Panton-Valentine leukocidin-positive novel sequence type 5959 community-acquired methicillin-resistant Staphylococcus aureus meningitis complicated by cerebral infarction in a 1-month-old infant.

Community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) has become a pathogen of major importance in pediatric patients. CA-MRSA can cause skin and soft tissue infection in children and young active adults with no predisposing factors, and life-threatening infections such as meningitis or necrotizing pneumonia have been reported. We report here a case of CA-MRSA meningitis complicated by acute left middle cerebral artery (MCA) infarction and necrotizing pneumonia in a previously healthy 1-month-old Vietnamese boy. He was firstly treated with vancomycin, but changed to linezolid because of persistent fever and low vancomycin trough level. He recovered successfully with residual right-sided hemiparesis. The mode of transmission of CA-MRSA and the mechanism of cerebral infarction (thrombotic or embolic) were unknown. The isolate was genotyped as staphylococcal cassette chromosome (SCC) mec type V with a novel sequence type (ST) 5959 harboring the Panton-Valentine leukocidin (PVL) gene. ST 5959 is a double locus variant of ST 59, which is a major PVL-positive CA-MRSA strain isolated in invasive disease in Asian countries. This case report may serve as a warning about the dissemination of PVL-positive CA-MRSA in and around Japan, with the possibility of causing serious life-threatening disease. The potential of linezolid for the treatment of MRSA meningitis as one of the alternative MRSA therapeutic drugs is also discussed.

Sivelestat sodium hydrate treatment for refractory Kawasaki disease.

BACKGROUND: There is still no definite treatment for refractory Kawasaki disease (KD). In this pilot study, we evaluated the safety and efficacy of a new protocol consisting of sivelestat sodium hydrate (SSH) combined with additional i.v. immunoglobulin (IVIG) for KD resistant to initial IVIG therapy. METHODS: This study is a prospective non-randomized, open-label and single-arm study undertaken in a population of refractory KD patients at Chiba University Hospital from December 2006 to March 2016. The subjects had KD resistant to initial IVIG (2 g/kg) and received SSH (0.2 mg/kg/h for 5 days) combined with additional IVIG (2 g/kg) as a second-line therapy. We evaluated the safety and efficacy of the treatment during the study period. RESULTS: Forty-six KD patients were enrolled in this study and no serious adverse event was noted. Of these, 45 patients were evaluated for the incidence of coronary artery lesions, which occurred in one patient (2.2%; 95% CI: 0.5-15.2). Twenty-eight (62.2%) responded promptly and were afebrile after the therapy. The median total duration of fever was 8 days (range, 6-28 days). CONCLUSIONS: Additional IVIG combined with SSH as a second-line therapy for KD refractory to initial IVIG therapy was safe and well tolerated and could be a promising option for severe KD. Further investigations are expected to clarify the safety and timing of SSH treatment for KD.

Factors influencing the development of infantile traumatic brain injury with a biphasic clinical course and late reduced diffusion.

BACKGROUND: Infantile traumatic brain injury (TBI) with a biphasic clinical course and late reduced diffusion (TBIRD) has been reported as a type of TBI. However, it remains uncertain which pediatric patients with TBI develop TBIRD. METHODS: Patients with TBI who were admitted to our hospital and underwent magnetic resonance imaging (MRI) between December 2006 and October 2022 were included in this study. A diagnosis of TBIRD was made in patients with or suspected TBI, with initial symptoms being convulsions or disturbance of consciousness and late-onset subcortical reduced diffusion, the so-called bright tree appearance. Clinical features, neuroimaging (computed tomography (CT) and MRI) findings, laboratory data, and Tada score were retrospectively compared between TBIRD and non-TBIRD patients. Neurological prognosis was assessed using the Pediatric Cerebral Performance Category scale. RESULTS: Of 21 patients who met the inclusion criteria, a diagnosis of TBIRD was made in 7 patients (median age: 8 months). The factors contributing to TBIRD development were seizures lasting over 30 min as the initial symptom (5/7 in TBIRD vs. 0/14 in non-TBIRD), tracheal intubation during initial treatment (5/7 vs. 0/14), and brain parenchymal lesions on CT (3/7 vs. 0/14), suggesting that severe TBI may progress to TBIRD. The Tada score was more positive in patients with TBIRD (6/7) than in those without (0/14). CONCLUSIONS: It is important to monitor infant patients with severe TBI for the development of TBIRD. The Tada score can be a useful tool for TBIRD prediction.

