Clinical features and new diagnostic criteria for the syndrome of periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis.

AIM: The syndrome of periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) is a common inflammatory disease that presents with periodic fever. We aimed to establish more specific diagnostic criteria for PFAPA based on the clinical characteristics of PFAPA patients in our directory. METHOD: The clinical, laboratory, genetic, and family history details of 257 Japanese PFAPA patients treated at our and other affiliated hospitals between April 2000 and April 2018 were analyzed along with quantitative measurements of the number of CD64 molecules on neutrophils, and the levels of serum inflammatory cytokines. The sensitivity and specificity of the criteria were calculated for several diseases. RESULTS: Because recurrent fevers were crucial findings, they were defined as the required criterion. Tonsillitis/pharyngitis with white moss were important accompanying signs. Other symptoms associated with febrile episodes were cervical lymphadenitis with tenderness, aphthous stomatitis, sore throat, vomiting, and headache but not cough. A total of 159 (62%) patients had a family history of recurrent fevers, indicating autosomal dominant inheritance. C-reactive protein levels were extremely elevated during febrile attacks but normal in attack-free periods. Serum immunoglobulin D levels were high in 72 of the 199 tested patients. Oral glucocorticoid and cimetidine were extremely effective in all and 51.6% of the patients, respectively. We defined the above as supportive criteria. These criteria were sensitive and specific enough to distinguish PFAPA from other recurrent fever diseases. Raised serum interferon-γ levels and remarkable CD64 expression on neutrophils during flare-ups were recognized, indicating they contributed to diagnosis. CONCLUSION: Our new criteria are useful for diagnosing PFAPA.

Efficacy of primary treatment with immunoglobulin plus ciclosporin for prevention of coronary artery abnormalities in patients with Kawasaki disease predicted to be at increased risk of non-response to intravenous immunoglobulin (KAICA): a randomised controlled, open-label, blinded-endpoints, phase 3 trial.

BACKGROUND: Genetic studies have indicated possible involvement of the upregulated calcium-nuclear factor of activated T cells pathway in the pathogenesis of Kawasaki disease. We aimed to assess safety and efficacy of ciclosporin, an immunosuppressant targeting this pathway, for protection of patients with Kawasaki disease against coronary artery abnormalities. METHODS: We did a randomised, open-label, blinded endpoints trial involving 22 hospitals in Japan between May 29, 2014, and Dec 27, 2016. Eligible patients predicted to be at higher risk for intravenous immunoglobulin (IVIG) resistance were randomly assigned to IVIG plus ciclosporin (5 mg/kg per day for 5 days; study treatment) or IVIG (conventional treatment) groups, stratified by risk score, age, and sex. The primary endpoint was incidence of coronary artery abnormalities using Japanese criteria during the 12-week trial, assessed in participants who received at least one dose of study drug and who visited the study institution at least once during treatment. This trial is registered to Center for Clinical Trials, Japan Medical Association, number JMA-IIA00174. FINDINGS: We enrolled 175 participants. One patient withdrew consent after enrolment and was excluded and one patient (in the study treatment group) was excluded from analysis because of lost echocardiography data. Incidence of coronary artery abnormalities was lower in the study treatment group than in the conventional treatment group (12 [14%] of 86 patients vs 27 [31%] of 87 patients; risk ratio 0·46; 95% CI 0·25-0·86; p=0·010). No difference was found in the incidence of adverse events between the groups (9% vs 7%; p=0·78). INTERPRETATION: Combined primary therapy with IVIG and ciclosporin was safe and effective for favourable coronary artery outcomes in Kawasaki disease patients who were predicted to be unresponsive to IVIG. FUNDING: Japan Agency for Medical Research and Development (grant CCT-B-2503).

Transcatheter closure of perimembranous ventricular septal defects with Amplatzer® duct occluder I; The first case report in Japan.

