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.     

Treatment of Kawasaki syndrome: a comparison of two dosage regimens of intravenously administered immune globulin

Because intravenously administered immune globulin (IVIG) is effective in reducing the incidence of coronary artery aneurysms in Kawasaki syndrome when given at a dose of 400 mg/kg daily for 4 days, we undertook a multicenter clinical trial comparing two dosage regimens of IVIG. Patients were randomly assigned to receive IVIG at either 400 mg/kg daily for 4 days (22 patients) or 1 gm/kg as a single dose (22 patients). All patients received aspirin therapy, and all were enrolled within 7 days of onset of fever. The presence of coronary artery aneurysms was evaluated by means of two-dimensional echocardiography before infusion; at days 4 to 6, 14 to 21, and 42 to 49 after infusion; and at 1 year. Coronary artery aneurysms were detected in 3 of the 44 patients, including one patient receiving 400 mg/kg and two patients receiving 1 gm/kg (p value not significant). No giant aneurysms were detected. No major side effects occurred with either dosage regimen. Patients receiving the 1 gm/kg dose had a faster resolution of fever and were discharged from the hospital approximately 1 day sooner than the 400 mg/kg group (p = 0.01). Although the relatively small sample size in this trial does not allow for a more definitive statement regarding the occurrence of coronary artery aneurysms, it appears that the 1 gm/kg dose is associated with a more rapid clinical improvement and a shorter hospital stay.     

Giant coronary aneurysms due to Kawasaki disease: A case−control study

BACKGROUND: Epidemiologic features of giant coronary aneurysm due to Kawasaki disease and its risk factors are still not clear. METHODS: Sixty-six patients with giant coronary aneurysms were reported to a 15th nationwide survey of Kawasaki disease in Japan. With all other patients treated in the same hospital as a control group, odds ratios were calculated for certain potential risk factors. RESULTS: Infant males aged less than 1 year,neutrophil concentration among leukocyte, late administration of intravenous gammaglobulin (IVGG) therapy and additional administration of IVGGwere considered as risk factors of giant coronary aneurysms due to Kawasaki disease. In univariate analysis, use of IVGG therapy and a large amount of IVGG (2500+ mg/kg)elevated the risk, whereas the relationship disappeared after the adjustment. CONCLUSIONS: The observation of 66 cases with giant coronary aneurysms due to Kawasaki disease reported to the nationwide survey provides some risk factors and consideration about the aneurysms.     

Optimal dosage and differences in therapeutic efficacy of IGIV in Kawasaki disease

In an initial study, three groups of patients with Kawasaki disease received either aspirin alone or alkylated immunoglobulin G intravenous preparation (IGIV) 200 mg/kg daily x3 days + aspirin, or 400 mg/kg alkylated IGIV daily x3 days + aspirin. In a second study, three groups of patients were treated with either 100, 200 or 400 mg/kg of native IGIV in combination with aspirin daily for 5 days. While the regimen of 200 mg/kg native IGIV daily x 5 days was found to be effective, the incidence of coronary artery lesions (CAL) was even less on a regimen of 400 mg/kg daily x 5 days. It is therefore suggested that a better therapeutic effect can be achieved with a 400 mg/kg dose of native IGIV. Based on the results from these two studies, it is assumed that native IGIV is more effective in inhibiting CAL formation and persistence than the chemically modified preparation in which the biological activity of the Fc region in the immunoglobulin G molecule is altered.     

Corticosteroids in the treatment of the acute phase of Kawasaki disease.