Multimodal MR imaging in acute exacerbation of methylmalonic acidemia.

Methylmalonic acidemia (MMA) is a disorder of methylmalonic acid metabolism caused by impaired methylmalonyl CoA mutase. Neuroimaging shows symmetric hypodensity on CT, and T2 prolongation on MRI in the globus pallidus; however, there have been only a few reports on MR spectroscopy findings and no previous reports on arterial spin labeling (ASL), both of which could reflect neurochemical derangement in MMA. We herein report an 18-month-old Sri Lankan boy presented with severe acute exacerbation of MMA due to bacteremia of Salmonella sp. O7. MRI on the seventh day showed T1 and T2 prolongation with decreased diffusion in the bilateral globus pallidus. ASL revealed hyperperfusion in the bilateral globus pallidus. MR spectroscopy showed increased choline (Cho), myo-inositol (mIns), glutamine (Gln), and lactate (Lac) in the globus pallidus; and increased Gln and Lac in the white matter. The globus pallidus is the site of high energy demand around the age of 1 year. In severe acute exacerbation of MMA, increased anaerobic metabolism due to impaired mitochondrial function may lead to hyperperfusion in the globus pallidus to compensate for a disturbed energy supply. Increased Cho, mIns, and Lac in the globus pallidus may result from active demyelination, astrogliosis, and increased anaerobic metabolism. Increased Gln in the basal ganglia and white matter may reflect excitotoxicity.

Common variants in CASP3 confer susceptibility to Kawasaki disease.

Kawasaki disease (KD; OMIM 611775) is an acute vasculitis syndrome which predominantly affects small- and medium-sized arteries of infants and children. Epidemiological data suggest that host genetics underlie the disease pathogenesis. Here we report that multiple variants in the caspase-3 gene (CASP3) that are in linkage disequilibrium confer susceptibility to KD in both Japanese and US subjects of European ancestry. We found that a G to A substitution of one commonly associated SNP located in the 5' untranslated region of CASP3 (rs72689236; P = 4.2 x 10(-8) in the Japanese and P = 3.7 x 10(-3) in the European Americans) abolished binding of nuclear factor of activated T cells to the DNA sequence surrounding the SNP. Our findings suggest that altered CASP3 expression in immune effecter cells influences susceptibility to KD.

Fosphenytoin dosing regimen including optimal timing for the measurement of serum phenytoin concentration in pediatric patients.

INTRODUCTION: We aimed to evaluate the pediatric fosphenytoin dosing regimen, including optimal timing for the measurement of total serum phenytoin concentration (CPHT). METHODS: We retrospectively investigated pediatric patients with status epilepticus or seizure clusters treated with fosphenytoin between April 2013 and March 2018. Two CPHT measurements were analyzed, one 2-4 h after the loading dose and another before the second dose. Individual pharmacokinetic parameters were estimated using the Bayesian method and were used to simulate CPHT. RESULTS: The present study involved 12 pediatric patients; the loading dose of fosphenytoin was 22.1 (17.2-27.2) mg/kg. The CPHT was 13.4 (8.6-18.9) µg/mL 2-4 h after the loading dose. The CPHT estimated from individual pharmacokinetic parameters 12 and 24 h after the loading dose was 9.5 (6.7-14.2) and 5.8 (3.7-10.0) µg/mL, respectively. If fosphenytoin was administered at a loading dose of 22.5 mg/kg and a maintenance dose of 5 or 7.5 mg/kg (administered every 12 h, starting 12 h after the loading dose), then the CPHT on day 8 was estimated to be 5.74 (2.6-15.4) µg/mL at 5 mg/kg and 13.9 (5.7-31.0) µg/mL at 7.5 mg/kg. CONCLUSIONS: In pediatric patients, a maintenance dose of fosphenytoin should be started 12 h after the loading dose, and a maintenance dose of 5-7.5 mg/kg/dose every 12 h may be better than every 24 h. We recommend measuring CPHT at 2 and 12 h after the loading dose to simplify and safely adjust the dosage in clinical practice.