We report the first case of transcatheter perimembranous ventricular septal defect (pmVSD) closure in Japan where none of existing devices for VSD closure has been approved. The pmVSD was successfully closed with first generation Amplatzer® duct occluder (ADO-I; St Jude Medical, St Paul, MN, USA). The procedure was performed under general anesthesia with transesophageal echocardiographic and fluoroscopic guidance. The left ventricular volume overload after the procedure was remarkably improved and no major complications occurred. ADO-I can be a safe and effective option for transcatheter pmVSD closure. The incidence of heart block may be less than reported with the original device. .

Percutaneous pulmonary debanding for an infant complicated by spontaneously closing muscular ventricular septal defect: A case report and in vitro study.

Pulmonary artery banding (PAB) is a standard operation for various congenital heart defects complicated by pulmonary hypertension (PH) and judged unsuitable for primary intracardiac repair. We report successful percutaneous pulmonary artery debanding in a baby complicated by muscular ventricular septal defect (VSD), that was initially large and multiple, but closed spontaneously later. The 5-month-old boy was referred to our hospital on day 3, diagnosed as having aortic coarctation (CoA), with multiple muscular VSDs and severe PH. On day 6, he underwent CoA repair and PAB using expanded polytetrafluoroethylene (ePTFE), while the muscular VSDs were left open. We planned percutaneous pulmonary debanding at the age of 5 months, as the muscular VSDs had become small. After dilation with a Mustang® (Boston Scientific, Marlborough, Massachusetts, United State) balloon (12 mm diameter) there was a persistent waist indicating a residual narrowing. Use of an extra-high pressure balloon, Conquest® (Medicon, Osaka, Japan) balloon of the same size, completely eliminated the waist. In in vitro experiments, the Mustang® partially tore the ePTFE, while a Conquest® of the same diameter completely opened the band. The mechanism of debanding was tearing of the ePTFE by the knot of the suture thread. Percutaneous pulmonary debanding to avoid unnecessary surgery is feasible in such a patient if the VSD becomes small. .

Static balloon atrial septostomy for the purpose of left heart intervention in postoperative adult CHD.

Background and purposeStatic balloon atrial septostomy is a widely accepted intervention for children with CHD. Successful surgical palliation is creating increasing numbers of adult CHD patients who need subsequent left heart intervention requiring transseptal access. In these patients, the interatrial septum is usually thick and fibrotic because of a previous open heart surgery or catheter intervention, and conventional transseptal puncture may be unsuccessful. Static balloon atrial septostomy to access the left atrium may facilitate intervention via the interatrial septum in such situations. The purpose of this study was to investigate the usefulness and the safety of static balloon atrial septostomy, and the evolution of an iatrogenic atrial septal defect post procedure in adult CHD. METHODS: We retrospectively reviewed six procedures in five adults with CHD and collected demographic characteristics, details of the procedures, clinical outcome, and size changes of the iatrogenic atrial septal defect. RESULTS: The mean age at the time of the procedure was 35 years. The intended primary interventions were pulmonary vein isolation, stenting for pulmonary vein obstruction, and catheter ablation for focal atrial tachycardia. All static balloon atrial septostomies were effective, and the left heart interventions were successfully achieved via transseptal sheaths. There were no major complications associated with the static balloon atrial septostomy. There were no adverse clinical outcomes related to iatrogenic atrial septal defect, and the size of the defects regressed over time in all cases. CONCLUSIONS: Static balloon atrial septostomy can be a safe and useful technique in adult CHD patients needing left heart procedures. The thick interatrial septum found in postoperative patients may reduce the risk of persistent iatrogenic atrial septal defect.

Prognostic predictive value of gene mutations in Japanese patients with hypertrophic cardiomyopathy.

