hepatomegaly and evidence of histiocytic haemophagocytosis in the bone marrow. Serum levels of interferon- and tumour necrosis factor, but not of interleukin-1, increased in parallel with his symptoms. No confirmation was obtained of the association of toxic reactions to the used drugs. No coronary lesions remained as sequelae.Conclusion Cytopenia in Kawasaki disease could herald HPS, and the hypercytokinaemia involved in the two febrile syndromes might be of distinct nature.     

Macro Creatine Kinase in Kawasaki Disease

This report describes a case of Kawasaki disease with macro creatine kinase (CK). A 13-month-old boy developed typical symptoms of Kawasaki disease and was treated with flurbiprofen, dipyridamole, and intravenous γ-globulin. The serum level of CK increased during treatment from 371 U/L, at 4 days after the onset of Kawasaki disease, to 13,222 U/L 3 days later. Immunofixation electrophoresis identified macro CK as containing immunoglobulin A (κ, λ). The presence of macro CK may result from muscle tissue involvement in Kawasaki disease.     

Management of Kawasaki disease in the British Isles.

Kawasaki disease in the British Isles was surveyed by an active reporting scheme, based on all cases reported to the British Paediatric Surveillance Unit that were diagnosed between 1 January and 31 December 1990. The study was prompted by the need to investigate the high case fatality rate of Kawasaki disease of 2% observed in 1988. One hundred and sixty three patients were identified of whom six (3.7%) died. Forty five children (28%) suffered cardiac complications of which 39 (24%) were coronary artery abnormalities; five children were diagnosed at postmortem examination, and coronary artery abnormalities were detected by echocardiography in 34. One hundred and forty nine children (93%) had echocardiography. High thrombocytosis, leucocytosis, duration of fever, and younger age were associated with the presence of coronary artery abnormalities. Erythrocyte sedimentation rate, sex, and the number of diagnostic criteria were not. One hundred and thirty three children (87%) received aspirin. Ninety three children (61%) received intravenous gammaglobulin (IVGG). Children were more likely to receive IVGG if they had thrombocytosis or typical Kawasaki disease. The incidence of coronary artery abnormalities was found to be similar in those treated with IVGG (29%) and those untreated (20%), including those treated within 10 days of onset. This may have reflected selection of the more serious cases to receive IVGG or that Kawasaki disease in the British Isles is a different illness to that experienced elsewhere. It amy be, however, that IVGG is less effective in the treatment of British patients with Kawasaki disease than has been the experience in the United States and Japan. These observations emphasise the need for a therapeutic trial of treatment modalities for Kawasaki disease in the UK and the Republic of Ireland.     

Kawasaki disease in New Zealand

AIM: To determine the epidemiology, management and outcome of Kawasaki disease (KD) in New Zealand. DESIGN: Prospective audit using New Zealand Paediatric Surveillance Unit (NZPSU) Reports. SETTING: Single country 2-year epidemiological study. Patients: All patients diagnosed with KD in New Zealand reported to the NZPSU from January 2001 to December 2002. MAIN OUTCOME MEASURES: Incidence of KD; time to diagnosis; use of intravenous immunoglobulin; cardiac features and outcome. RESULTS: Forty-nine new cases were identified. The annual incidence was 8.0 cases/100,000 children aged less than 5 years. Age at onset was less than 5 years in 86% of cases. Incidence was 4.6/100,000 for children of European origin, 9.6 for Maori, 12.2 for Pacific Islanders and 32.2 for children of East Asian origin. KD was diagnosed at a median of 6 days from onset of illness. 89% had fever and four or more diagnostic features. All patients had at least one echocardiogram: There was one small (2%) coronary artery aneurysm only; 13 (26%) had mild coronary artery dilatation. Thirty-five per cent did not have an echocardiogram performed four or more weeks from illness onset. 45 (92%) cases received intravenous immunoglobulin at median day six. There was one death due to occlusive coronary artery disease in a 3-month-old boy with atypical symptoms in whom KD was diagnosed at post-mortem. CONCLUSIONS: The incidence of KD in New Zealand is defined with significantly variable risk according to ethnicity. Most patients received appropriate rapid diagnosis and treatment but there was considerable variation in practice in regard to number and timing of echocardiograms. There was a low coronary artery aneurysm rate (2%). Accelerated vaso-occlusive disease was responsible for the single fatality in an atypical case.     

