Yoshinari Inoue

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.

Increased CD11b expression on polymorphonuclear leucocytes and cytokine profiles in patients with Kawasaki disease

Clinical evidence implicates polymorphonuclear leucocytes in the pathogenesis of vasculitis in Kawasaki disease. We examined modulation of expression of adhesion molecules (CD11b and CD62L) on polymorphonuclear leucocytes and how this expression is related to serum cytokine concentrations. In 18 patients with Kawasaki disease and 15 control subjects, adhesion molecule expression was determined by two‐colour immunofluorescence staining of blood leucocytes and flow cytometry. Eight cytokines and chemokines were also measured. In patients with Kawasaki disease, mean fluorescence intensity for CD11b before giving intravenous immunoglobulin was significantly higher than in normal subjects (P < 0·005). After intravenous immunoglobulin, mean fluorescence intensity for CD11b decreased significantly. With coronary artery lesions present, mean CD11b fluorescence intensity was significantly higher than without coronary artery lesions (P = 0·005 before intravenous immunoglobulin; P = 0·024 after intravenous immunoglobulin). No differences were seen in CD62L expression on polymorphonuclear leucocytes between patients with Kawasaki disease and normal subjects. CD11b expression on polymorphonuclear leucocytes correlated positively with serum interleukin (IL)‐6, IL‐10, granulocyte colony‐stimulating factor, percentage of neutrophils among white cells and C‐reactive protein. Polymorphonuclear leucocytes from patients with Kawasaki disease showed increased CD11b expression, which was associated with increased serum cytokines and appeared to be related to coronary artery lesions.

Successful Treatment of a Child with Inferior Vena Cava Thrombosis Using a Temporary Inferior Vena Cava Filter

We describe a 6-year-old girl with Epstein-Barr virus-related hemophagocytic lymphohistiocytosis who developed inferior vena cava (IVC) thrombosis during chemotherapy. Treatment with an anticoagulant, thrombolytic agent and short-term placement of an IVC filter was followed by complete resolution. Pulmonary perfusion scintigraphy performed subsequently revealed no evidence of pulmonary embolism. We conclude that temporary placement of an IVC filter can be an important part of the treatment of IVC thrombosis in children.

Rescue of a Child with Fulminant Myocarditis Using Percutaneous Cardiopulmonary Support

Abstract. This report describes a 14-year-old girl with fulminant myocarditis who was successfully treated with a percutaneous cardiopulmonary support (PCPS). She developed progressive cardiac failure after a 3-week history of progressive fatigue, fever, tachypnea, and dyspnea requiring inotropic support, mechanical ventilation, and intra-aortic balloon pumping. Her condition continued to deteriorate, and she was cannulated for PCPS using a right femoral artery/femoral vein approach, which resulted in rapid improvement and hemodynamic stabilization. This case documents that circulatory support with PCPS is effective for treating children with fulminant myocarditis.

Atlanto-axial subluxation (Grisel’s syndrome) associated with mumps

Grisel’s syndrome is a rare condition of uncertain etiology characterized by atlanto-axial subluxation due to an infectious process in the head and cervical region. 1,2 The infection usually starts from the head or neck and then spreads to the cervical vertebrae, although the exact route is often uncertain. The inflammation causes ligamentous laxity with the possible risk of atlanto-axial subluxation and in severe cases can cause spinal cord injury. 3

Acute effects of prostaglandin D2 to induce airflow obstruction and airway microvascular leakage in guinea pigs: role of thromboxane A2 receptors.

BACKGROUND Although prostaglandin D2 (PGD2), a mast cell-derived inflammatory mediator, may trigger allergic airway inflammation, its potency and the mechanism by which it induces airway microvascular leakage, a component of airway inflammation, is not clear. OBJECTIVE We wanted to evaluate the relative potency of PGD2 to cause microvascular leakage as compared to airflow obstruction, because both responses were shown to occur simultaneously in allergic airway diseases such as asthma. The role of thromboxane A2 receptors (TP receptors) in inducing these airway responses was also examined. METHODS Anesthetized and mechanically ventilated guinea pigs were given i.v. Evans blue dye (EB dye) and, 1 min later, PGD2 (30, 100, 300 or 1,000 nmol/kg). For comparison, the effect of 150 nmol/kg histamine or 2 nmol/kg leukotriene D4 (LTD4) was also examined. Lung resistance (R(L)) was measured for 6 min (or 25 min for selected animals) and the lungs were removed to calculate the amount of extravasated EB dye into the airways as a marker of leakage. In some of the animals, specific TP receptor antagonists, S-1452 (10 microg/kg) or ONO-3708 (10 mg/kg), or a thromboxane A2 synthase inhibitor, OKY-046 (30 mg/kg), was pretreated before giving PGD2. RESULTS Injection of PGD2 produced an immediate and dose-dependent increase in RL (peaking within 1 min), which was significant at all doses studied. At 1,000 nmol/kg, PGD2 induced a later increase in R(L), starting at 3 min and reaching a second peak at 8 min. By contrast, only PGD2 at doses of 300 and 1,000 nmol/kg produced a significant increase in EB dye extravasation. The relative potency of 1,000 nmol/kg PGD2 to induce leakage as compared to airflow obstruction was comparable to histamine at most of airway levels, but less than LTD4. Both responses caused by PGD2 were completely abolished by S-1452 and ONO-3708, but not by OKY-046. CONCLUSION PGD2 may induce airway microvascular leakage by directly stimulating TP receptors without generating TXA2 in guinea pigs. Microvascular leakage may play a role in the development of allergic airway inflammation caused by PGD2.

INCREASED CIRCULATING GRANULOCYTE COLONY-STIMULATING FACTOR IN ACUTE KAWASAKI DISEASE

childhood characterized by multiple clinical and biochemical features of inflammation and histopathologic features of vasculitis. Although epidemiologic evidences strongly support an infectious etiology for this disease, its pathogenesis remains unclear.1 During the acute phase, toxic neutrophils are seen along with leukocytosis and left shift. Serial immunoregulatory abnormalities have been demonstrated, including increased production of interleukin (IL)-1, tumor necrosis factor (TNF)-α, IL-2, interferon-γ, IL-6, IL-8, soluble IL-2 receptor and marked T cell and polyclonal B cell activation.2 It has been proposed that an increase in oxygen radical generation may induce coronary vascular tissue damage, resulting in thromboarteritis and coronary occlusion.3,4 Niwa and Sohmiya3 reported that oxygen radicals produced by activated neutrophils induced the endothelial cell damage in KD. In the present study, we investigated the serum levels of granulocyte colony-stimulating factor (G-CSF) in KD, and compared them with leukocyte counts. Granulocyte colonystimulating factor has been identified as a glycoprotein that stimulates the production and functional activation of neutrophilic granulocytes both in vivo and in vitro.5 We also studied serum lipid peroxide levels as a marker of endothelial damage in the acute phase of KD. Patients and methods

Amatoxin Poisoning from Ingestion of Japanese Galerina Mushrooms

Background: Although some Japanese Galerina species poisonings manifest as gastrointestinal symptoms followed by late-onset hepatorenal failure (phalloides syndrome), the toxin responsible for this has not been determined. Case Report: We report a 6-year-old boy who developed characteristic cholera-like diarrhea and late-onset severe hepatic deterioration after eating mushrooms, later identified as a Galerina species, most likely Galerina fasciculata. A residual mushroom revealed α-amanitin. This account is the first known reported case of poisoning by Japanese Galerina species where an amatoxin was demonstrated to be responsible for the toxicity.