Tomio Kobayashi

Prediction of Intravenous Immunoglobulin Unresponsiveness in Patients With Kawasaki Disease

Background— In the present study, we developed models to predict unresponsiveness to intravenous immunoglobulin (IVIG) in Kawasaki disease (KD). Methods and Results— We reviewed clinical records of 546 consecutive KD patients (development dataset) and 204 subsequent KD patients (validation dataset). All received IVIG for treatment of KD. IVIG nonresponders were defined by fever persisting beyond 24 hours or recrudescent fever associated with KD symptoms after an afebrile period. A 7-variable logistic model was constructed, including day of illness at initial treatment, age in months, percentage of white blood cells representing neutrophils, platelet count, and serum aspartate aminotransferase, sodium, and C-reactive protein, which generated an area under the receiver-operating-characteristics curve of 0.84 and 0.90 for the development and validation datasets, respectively. Using both datasets, the 7 variables were used to generate a simple scoring model that gave an area under the receiver-operating-characteristics curve of 0.85. For a cutoff of 0.15 or more in the logistic regression model and 4 points or more in the simple scoring model, sensitivity and specificity were 86% and 67% in the logistic model and 86% and 68% in the simple scoring model. The kappa statistic is 0.67, indicating good agreement between the logistic and simple scoring models. Conclusions— Our predictive models showed high sensitivity and specificity in identifying IVIG nonresponders among KD patients.

Effect of corticosteroids in addition to intravenous gamma globulin therapy on serum cytokine levels in the acute phase of Kawasaki disease in children

OBJECTIVE The aim of this multicenter prospective and randomized study was to determine the effect of adding corticosteroids to intravenous gamma globulin (i.v.GG) therapy on serum cytokine levels, as well as to see its effect on the clinical course in children in the acute phase of Kawasaki disease (KD). STUDY DESIGN Patients with KD (n=32) were randomized to receive either i.v.GG alone (G group) or i.v.GG plus corticosteroids (G+S group). The clinical course and cytokine responses between groups were compared. RESULTS The pretreatment serum levels of interleukin (IL)-2, IL-6, IL-8, and IL-10 were significantly higher in patients with KD than in healthy controls. Although i.v.GG alone failed to reduce cytokine concentrations within 24 hours of i.v.GG administration, corticosteroids plus i.v.GG reduced IL-2, IL-6, IL-8, and IL-10 levels. The levels of IL-2, IL-6, IL-8, and IL-10 within 24 hours after initiating i.v.GG therapy were significantly lower in the G+S group than in the G group. The duration of fever was shorter, and the C-reactive protein concentration decreased more quickly in the G+S group than in the G group. CONCLUSIONS These findings suggest that corticosteroids rapidly ameliorate symptoms by reducing cytokine levels in children with KD.

Risk Stratification in the Decision to Include Prednisolone With Intravenous Immunoglobulin in Primary Therapy of Kawasaki Disease

Background: We reported previously that intravenous immunoglobulin (IVIG) plus prednisolone for initial therapy for Kawasaki disease (KD) prevented coronary artery abnormalities (CAA) more effectively than IVIG alone. However, questions remain as to whether PSL has potential benefit in all KD patients. The present study was designed to explore the possibility of stratified initial therapy including PSL in patients with and without a high predicted risk of being an IVIG nonresponder. Methods: We retrospectively analyzed data from KD patients who received IVIG (n = 896) or IVIG + PSL (n = 110) by scoring the likely risk of being an IVIG nonresponder. We compared clinical and coronary outcomes between treatment-defined groups separately for high- and low-risk patients. Results: Among low-risk patients (score 0–4), clinical and coronary outcomes were similar. Among high-risk patients (score 5 or more), incidences of treatment failure and coronary artery abnormalities until 1-month follow-up were more frequent in the IVIG than in the IVIG + PSL group. Sex- and score point-adjusted odds ratios for IVIG + PSL were 0.17 (95% confidence interval, 0.08–0.39) for treatment failure and 0.27 (95% confidence interval, 0.07–0.85) for coronary artery abnormalities A among high-risk patients. Conclusions: IVIG + PSL treatment was associated with improving clinical and coronary outcomes in patients at high risk of being IVIG nonresponders.