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.     

Prediction of the risk of coronary arterial lesions in Kawasaki disease by serum 25-hydroxyvitamin D3

Kawasaki disease (KD) is associated with the development of coronary arterial lesions (CALs) in children. We aimed to test the hypothesis that circulating 25-hydroxyvitamin D₃ [25-(OH)D₃] could be identified as a clinical parameter for predicting CALs secondary to KD in children. We enrolled 35 children with KD in the acute phase and measured serum 25-(OH)D₃ levels in all of them, then followed up by echocardiography for CALs. Additionally, serum 25-(OH)D₃ levels were obtained in 23 febrile children with respiratory tract infections and 30 healthy children. Of the 35 KD children, nine had CALs according to echocardiography and 26 did not (NCALs). Serum 25-(OH)D₃ levels were not significantly different between NCALs and healthy children (49.2?±?23.8 versus 44.1?±?30.2 ng/ml; P?=?0.49). Serum 25-(OH)D₃ levels were significantly higher in children with CALs than those without CALs (83.9?±?26.3 versus 49.2?±?23.8 ng/ml; P?=?0.001). The cutoff value of 65 ng/ml to predict subsequent CALs had a specificity of 0.73, sensitivity of 0.78, and diagnostic accuracy of 0.74. Conclusion: Serum 25-(OH)D₃ levels were elevated dur-ing the acute phase in KD children who had subsequent CALs. Serum 25-(OH)D₃ levels in the acute phase of KD may be used to predict subsequent CALs.     

儿童不完全川崎病的临床特点分析

目的 探讨不完全川崎病 （IKD）患儿的临床特点,为早期诊断该病提供可借鉴的经验。方法 回顾性分析22例住院IKD患儿的临床资料,并与同期住院的63例川崎病 （KD）患儿和20例发热患儿进行对比研究。结果 所有患儿均有发热,IKD组患儿的肢端变化、结膜充血及颈部淋巴结肿大的发生比例均显著低于KD组 （均P < 0.05）;且IKD组患儿的血清谷丙转氨酶显著高于KD组 （P < 0.05）,而血浆白蛋白、血清钠、白介素6水平均显著低于KD组 （均P < 0.05）。IKD组丙球使用率与KD组无差异,而IKD组冠脉损害的发生率却显著高于KD组 （P < 0.05）。结论 IKD患儿的症状体征均不典型。肝功能检测及血钠、白介素6水平检测可能有助于IKD的诊断。     

Characteristics of Kawasaki disease in infants younger than six months of age

BACKGROUND: Kawasaki disease is the leading cause of acquired heart disease in childhood. However, there are only a few reports in infants younger than 6 months. The objective of this study is to investigate the clinical and laboratory characteristics of Kawasaki disease in infants younger than 6 months. METHODS: From 1994 to 2003, 120 patients with Kawasaki disease diagnosed at our institution were included. Group 1 consisted of 20 (17%) patients younger than 6 months, and group 2 consisted of 100 (83%) patients older than 6 months. Clinical manifestations, laboratory results, echocardiographic findings, treatment and outcome were compared between these 2 groups. RESULTS: Clinical manifestations (hydrops of gallbladder: 0% versus 16%, P < 0.001) and laboratory results (white blood cell count 21,740 +/- 11,706 versus 11,830 +/- 4390/mm3, P < 0.001; hemoglobin 9.98 +/- 1.25 versus 10.8 +/- 1.37 g/dL, P = 0.015; platelet 483 +/- 393 versus 355 +/- 138 x 1000/mm3, P = 0.011; triglyceride 138 +/- 77.5 versus 107 +/- 17 mg/dL, P < 0.001) were different between patients with Kawasaki disease younger and older than 6 months, respectively. Younger infants were more likely to have incomplete presentation (35% versus 12%, P = 0.025), coronary involvement (65% versus 19%, P < 0.001), late intravenous immunoglobulin treatment and relatively poor outcome. CONCLUSIONS: Infants younger than 6 months with prolonged unexplained febrile illnesses should be suspected as having Kawasaki disease, despite the incomplete clinical presentation. Because early diagnosis and timely treatment are difficult in younger infants with Kawasaki disease because of delayed and incomplete clinical presentations, echocardiogram becomes an important implement for diagnosis. Early intravenous immunoglobulin treatment is required in view of the highest risk of coronary involvement in them.     