Increased production of vascular endothelial growth factor-d and lymphangiogenesis in acute Kawasaki disease.

BACKGROUND: Kawasaki disease (KD) is characterized by systemic vasculitis with tissue edema. During the healing process of inflammation, lymphangiogenesis is essential for reducing tissue edema. One potential responsible candidate for the induction of lymphangiogenesis in the healing process of acute KD is vascular endothelial growth factor-D (VEGF-D). METHODS AND RESULTS: Sequential changes in serum VEGF-D levels in patients with acute KD (n = 47) using an enzyme-linked immunosorbent assay were investigated. Cross-sectional areas of lymphatic vessels and VEGF-D protein expression were evaluated immunohistochemically in cardiac tissues of patients (n = 6) who died of KD. Regulation of VEGF-D messenger RNA (mRNA) expression in cultured fibroblasts was assessed using quantitative real-time polymerase chain reaction. Serum VEGF-D levels increased after intravenous immunoglobulin therapy in patients with acute KD (P < 0.001). In addition, they were significantly lower in patients with coronary artery lesions (CAL) than in those without CAL (P < 0.05). The cross-sectional areas of lymphatic vessels in cardiac tissues were enlarged in patients with acute KD. VEGF-D protein was detected on the endothelium of the enlarged lymphatic vessels. In vitro, tumor necrosis factor- significantly down-regulated VEGF-D mRNA expression in cultured fibroblasts (P = 0.004). CONCLUSIONS: This study indicates that the production of VEGF-D increases and is related to lymphangiogenesis in patients with acute KD. In addition, low VEGF-D production appears to be associated with the development of CAL.

Kawasaki Disease Shock Syndrome in Japan and Comparison With Multisystem Inflammatory Syndrome in Children in European countries.

Multisystem inflammatory syndrome in children (MIS-C) is a severe Kawasaki-like illness that was first linked to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in European countries in the spring of 2020 and has been suggested to have overlap with Kawasaki disease shock syndrome (KDSS). There are few reports of MIS-C from Asia. This observational study aimed to identify the clinical features in children presenting with KDSS in Japan over a 5-year period and to summarize similarities and differences between KDSS and MIS-C. We retrospectively collected data on patient characteristics, clinical signs and symptoms, treatment, and prognosis including coronary artery abnormalities (CAAs), which were compared with data of patients with KDSS worldwide and patients with MIS-C from a review. KDSS was identified in 6 (1.1%) of 552 patients with Kawasaki disease (KD) treated at a single institution in Japan between 2015 and 2020 (1 in 2020). In patients with KDSS in Japan or worldwide vs. patients with MIS-C, KDSS was more likely to have a diagnosis of complete KD (100, 70 vs. 6.3%), a higher incidence of CAAs (50, 65 vs. 11%), and a greater requirement for vasoactive agonists (67, 67 vs. 43%) because of circulatory shock (100, 50 vs. 26%). Both KDSS and MIS-C had good prognosis (mortality 0, 6.7 vs. 1.7%). Although KDSS in Japan and MIS-C show some overlap in clinical symptoms, they are unlikely to be the same disease entity. KDSS is more likely to have a cardiovascular phenotype with CAAs and requires treatment with cardiovascular agents.

Zebrafish gene knockdowns imply roles for human YWHAG in infantile spasms and cardiomegaly.