OBJECTIVES: Corticosteroids are considered to be contraindicated during the acute phase of Kawasaki disease (KD) based on unfavorable results in early studies. In our hospital, however, corticosteroids have been used in some cases of KD with satisfactory results. We analyzed outcomes of patients with KD treated with or without corticosteroids. STUDY DESIGN: Medical records of 299 children with KD treated with one of the 4 regimens were reviewed retrospectively. Regimen 1 consisted of aspirin, dipyridamole, and propranolol; regimen 2 was regimen 1 plus prednisolone, 2 mg/kg/d, for 1 week, followed by tapering over 2 weeks; regimen 3 was regimen 1 plus intravenous gamma-globulin (IVGG), 200 or 400 mg/kg/d, for 5 consecutive days; and regimen 4 was regimen 1 plus both prednisolone and IVGG. RESULTS: Although patients treated with regimens 2 and 4 were more ill at presentation than those treated with regimens 1 and 3, respectively, the duration of fever was shorter in the former patient groups (P =.0013). Coronary aneurysms developed least frequently in patients treated with regimen 4 and less frequently with regimen 2 than with regimen 1 (P =.0730). Multiple regression analysis showed significant reductions of fever and coronary aneurysm incidence with prednisolone (P <.0001 and P =.0307, respectively). CONCLUSION: Our data suggest a possible role of corticosteroids in the treatment of the acute phase of KD.     

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.     

大剂量静脉滴注丙种球蛋白治疗新生儿ABO溶血病的疗效观察

目的　观察大剂量静脉滴注丙种球蛋白(IVIG)治疗新生儿ABO溶血病的临床效果。方法　对符合新生儿ABO溶血病诊断标准且无其它合并症的63例患儿,分为常规治疗组和大剂量IVIG治疗组。IVIG治疗组在常规治疗的基础上给予IVIG80 0mg/kg·d静脉滴注,每日一次,连续3日。结果　IVIG治疗组在治疗前血清胆红素水平比较高的情况下,黄疸消退时间为4 1 8±1 0 3天,常规治疗组为5 .2 8±1 .5 0天,t=3.72 4 ,P <0.0 1。结论　大剂量静脉滴注丙种球蛋白协同治疗新生儿ABO溶血病临床效满意     

Factors related to cardiac sequelae of Kawasaki disease

Among the 35,210 patients with Kawasaki disease who were reported in nationwide surveys from 1991 to 1996, 83% were treated with gamma-globulin (GG). Those treated with a total dose of 1000 mg/kg (9098 patients) and 2000 mg/kg (7012 patients) were selected as the subjects of the study on the relationship between the development of cardiac sequelae, in particular of giant aneurysms, and related factors using logistic regression models. Among the two groups that received 1000 mg/kg and 2000 mg/kg, respectively, the odds ratios for cardiac sequelae were significantly high for males, those <6 months and ≧ 7 years of age, and typical or recurrent cases. Except for those <6 months of age, the odds ratios of all the factors mentioned above were higher for the incidence of giant coronary aneurysms than those for cardiac sequelae. The preventive effects of GG therapy for cardiac sequelae and in particular giant aneurysms, were significantly low when GG administration was initiated on day 8 or later after onset. In the group treated with 1000 mg/kg, the preventive effect was low when GG administration was spread over 3 days or longer. Conclusion To prevent the development of cardiac sequelae, in particular giant coronary aneurysms, gamma-globulin therapy should be started as soon as possible and be completed within 2 days. Received: 8 July 1998 / Accepted: 18 December 1998     

Efficacy of intravenous immune globulin therapy combined with dexamethasone for the initial treatment of acute Kawasaki disease

We studied the effects of a new regimen consisting of intravenous immune globulin (IVIG) combined with dexamethasone (DEX) on clinical outcome and serum levels of vascular endothelial growth factor (VEGF) in the initial treatment of Kawasaki disease (KD). A total of 46 KD patients received 0.3 mg/kg per day DEX plus heparin i.v. for 3 consecutive days, together with 2 g/kg IVIG over 4 to 5 days (DEX group). Low-dose acetylsalicylic acid was started after completion of DEX therapy. The control group consisted of 46 KD patients retrospectively treated earlier with 2 g/kg IVIG over 4 to 5 days plus higher dose acetylsalicylic acid (CONTROL group). No serious adverse effect was noted in either group. There were no differences in baseline and post-treatment laboratory data except for C-reactive protein between the groups. Post-treatment C-reactive protein in the DEX group (median 0.9 mg/dl, range 0.0 to 24.7 mg/dl) was lower than that (1.2 mg/dl, range 0.2 to 19.5 mg/dl) in the CONTROL group ( P =0.033 by Mann-Whitney U test). In addition, the mean duration of fever after the first IVIG infusion was 2.2 days (median 1 day, range 1 to 12 days) in the DEX group and 2.8 days (2 days, 1 to 16 days) in the CONTROL group ( P =0.015 by Mann-Whitney U test). The new regimen did not reduce VEGF levels. Two patients in each group developed small- or medium-sized coronary artery aneurysms. Conclusion:although this regimen did not affect coronary outcome, intravenous immune globulin therapy combined with dexamethasone for the initial treatment of Kawasaki disease was safe and may accelerate the resolution of systemic inflammation.Abbreviations CAA coronary artery aneurysms - DEX dexamethasone - IVIG intravenous immune globulin - KD Kawasaki disease - VEGF vascular endothelial growth factor     