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.     

Increased prevalence of atopic dermatitis in Kawasaki disease

Atopic dermatitis is associated with immunoregulatory abnormalities similar to those observed in acute Kawasaki disease. We investigated whether the prevalence of atopic dermatitis is increased among children who acquire Kawasaki disease. In a case-control telephone survey 83 Kawasaki disease patients and 83 children with innocent heart murmurs were matched for age and time between clinic visit and interview. The interviewer was blinded to the hypothesis of the study. Nine (11%) Kawasaki disease patients but only one (1%) unaffected child had atopic dermatitis; the incidence of atopic dermatitis among children with Kawasaki disease was 9 times greater than that of controls (95% confidence limits, 1.6 to 49.4). Serum immunoglobulin E concentrations were significantly higher (P = 0.02, Mann-Whitney) in 44 unselected Kawasaki disease patients (median, 22; range, less than or equal to 4 to 900 IU/ml) studied 6 to 12 months after onset than in 27 children of similar age (median, less than or equal to 4; range, less than or equal to 4 to 164 IU/ml). We observed that there is a strong association between atopic dermatitis and Kawasaki disease.     

Kawasaki disease in Adelaide: A review

Abstract The role of Kawasaki disease (KD) as a contributor to early childhood cardiac morbidity in Adelaide was investigated by a review of hospital admission and case-note data from January 1979 to June 1990. There were 57 episodes in 55 patients. The epidemiological data in this South Australian series are similar to that seen in other Australian and New Zealand centres and correlate better with the clinical data from North America than from Japan. The average age of admission was 3.2 years (median 2.7 years) with 38 and 85% of cases being less than 2 and 5 years respectively. The male to female ratio was 1.5. The incidence of KD in the 0–5 year age group was 3.9 cases per 100000 children. This series represents a minimum number of cases for this period and illustrates an association of aneurysm-risk with prolonged fever, improved defervescence with the combination of intravenous γ-globulin (IVGG) and aspirin compared with aspirin alone; and a more severe disease process in the very young. The series supports the efficacy of single dose IVGG therapy. Antibiotics were given prior to diagnosis of KD in 79% of patients, often causing diagnostic confusion with possible drug reactions. The pathogenic mechanisms of KD are reviewed and a new hypothesis is proposed that incorporate mechanisms of vessel pathology resulting from release of endothelin and recognized mediators of endothelial damage including tumour necrosis factor-α and interleukin-1β.     

Acute Coronary Artery Dilation Due to Kawasaki Disease and Subsequent Late Calcification as Detected by Electron Beam Computed Tomography

We wanted to clarify the relationships between the degree of acute coronary artery dilation caused by Kawasaki disease and subsequent late calcification. Electron beam computed tomography (EBCT) was used to study 79 patients who had previously undergone selective coronary angiograms less than 100 days after the onset of Kawasaki disease. The EBCT was performed using an Imatron C-150 with a 100-ms exposure time and consecutive images at 6-mm intervals. The interval from the onset of Kawasaki disease to EBCT ranged from 2 to 242 months (median, 103 months). The maximum diameters of the right coronary, the left anterior descending, and the left circumflex arteries, as well as the bifurcation of the left coronary artery were measured in the initial coronary angiograms. A total of 250 branches, including 53 left coronary arteries, were measured, and the relationship between the degree of the initial coronary artery dilation and subsequent calcification in the branches and left coronary artery was analyzed. The coronary arterial diameter of all branches that eventually calcified was 6 mm or greater. The incidence of calcification in branches measuring 6 mm or greater on the initial coronary angiogram was 12% at 5 years, 44% at 10 years, and 94% at 20 years (n = 141). Dilation greater than 6 mm is associated with a high probability of late calcification.     