Williams-Beuren syndrome (WBS) is a neurodevelopmental disorder presenting with an elfin-like face, supravalvular aortic stenosis, a specific cognitive-behavioral profile, and infantile hypercalcemia. We encountered two WBS patients presenting with infantile spasms, which is extremely rare in WBS. Array comparative genomic hybridization (aCGH) and fluorescent in situ hybridization (FISH) analyses revealed atypical 5.7-Mb and 4.1-Mb deletions at 7q11.23 in the two patients, including the WBS critical region and expanding into the proximal side and the telomeric side, respectively. On the proximal side, AUTS2 and CALN1 may contribute to the phenotype. On the telomeric side, there are two candidate genes HIP1 and YWHAG. Because detailed information of them was unavailable, we investigated their functions using gene knockdowns of zebrafish. When zebrafish ywhag1 was knocked down, reduced brain size and increased diameter of the heart tube were observed, indicating that the infantile spasms and cardiomegaly seen in the patient with the telomeric deletion may be derived from haploinsufficiency of YWHAG.

Neurochemistry of hyponatremic encephalopathy evaluated by MR spectroscopy.

MR spectroscopy in a patient with hyponatremic encephalopathy due to the syndrome of inappropriate secretion of antidiuretic hormone revealed decreased N-acetyl-aspartate, creatine plus phosphocreatine, choline-containing compounds, and myo-inositol, with normal glutamate and increased glutamine, which normalized after Na normalization. The decreased concentrations of creatine plus phosphocreatine, choline-containing compounds and myo-inositol are explained by their release as osmolytes from brain cells to adapt to hypo-osmolality induced cerebral edema. Increased glutamine, which not only acts as an osmolyte but also protects neurons under excitotoxic conditions, may suggest that a disrupted glutamate-glutamine cycle may play an important role in the pathogenesis of hyponatremic encephalopathy.

Prognostic value of MR spectroscopy in patients with acute excitotoxic encephalopathy.

PURPOSE: Acute excitotoxic encephalopathy is the most common encephalopathy syndrome in Japan, and consists of acute encephalopathy with biphasic seizures and late reduced diffusion (AESD) and mild encephalopathy associated with excitotoxicity (MEEX). Neurological sequelae remain in approximately 70% of patients with AESD, however, it is difficult to predict the prognosis early in the course. We evaluated the brain metabolites observed on MRS as to whether they can predict the neurological outcome. METHODS: 16 previously healthy Japanese patients with excitotoxic encephalopathy (8 with AESD and 8 with MEEX) were included in this study. MR spectroscopy (MRS) was acquired from the fronto-parietal white matter (TR/TE = 5000/30 msec) with a 3.0 T scanner. Quantification of metabolites was performed using an LCModel. Neurological outcome was assessed with the Pediatric Cerebral Performance Category score, score 1 being classified as G1 (normal), scores 2 and 3 as G2 (mild to moderate), and scores 4-6 as G3 (severe). RESULTS: MRS data which predict a poor neurological outcome (G2 and 3) include the following: decreased N-acetyl aspartate (NAA) (sensitivity 88%, specificity 100%), decreased creatine (47%, 100%), increased lactate (47%, 100%), and decreased glutamate (sensitivity 35%, specificity 100%). Limited to the acute stage within seven days of onset, those for a poor prognosis are as follows, decreased NAA (88%, 100%), decreased creatine (38%, 100%), and increased lactate (38%, 100%). CONCLUSION: MRS is useful for prognosis prediction of acute excitotoxic encephalopathy. Decreased NAA will be the most effective metabolite for neurological prognosis prediction.

Aspirin Dose and Treatment Outcomes in Kawasaki Disease: A Historical Control Study in Japan.