Aerobic exercise function of patients with persistent coronary artery aneurysms secondary to Kawasaki disease

Nine patients with persistent coronary artery aneurysms 1.7–14.0 years after an episode of Kawasaki disease underwent progressive bicycle ergometry with expiratory gas analysis. Two of the patients had aneurysms complicated by angiographically documented coronary artery stenosis. Results of the exercise tests were compared to those obtained from a group of age- and gender-matched normal control subjects. The Kawasaki disease patients did not differ significantly from the control subjects with regard to peak oxygen consumption (81 ± 7% versus 79 ± 12% predicted), peak workload (75 ± 13% versus 77 ± 9% predicted), anaerobic threshold (21.9 ± 6.5 versus 18.9 ± 4.0 ml/kg per minute) or oxygen pulse (96 ± 7% versus 90 ± 14% predicted). None of the patients developed significant ST segment changes or rhythm disturbances during exercise. The exercise function of the patients with coronary artery stenosis did not differ from that of patients without stenosis. It was concluded that the aerobic exercise function of patients with persistent coronary artery aneurysms after an episode of Kawasaki disease appears to be well preserved. Kawasaki disease patients with significant coronary artery pathology are not accurately identified by a single assessment of aerobic exercise function.     

Selective high dose gamma-globulin treatment in Kawasaki disease: Assessment of clinical aspects and cost effectiveness

BACKGROUND: High-dose intravenous gamma-globulin (IVGG) plus aspirin (ASA) treatment is effective in preventing coronary artery complications in acute Kawasaki disease (KD). However, gamma-globulin is very expensive, especially in Japan. Furthermore the indication for IVGG treatment and the optimal dose of gamma-globulin remain controversial. OBJECTIVES: To examine these two issues, we used Harada's scoring system to investigate whether a single 2 g/kg dose therapy has any advantage over the 5 day 400 mg/kg per day therapy. METHODS: We studied 203 patients with KD who had no coronary artery complications on admission. Of these, 145 patients scored 4 or more on Harada score within the first 9 days of illness and were treated with IVGG treatment. Using a random number table, 72 patients were selected to receive a single 2 g/kg dose (2 g group), while the remaining 73 patients were treated with 400 mg/kg per day for 5 consecutive days (400 mg group). Those who had a Harada score of three or less received no IVGG (non-IVGG group) treatment (58 patients). RESULTS: The incidence rate of coronary artery complications in the 2 g group was significantly lower than in the 400 mg group. The duration of high fever, positive duration of C-reactive protein and the number of hospital days in the 2 g group were each significantly shorter than in the 400 mg group. The total medical expense in the 2 g group was significantly lower than in the 400 mg group. There were no coronary artery complications in the non-IVGG group. CONCLUSIONS: It was found to be clinically more effective and more cost effective to select a patient by Harada's scoring system and, where a score of four or more was obtained, to administer a single 2 g/kg intravenous dose of gamma-globulin for acute KD.     