Ulinastatin, a Urinary Trypsin Inhibitor, for the Initial Treatment of Patients With Kawasaki Disease A Retrospective Study

Background— Markedly activated neutrophils or higher plasma levels of neutrophil elastase are involved in the poor response to intravenous immunoglobulin (IVIG) and the formation of coronary artery lesions (CAL) in patients with acute Kawasaki disease. We hypothesized that ulinastatin (UTI), by both direct and indirect suppression of neutrophils, would reduce the occurrence of CAL. Methods and Results— We retrospectively analyzed the clinical records of patients with Kawasaki disease between 1998 and 2009. Three hundred sixty-nine patients were treated with a combination of UTI, aspirin, and IVIG as an initial treatment (UTI group), and 1178 were treated with a conventional initial treatment, and IVIG with aspirin (control group). The baseline characteristics did not demonstrate notable differences between the two groups. The occurrence of CAL was significantly lower in the UTI group than in the control group (3% versus 7%; crude odds ratio [OR], 0.46; 95% confidence interval [CI], 0.25–0.86; P=0.01). The OR adjusted for sex, Gunma score (the predictive score for IVIG unresponsiveness), and dosage of initial IVIG (1 or 2 g/kg) was 0.32 (95% CI, 0.17–0.60; P<0.001). In addition, most CAL occurred in patients requiring additional rescue treatment and the proportion of those patients was significantly lower in the UTI group than in the control group (13% versus 22%; crude OR, 0.52; 95% CI, 0.38–0.73; P<0.001). The adjusted OR was 0.30 (95% CI, 0.20–0.44; P<0.001). Conclusions— UTI was associated with fewer patients requiring additional rescue treatment and reduction of CAL in this retrospective study.

Giant Coronary Aneurysm of Kawasaki Disease Developing During Postacute Phase

The patient suffered from Kawasaki disease at 5 months of age. The first angiography, performed 14 months after the onset of disease, showed a right coronary aneurysm with a maximal diameter of 6 mm and normal left coronary artery (Figure 1⇓). Dipyridamole and propranolol were given as antiplatelet therapy and for reduction of myocardial oxygen consumption, respectively. The second angiography, performed 6 years later, revealed enlargement of the right coronary aneurysm, with a maximal diameter of 15 mm (Figure 2⇓). Treatment with dipyridamole and …

Outcomes of childhood pulmonary arterial hypertension in BMPR2 and ALK1 mutation carriers

Mutations in the bone morphogenetic protein receptor type 2 (BMPR2) gene and the activin receptor-like kinase 1 (ALK1) gene have been reported in heritable pulmonary arterial hypertension (HPAH) and idiopathic pulmonary arterial hypertension (IPAH). However, the relation between clinical characteristics and each gene mutation in IPAH and HPAH is still unclear, especially in childhood. The aim of this study was to determine, in a retrospective study, the influence and clinical outcomes of gene mutations in childhood IPAH and HPAH. Fifty-four patients with IPAH or HPAH whose onset of disease was at <16 years of age were included. Functional characteristics, hemodynamic parameters, and clinical outcomes were compared in BMPR2 and ALK1 mutation carriers and noncarriers. Overall 5-year survival for all patients was 76%. Eighteen BMPR2 mutation carriers and 7 ALK1 mutation carriers were detected in the 54 patients with childhood IPAH or HPAH. Five-year survival was lower in BMPR2 mutation carriers than mutation noncarriers (55% vs 90%, hazard ratio 12.54, p = 0.0003). ALK1 mutation carriers also had a tendency to have worse outcome than mutation noncarriers (5-year survival rate 64%, hazard ratio 5.14, p = 0.1205). In conclusion, patients with childhood IPAH or HPAH with BMPR2 mutation have the poorest clinical outcomes. ALK1 mutation carriers tended to have worse outcomes than mutation noncarriers. It is important to consider aggressive treatment for BMPR2 or ALK1 mutation carriers.