Aspirin has been used as a concomitant drug in the treatment of Kawasaki disease (KD). In recent years, there has been discussion concerning whether high-dose aspirin is appropriate for treatment in the acute phase of KD. We retrospectively investigated the incidence of coronary artery abnormalities (CAAs) and the antipyretic effect of 30 to 50 mg/kg/day aspirin, the minimum and the maximum approved doses in Japan. This was a single-center, non-randomized, retrospective, historical cohort study. Patients were routinely treated with 50 mg/kg/day aspirin (50-mg Group) between 2007 and April 2014, and with 30 mg/kg/day aspirin (30-mg Group) between May 2014 and 2016. All patients were given initial and, if necessary, subsequent intravenous immunoglobulin (IVIG) 2.0 g/kg. The primary endpoint was incidence of CAAs defined as a CA diameter with a Z score ≥2.5 at treatment week 4. The secondary endpoint was incidence of further treatment. Incidences were compared using inverse probability weighting analysis adjusting for age, sex, and risk scores. In 587 patients, there was no significant difference in incidence of CAAs (odds ratio in 30-mg Group 0.769, 95% confidence interval (CI): 0.537-1.101, p = 0.151). Risk of further treatment after the first IVIG in the 30-mg Group was significantly higher than that in the 50-mg Group (odds ratio 1.379, 95% CI: 1.051-1.811, p = 0.021). Although this study has some limitations, the findings suggest that aspirin 50 mg/kg/day may have no significant effect on improving incidence of CAAs compared with 30 mg/kg/day but may have a lower rate of further treatment.

Elevated granulocyte colony-stimulating factor levels predict treatment failure in patients with Kawasaki disease.

BACKGROUND: Kawasaki disease (KD) is an acute vasculitis in young children, frequently associated with coronary artery aneurysms. The intravenous infusion of high-dose IgG (IVIG) effectively reduces the systemic inflammation and the incidence of coronary artery lesions, although the precise underlying mechanisms are unknown. OBJECTIVE: We performed expression profiling of whole blood cells to investigate the mechanisms underlying the effect of IVIG and to identify biomarkers associated with unresponsiveness to IVIG. METHODS: We compared the transcript abundance among pre-IVIG and post-IVIG patients and febrile control patients. Then we analyzed the mRNA levels and the protein levels among the different cohort of patients with KD who were either responsive or nonresponsive to the initial IVIG. RESULTS: A total of 298 transcripts were overrepresented or underrepresented in the pre-IVIG patients compared with post-IVIG patients and febrile controls, of which 15 transcripts were differentially expressed in nonresponsive patients with KD compared with responsive patients before IVIG. The protein levels of polycythemia rubra vera 1, which was one of the most variably expressed transcripts in pre-IVIG patients, and the serum granulocyte colony-stimulating factor levels were significantly higher in nonresponsive patients than in responsive patients before the initial IVIG administration. CONCLUSION: These findings suggest that the variable gene expression profiles were correlated to the responses of patients with KD to IVIG administration. Polycythemia rubra vera 1 and granulocyte colony-stimulating factor levels may be good biomarkers for predicting response to IVIG in patients with KD.

IgG levels in Kawasaki disease and its association with clinical outcomes.

Previous studies have suggested an association of IgG levels (before and after IVIG infusion) with clinical outcomes in Kawasaki disease. A retrospective analysis was performed that included 418 patients with KD admitted to Tokyo Women's Medical University Yachiyo Medical Center to evaluate pre- and post-IVIG IgG levels and its relation to outcomes. All patients received an initial IVIG infusion and aspirin; IgG levels were measured in 350 patients before IVIG (pre-IVIG IgG levels) and in 373 patients 48 h after starting IVIG infusion (post-IVIG IgG levels). Media and standard deviation of the pre- and post-IVIG IgG levels were reported and classified according to age. Also, IgG z-scores were calculated according to normal values of IgG by age. The number of cases and corresponding percentage of non-responders were reported by age and total patients. The association of pre-IVIG, post-IVIG IgG levels and post-IVIG IgG level/pre-IVIG IgG level ratio with no-response was evaluated by simple logistic regression model based on the IgG z-score, and regression coefficient, X2 value, p, and R2 of Nagelkerke were reported. Pre-IVIG and post-IVIG IgG levels presented an association with non-responders with statistical significance. This association was more evident between post-IVIG IgG levels and non-responders. Regarding coronary alterations, it was not possible to perform an adequate statistical analysis due the small number of patients. Pre- and post-IVIG infusion IgG levels could be an important biomarker in KD as well as in other inflammatory conditions. Higher IgG levels could be associated with a more effective immunomodulatory action and associated with better clinical outcomes.