Although some studies have attempted to find useful prognostic factors in hypertrophic cardiomyopathy (HCM), those results are not fully helpful for use in actual clinical practice. Furthermore, several genetic abnormalities associated with HCM have been identified. However, the genotype-phenotype correlation in HCM remains to be elucidated. Here, we attempted to assess patients with different types of gene mutations causing HCM and investigate the prognosis. A total of 140 patients with HCM underwent a screening test for myofilament gene mutations by direct sequencing of eight sarcomeric genes. Patients with a single mutation in cardiac troponin T, cardiac troponin I, α-tropomyosin, and regulatory and essential light chains were excluded from the study because the number of cases was too small. The clinical presentations and outcomes of the remaining 127 patients with HCM, 31 ß-myosin heavy chain (MYH7) mutation carriers, 19 cardiac myosin-binding protein C (MYBPC3) mutation carriers, and 77 mutation non-carriers were analyzed retrospectively. MYBPC3 mutation carriers had a high frequency of ventricular arrhythmia and syncope. Kaplan-Meier curves revealed no significant difference in prognosis among the three groups, but a lack of family history of sudden death (SD) and a past history of syncope were significantly related to poor prognosis. An absence of family history of SD and past history of syncope are useful prognostic factors in patients with HCM. MYH7 and MYBPC3 mutations did not significantly influence prognosis compared to non-carriers. However, patients with the MYBPC3 mutation should be closely followed for the possibility of SD.

Divergent clinical outcomes of alpha-glucosidase enzyme replacement therapy in two siblings with infantile-onset Pompe disease treated in the symptomatic or pre-symptomatic state.

Pompe disease is an autosomal recessive, lysosomal glycogen storage disease caused by acid α-glucosidase deficiency. Infantile-onset Pompe disease (IOPD) is the most severe form and is characterized by cardiomyopathy, respiratory distress, hepatomegaly, and skeletal muscle weakness. Untreated, IOPD generally results in death within the first year of life. Enzyme replacement therapy (ERT) with recombinant human acid alpha glucosidase (rhGAA) has been shown to markedly improve the life expectancy of patients with IOPD. However, the efficacy of ERT in patients with IOPD is affected by the presence of symptoms and cross-reactive immunologic material (CRIM) status. We have treated two siblings with IOPD with ERT at different ages: the first was symptomatic and the second was asymptomatic. The female proband (Patient 1) was diagnosed with IOPD and initiated ERT at 4 months of age. Her younger sister (Patient 2) was diagnosed with IOPD at 10 days of age and initiated ERT at Day 12. Patient 1, now 6 years old, is alive but bedridden, and requires 24-hour invasive ventilation due to gradually progressive muscle weakness. In Patient 2, typical symptoms of IOPD, including cardiac failure, respiratory distress, progressive muscle weakness, hepatomegaly and myopathic facial features were largely absent during the first 12 months of ERT. Her cardiac function and mobility were well-maintained for the first 3 years, and she had normal motor development. However, she developed progressive hearing impairment and muscle weakness after 3 years of ERT. Both siblings have had low anti-rhGAA immunoglobulin G (IgG) antibody titers during ERT and have tolerated the treatment well. These results suggest that initiation of ERT during the pre-symptomatic period can prevent and/or attenuate the progression of IOPD, including cardiomyopathy, respiratory distress, and muscle weakness for first several years of ERT. However, to improve the long-term efficacy of ERT for IOPD, new strategies for ERT for IOPD, e.g. modifying the enzyme to enhance uptake into skeletal muscle and/or to cross the blood brain barrier (BBB), will be required.

Clinical Features of Acute and Fulminant Myocarditis in Children　- 2nd Nationwide Survey by Japanese Society of Pediatric Cardiology and Cardiac Surgery.