External validation of a risk score to predict intravenous immunoglobulin resistance in patients with kawasaki disease.

Background: We previously developed a new risk score to predict intravenous immunoglobulin (IVIG) resistance in Kawasaki disease. However, the IVIG dosage used in that study (1 g/kg/d for 2 consecutive days) differs from the single infusion of 2 g/kg recommended in the United States and elsewhere. Our aim was to assess the validity and applicability of our risk score in patients treated with a single infusion. Methods: We used a database of 1626 patients with Kawasaki disease given initial IVIG treatment at a dose of 1 g/kg/d for 2 consecutive days (n = 990; IVIG- 1 g/kg × 2) or 2 g/kg/d for 1 day (n = 636; IVIG- 2 g/kg × 1) across 17 hospitals in Japan. Patients received the total IVIG dose within 36 hours in IVIG- 1 g/kg × 2 and 24 hours in IVIG- 2 g/kg × 1. We stratified the patients according to a risk scoring system developed to predict IVIG unresponsiveness, based on scores of ≥5 points. We compared the accuracy of prediction between the 2 groups using receiver operating characteristic analysis. Results: Baseline characteristics and clinical outcomes were similar between both groups. The areas under the receiver operating characteristic curve in IVIG- 2 g/kg × 1 were similar to those of IVIG- 1 g/kg × 2. Using a cut-off risk score of ≥5 points, we could identify IVIG resistance in terms of coronary artery abnormalities within 1 month and coronary artery abnormalities at 1 month with equivalent sensitivity and specificity in both groups. Conclusion: Our risk score can be used to predict IVIG unresponsiveness to a regimen based on a single infusion of 2 g/kg IVIG.

Staged repair of truncus arteriosus with interrupted aortic arch: adjustable pulmonary artery banding.

We report a successful two-stage treatment for an infant with truncus arteriosus with aortic arch interruption. The treatment consisted of flow-adjustable bilateral pulmonary artery banding using clipping and postoperative balloon dilation, followed by staged repair. The merits of this strategy are as follows: (1) bilateral pulmonary artery banding is less invasive than neonatal one-stage repair; (2) use of cardiopulmonary bypass can be avoided in the newborn period; and (3) control of pulmonary blood flow adjusted for body size is possible. Although further studies are needed, our therapeutic strategy might provide a clinically important option for managing severe congenital heart disease.

Effect of dipyridamole on the blood flow in coronary aneurysms resulting from Kawasaki disease.

SummaryDipyridamole has been widely used in Japan to treat patients with a coronary aneurysm resulting from Kawasaki disease, but its effect in these patients has not been established. In the present study we assessed the effect of dipyridamole on the coronary arteries of patients with a history of Kawasaki disease by measuring the diameter of the coronary arteries and by quantifying the disappearance time of contrast medium (runoff time) on coronary angiography. Intravenous injection of dipyridamole increased the diameter of nondilated arteries by 7.9%. Its effect on the diameter of dilated coronary arteries (coronary aneurysm) was less than 3% (p<0.01). Runoff time of dilated coronary arteries was significantly (p<0.01) greater than that of nondilated coronary arteries. Dipyridamole accelerated runoff time not only in nondilated coronary arteries (p<0.01) but also in coronary arteries with various degrees of dilatation (p<0.01). We conclude that dipyridamole increases blood flow in coronary arteries without dilating the proximal aneurysm in children with a history of Kawasaki disease.

Rupture of a coronary artery aneurysm in Kawasaki disease: A rare case and review of the literature for the past 15 years

We describe the rare case of a 3-month-old boy who had a ruptured coronary artery aneurysm (CAA) in the right coronary artery (RCA) combined with multiple CAAs in the left circumflex and left anterior descending coronary arteries. We also present a statistical analysis of all the ruptured CAAs previously reported and review the literature of the past 15 years, focusing on the location, etiology, diagnosis, management, and prognosis of giant CAAs.