Mediastinal lymphadenopathy: a variant of incomplete Kawasaki disease

A 14-month-old girl presented with a 4-d history of fever and generalized exanthema. Four characteristic symptoms of incomplete Kawasaki disease (KD) were present on admission (fever, rash, non-purulent conjunctival injection, oropharyngeal changes) and then followed by oedema of the hands and feet and mild plantar desquamation. The typical laboratory features of KD, such as elevated erythrocyte sedimentation rate, leukocytosis, thrombocytosis, and positive C-reactive protein were also seen. Ultrasound examination of the mediastinum revealed the presence of a lymph node, 30 mm in diameter, below the tracheal carina. Thoracic CT scan confirmed the mediastinal lymph node. The patient was treated with aspirin and intravenous γ -globulin. Ultrasound study of the mediastinum, which was carried out 6 weeks after hospital discharge, showed that the lymph node had disappeared. This case illustrates that lymph nodes other than cervical lymphadenopathy should be sought when the diagnosis of classical or atypical KD is suspected.     

High-dose gammaglobulin therapy for Kawasaki disease

To evaluate the effectiveness of gammaglobulin in decreasing the incidence of coronary artery lesions in Kawasaki disease, a randomized controlled study in 136 patients was conducted using high doses of gammaglobulin 400 mg/kg/d for 3 days plus aspirin 30 mg/kg/d (gammaglobulin group) and aspirin alone at the same dosage (aspirin group). The total febrile period and the duration of fever after treatment were significantly shorter in the gammaglobulin group than in the aspirin group (P less than 0.001). The incidence of coronary artery lesions and of coronary artery aneurysms was significantly lower in the gammaglobulin group than in the aspirin group up to 30 days after the onset of Kawasaki disease (P less than 0.01 and P less than 0.05, respectively). In 16 of 69 patients given gammaglobulin, fever persisted for longer than 3 days, and there was a higher incidence of coronary artery lesions among them. The effectiveness of high doses of gammaglobulin in preventing coronary artery lesions has been demonstrated, but the indications and the optimal dose of gammaglobulin remain to be determined.     

Clinical responses of patients with Kawasaki disease to different brands of intravenous immunoglobulin

OBJECTIVE: To determine whether different brands of intravenous immunoglobulin (IVIG) administered to children with Kawasaki disease (KD) result in different outcomes. STUDY DESIGN: We analyzed children with KD and divided them into 4 groups according to the brand of IVIG. A coronary artery abnormality (CAA) was defined as having a lumen diameter (inner border to inner border) of > or =3 mm in KD cases <5 years old and > or =4 mm in cases > or =5 years old, and giant aneurysm was defined as a lumen diameter > or =8 mm. Patients were considered nonresponsive to IVIG therapy if fever persisted longer than 2 days after completion of treatment and needed retreatment with IVIG. RESULTS: We collected 437 cases, 29 (6.6%) were nonresponsive, 17 (3.9%) had CAA at convalescence, and 3 (0.7%) had giant aneurysm, 2 of whom had development of myocardial infarcts. Patients receiving Brand C IVIG, prepared with beta-propiolactone, had higher rates (10%, 9/93, P = .01) of CAA at convalescence and nonresponsiveness (13%, 12/93, P = .001); giant aneurysm occurred in 3/93 (3%) receiving Brand C IVIG and in 0/344 who received the other 3 brands (P = .008). CONCLUSIONS: IVIG, prepared with beta-propiolactone, was most significantly associated with nonresponsiveness, CAA at convalescence, and giant aneurysm. Physicians should be cautious when using IVIG prepared with beta-propiolactone or enzyme digestion to treat KD.