Loss of myelinated axons and astrocytosis in an autopsy case of acute encephalopathy with biphasic seizures and late reduced diffusion.

Acute encephalopathy with biphasic seizures and late reduced diffusion (AESD) is the most common pediatric encephalopathy in Japan, however, the exact neuropathology remains uncertain. The postmortem neuropathology in a patient with AESD revealed reduction of myelinated axons with early stage of astrocytosis in the absence of neuronal loss, which suggests the primary pathological damage in AESD involves myelinated axons and astrocytes rather than cortical neurons. An increased number of gemistocytic astrocytes at the corticomedullary junction may cause reduced diffusion, leading to the so-called bright tree appearance on magnetic resonance imaging, characteristic to AESD.

Excitotoxicity in encephalopathy associated with STEC O-157 infection.

Cytokines play an important role in the pathogenesis of the severe complications of Shiga toxin-producing Escherichia coli (STEC) infection, such as hemolytic uremic syndrome (HUS) and acute encephalopathy. A 3-year-old boy with acute encephalopathy associated with STEC O-157 HUS showed increased levels of IL-6 and IL-10, which normalized after methylprednisolone pulse therapy, and additionally exhibited a transient increase of glutamine on MR spectroscopy. This finding suggests that excitotoxicity, in addition to hypercytokinemia, may play an important role in the pathogenesis of HUS encephalopathy.

Infantile traumatic brain injury with a biphasic clinical course and late reduced diffusion.

Reduced diffusion in the subcortical white matter has been reported in some infants with traumatic brain injury (TBI), including abusive head trauma. However, the pathomechanisms of the lesions and clinical features are uncertain. We herein report two infants with TBI who presented with biphasic clinical courses and late reduced diffusion in the subcortical white matter, and reviewed seven clinically and radiologically similar patients with TBI. Their clinical features (secondary neurological symptoms on days 3 to 6) and radiological findings (normal diffusion on days 1 to 2, followed by reduced diffusion on days 3 to 6) are very similar to those observed in patients with acute encephalopathy with biphasic seizures and late reduced diffusion (AESD). MR spectroscopy in one patient revealed a transient increase of glutamine, which is also observed in AESD, suggesting excitotoxicity as a possible pathomechanism.

Vital Signs as Predictor Factors of Intravenous Immunoglobulin Resistance in Patients With Kawasaki Disease.

Kawasaki disease (KD) is the most common cause of acquired heart disease in children. Intravenous immunoglobulin (IVIG) may significantly lower the frequency of coronary artery complications. However, some patients do not respond to initial therapy and are at higher risk of developing coronary artery lesion. A retrospective analysis of data from 419 KD patients was performed. The patients were divided into IVIG responders (n = 318) and IVIG nonresponders (n = 101). Multivariate logistic regression analysis revealed neutrophil percentage, albumin, aspartate aminotransferase, heart rate, and body temperature were independent predictors of IVIG resistance. We generated a predictive scoring system by assigning 1 point for the presence of these parameters (neutrophil >80%, albumin <3.4 g/dL, aspartate aminotransferase >100 IU/L, heart rate >146 bpm, and body temperature >38.8°C). This scoring system had a sensitivity of 76.2% and specificity of 64.8%, and a positive predictive value of 40.1% and a negative predictive value of 89.4%. Vital signs may be helpful to detect KD patients with IVIG resistance.