BACKGROUND: The 1st nationwide survey by the Japanese Society of Pediatric Cardiology and Cardiac Surgery of acute or fulminant myocarditis (AMC/FMC) in children revealed that the survival rate of FMC was only 51.6%. The 2nd nationwide survey was performed to evaluate the recent outcomes of pediatric myocarditis.Methods and Results:Questionnaires regarding patients aged ≤18 years with AMC/FMC during the period from January 2006 to December 2011 were mailed. A total of 221 cases (age 6.5±5.3 years, 116 boys and 105 girls) were reported. There were 145 (65.6%) and 74 cases (33.5%) of AMC/FMC, respectively; the type of myocarditis was not reported in the remaining 2 cases (0.9%). Viruses were identified in 56 cases (25.3%), including coxsackie B in 9 and influenza A in 8. Histopathology by either endomyocardial biopsy or autopsy was obtained in 38 cases (19.2%). Intravenous immunoglobulin was effective in 49 (34.3%) of 143 cases. Steroid therapy was effective in 20 (32.8%) of 61 cases. Mechanical circulatory support was given in 54 cases (24.4%) and 94.2% of them were patients with FMC. The survival rates for the whole study population, acute myocarditis, and FMC were 75.6%, 91.0%, and 48.6%, respectively. CONCLUSIONS: The survival rate of children with myocarditis was almost identical to that of 10 years ago. (Circ J 2016; 80: 2362-2368).

[Concentration of Soluble CD14-Subtype (Presepsin) in Plasma of Non-Inflammatory and Septic Febrile Children].

CD14 is present in macrophage, monocyte, and granulocyte cell membranes. Its soluble fraction (soluble CD14-subtype), named presepsin (P-SEP) is present in blood in association with infections, due to phagocy- tosis of microorganisms. Increased serum concentration of P-SEP was reported in adult patients with se- vere bacterial sepsis, however, reports on pediatric patients have been limited. In order to clarify if P-SEP increases in pediatric patients with bacterial sepsis, we conducted a study of plasma P-SEP concentration in children with various febrile diseases. Eighty-eight subjects (49 males, 39 females, 18 days to 168 months after birth, mean 3.2 years old) who admitted to our hospital were enrolled. Among them, blood culture was performed for 56 children. As control, twelve afebrile, non-septic children who admitted for routine cardiac catheter examinations for con- genital heart anomaly were enrolled. Blood was withdrawn on admission. Plasma was obtained within 24 hours after blood withdrawal, stored at 4 Celsius degree until assays. P-SEP was assayed using PATHFAST(TM) chemiluminescent enzyme immunoassay system (LSI Medience Inc, Tokyo, Japan). Together with P-SEP assays, blood culture, white blood cell count, serum C-reactive protein (CRP) and procalcitonin (PCT) were assayed. Local ethic committee approved this study. P-SEP concentration ranged 195 to 866 (median 445) pg/mL in patients whose blood culture was positive on admission (n=7). On the other hand, patients with blood culture negative (n=49) remained low level, 82.1 to 770 (median 242) pg/mL(p=0.046). Control subjects (n=12) showed significantly low concentration of P-SEP (mean 160, SD 189, ranged 79.4 to 411 pg/mL) compared to those from blood culture positive children (mean 487, SD 478 pg/mL, p=0.010). Though number of samples was limited, P-SEP may possibly act as a new mark- er of febrile bacteremia even in children. More study is needed for reference intervals for children. [Original].

Novel curved balloon catheter for dilating postoperative angled lesions associated with congenital heart disease.

OBJECTIVES: This study aimed to analyze the surface stress generated by a novel curved balloon and assess its efficacy for treating angular lesions associated with congenital heart disease. BACKGROUND: Obstructions at the anastomosis of aortopulmonary shunts and cavopulmonary connections may occur postoperatively. Catheter interventions are often performed for such lesions; however, acute angulation may cause balloon slippage or inappropriate stress on the vessel wall. METHODS: We dilated the curved balloon in a curved vessel model and measured the resultant wall stress and its distribution. Clinical evaluations were performed using this balloon in angled lesions. RESULTS: In the curved vessel model, curved balloons generated uniform stress on the lesser and greater curvatures (curved type, lesser/greater = 0.343 MPa/0.327 MPa; P = 0.61), whereas straight balloons caused disproportionate stress (straight type, lesser/greater = 0.358 MPa/0.254 MPa; P = 0.19). However, the difference in average stress was not statistically significant. Furthermore, the stress was uniform along the entire length of the curved balloon, but differed between the mid and end portions of the straight balloon. Curved balloon dilations were performed for 10 lesions in 7 patients. The curved balloon conformed well to the angulated lesion without slipping. The median percent change in the minimal lumen diameter (MLD) was 64% (range, 0-206%). In 5 lesions, MLD increased by ≥50%. Oxygen saturation increased by 5% (0-9%). CONCLUSIONS: Although further clinical evaluation is necessary, this novel curved balloon may be a reasonable alternative in angled lesions, providing better conformability and preventing excessive stress to the vessel wall adjacent to the stenosis.