Studies on the Effect of Long-Term Use of Low Dose Aspirin in Kawasaki Disease

The inhibitory action of long-term low dose aspirin (1–2 mg/kg/day for over 10 months) on the cyclooxygenase pathway in platelets and vascular endothe-lium was evaluated in 10 patients with Kawasaki disease. The results were compared with those obtained after taking aspirin at 5–10 mg/kg/day during the acute phase of the illness. Platelet aggregations induced by adenosinedi-phosphate (ADP), epinephrine and collagen were inhibited by aspirin doses of 1–2 and 5–10 mg/kg/day, when compared with those of controls (p < 0.05). Platelet synthesis of thromboxane B₂ (TXB₂) under doses of 1–2 and 5–10 mg/kg/day was 0.57 ± 0.07 and 0.72 ± 0.09 ng/ml platelet-rich plasma (PRP) /10⁵ platelets, respectively (p > 0.1). These values were significantly lower than those of the control group (22.88± 3.42 ng/ml PRP/10⁵ platelets) (p < 0.05). No differences were found in platelet aggregation and TXB₂ productivity between the two aspirin doses. Levels of 6 keto-prostaglandin F₁α (6k-PGF₁α) in platelet-poor plasma (PPP) did not differ significantly in these 3 sets of data. The results indicate that long-term administration of low dose aspirin (1–2 mg/kg/day) inhibits platelet aggregation by inhibiting synthesis of thromboxane A₂ (TXA₂), without interfering with prostacyclin production probably in the endothelium of blood vessels.     

Coronary artery involvement in Kawasaki syndrome in Manhattan, New York: risk factors and role of aspirin

Since January 1980, 110 children having 113 attacks of Kawasaki syndrome were studied. Age at onset was 7 weeks to 12 years (mean 3 6/12 years, median 2 9/12 years); 77% were younger than 5 years of age; the male to female ratio was 1.8; racial distribution was 52% white, 19% black, 14% Hispanic, and 16% Asian. Protocol of management consisted of high-dose aspirin (100 mg/kg/d) until afebrile, and then 81 mg every day until free of coronary aneurysm. Two-dimensional echocardiograms were done weekly during the acute stage, at 2 and 6 months after onset, and yearly if a coronary abnormality was detected. At 1 month, 51 coronary arterial abnormalities were present in 25 patients. Risk factors for a coronary abnormality were duration of fever greater than or equal to 2 weeks, level of platelet count, marked elevation of ESR, and age younger than 5 years. No statistically significant difference in incidence of aneurysms was detected between patients on high-dose aspirin and those on medium-or low-dose aspirin.     

Reduction of peripheral blood macrophages/monocytes in Kawasaki disease by intravenous gammaglobulin

The effects of intravenous gammaglobulin (IVGG) on changes in the peripheral blood mononuclear cell subsets during acute Kawasaki disease (KD) were studied by a random selection trial of IVGG plus Aspirin (group G) compared to Aspirin alone (group A). Group G received IVGG with 200 mg/kg per day × 5 dose. The absolute counts of peripheral blood mononuclear cell subsets were assayed by a fluorescence-activated cell sorter using monoclonal antibodies of Leu series. Before therapy, patients in each treatment group had increased counts of CD14+ macrophage/monocytes compared to healthy childhood controls (P<0.01). After IVGG treatment, group G underwent a greater decrease in their CD14+ macrophage/monocyte counts (P<0.01) than group A. The changes of CD3+ T cells, Leu 7+ NK/K cells and CD19+ B cells in the peripheral blood mononuclear cell subsets with treatment in group G, were similar to those in group A. These results suggest the possibility that IVGG therapy is effective in KD by modulating macrophages/monocytes.     

Large pleural effusion necessitates chest tube drainage in a patient with Kawasaki disease

An 11-month-old Turkish boy was hospitalised with clinical and roentgen graphic evidence of large pleural effusion on the third day of fever and misdiagnosed as parapneumonic effusion. Due to worsening respiratory distress chest tube drainage was performed. Four days later the classic signs of Kawasaki disease appeared. His clinical condition improved gradually and fever subsided after intravenous gammaglobulin and aspirin treatment. A mild transient dilatation of the right coronary artery was seen and returned to the normal diameter within a few weeks. To our knowledge, large pleural effusion in a case of Kawasaki disease, in which chest tube drainage was needed, has not been reported. We describe here a patient with complete Kawasaki disease whose initial presentation mimicked a parapneumonic effusion.     

Treatment of Kawasaki's syndrome with high dose intravenous gammaglobulins

The apparition of coronary aneurysms in Kawasaki syndrome is the reason for the serious nature of this disease. Many attempts have been made to prevent this complication. Two children, respectively 10 and 28 months old, were treated in our unit with salicylate and high dose intravenous gammaglobulin by analogy with the treatment of idiopathic thrombocytopenic purpura. The clinical, electrical, radiological, echographic cardiac surveillance did not show any sign of aneurysms more than 6 months after the onset of the disease. Following the Furusho's study, high dose intravenous gammaglobulin seems to reduce the frequency of coronary aneurysms in patients with Kawasaki syndrome.     

Correlates of coronary artery aneurysm formation in patients with Kawasaki disease

Factors potentially associated with the formation or prevention of coronary artery aneurysms were investigated in 77 children with Kawasaki disease. The patients were divided into two groups. Group A consisted of those who developed coronary artery aneurysms and group B consisted of those who did not. The patients who developed aneurysms had a significantly longer duration of fever and a significantly lower minimum hemoglobin concentration than those who did not develop aneurysm. In patients who developed aneurysms, aspirin therapy was begun significantly later in the course of the illness compared with those who did not develop aneurysms. We suggest that the timing of the initiation of aspirin therapy may be important in the prevention of coronary artery aneurysms in patients with Kawasaki disease. We believe that it may be important to establish the diagnosis of Kawasaki disease as early as possible and to institute aspirin therapy at an appropriate dosage.     

Kawasaki Disease and Peripheral Gangrene in Infancy

Introduction:

Early diagnosis and treatment of Kawasaki disease as the most common cause of acquired heart disease in childhood, may significantly improve the prognosis. Diagnosing infantile Kawasaki (younger than a year) is difficult because of obscure symptoms; at the same time they are at the higher risk of coronary abnormalities.

Case Presentation:

We report three infants with prolonged (more than 5 days) fever and peripheral gangrene without any other clinical manifestations of Kawasaki disease. Kawasaki was diagnosed due to dilation of coronary artery and other aortic branches, thrombocytosis, and rising of ESR and CRP. All patients were treated with high dose aspirin, IVIG and pulse therapy with methylprednisolone. Additionally, cytotoxic drugs or infliximab were used for two of them because of severe aneurysms in the aortic branches. All 3 patients received aspirin with anti-platelet aggregation dose and 2 patients heparin as an anti-coagulant agent for longtime. After adequate treatment, peripheral gangrene, arterial dilations and aneurysms improved, but during 12 months follow-up coronary aneurysms did not improve completely.

Conclusions:

Peripheral gangrene must be regarded as an important sign of infantile Kawasaki disease early treatment of which can prevent severe permanent coronary involvements and sequels.     

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     

Case–control study of giant coronary aneurysms due to Kawasaki disease: The 19th nationwide survey

Background: The risk factors for recently reported cases of giant coronary aneurysms due to Kawasaki disease have not been elaborated. Methods: Fifty‐three patients with giant coronary aneurysms, diagnosed as Kawasaki disease in 2005 and 2006, were selected from the 19th nationwide survey of the disease in Japan. With all the other patients recorded at the same hospitals as a control group, OR and their 95%CI were calculated to delineate the risk factors. Results: In multivariate analyses, patients aged younger than 1 year (OR compared with 1–2‐year‐olds = 6.57) and those older than 5 years (OR compared with 1–2‐year‐olds = 4.24), those who received additional intravenous immunoglobulin (IVIG) without the use of steroid (OR = 8.38) and those who received steroid administration with or without the additional use of IVIG (OR = 220.51 and 83.83, respectively), showed significantly higher OR for giant coronary aneurysms. As for IVIG therapy, the additional use of IVIG (OR = 14.84), total dosage of IVIG exceeding 2500 mg/kg (OR compared with 1500–2499 mg/kg = 12.26) and the duration of IVIG administration for more than 3 days (OR = 30.12), were found to significantly increase the risk of developing giant aneurysms in univariate analyses that were adjusted for sex and age. Conclusions: The observation of 53 patients with giant coronary aneurysms due to Kawasaki disease among those included in the nationwide survey presented some risk factors, together with considerations about the associated aneurysms.