An infant with primary pulmonary vein stenosis, associated with fatal occlusion of intraparenchymal small pulmonary veins.

Primary pulmonary vein stenosis (PVS) is rare within the pediatric population and its pathophysiology remains unclear, especially as to how the histopathology relates to its refractoriness to treatment. We report the case of a 4-month-old girl with primary PVS. The lesion in this patient was characterized by fatal obstruction of intraparenchymal small pulmonary veins, associated with localized stenosis at the four pulmonary veno-atrial junctions. All four localized stenoses underwent transcatheter stent implantation. Although the procedure was technically successful, her clinical status failed to improve, and she died 2 months after stenting. Histopathological examination of lung specimens showed severe luminal obstruction by marked intimal proliferation with fibrosis in the intraparenchymal small pulmonary veins, and these findings were present in every lobe. To the best of our knowledge, the histopathological findings and clinical course in this case, including the response to treatments, are extremely rare. We suggest that the histological findings of the small pulmonary veins are important in deciding the indication and appropriate timing of intervention. .

Restored left ventricular function following transcatheter closure of a persistent ductus arteriosus in an adult.

Recently, transcatheter device occlusion has become the first choice treatment for adult persistent ductus arteriosus (PDA). However, various complications such as atrial fibrillation requiring anticoagulation, pulmonary hypertension, and ventricular dysfunction may challenge the interventionist. We report a 61-year-old patient with a large PDA complicated by left ventricular dysfunction, atrial fibrillation, and left atrial thrombus. Computed tomography documented the PDA of Krichenko type A with the narrowest diameter of 8 mm. We successfully closed the PDA using an Amplatzer duct occluder under anticoagulation with wafarin. His post-operative course was complicated by ventricular tachycardia and deteriorating left ventricular pump function. Although endomyocardial biopsy from the left ventricle showed myocardial hypertrophy and interstitial fibrosis, possibly caused by chronic volume overload, left ventricular pump function improved dramatically with restoration of sinus rhythm during follow-up. Left ventricular dysfunction, even when associated with histological changes, may be nearly normalized by volume unloading in an adult with a large PDA. .

Coil occlusion of PDA in patients younger than 1 year: risk factors for adverse events.

BACKGROUND: Transcatheter occlusion of infantile patent ductus arteriosus (PDA) challenges the interventionist. PURPOSE: To analyze the risk factors for adverse events from this procedure in patients younger than 12 months. SUBJECTS: We retrospectively analyzed data on 32 patients younger than 12 months in whom transcatheter coil occlusion of a PDA was attempted. Ages ranged from 1 to 11 (median, 7) months and body weight from 1.2 to 10 (6.0) kg. The minimum ductal diameter ranged from 1.0 to 4.6 (3.3) mm and pulmonary to systemic flow ratio from 0.7 to 12.5 (2.2). Major adverse events were defined as those requiring surgery, while minor adverse events included transient hemolysis not needing treatment, coil migration with successful transcatheter retrieval, and mild left pulmonary artery (PA) stenosis. We determined whether any factors such as age, body weight, minimum PDA diameter, angiographic type, operator, and use of a 0.052-in. Gianturco coil related to the occurrence of adverse events. RESULTS: In two patients, coils could not be deployed in the appropriate position. They underwent surgery following transcatheter retrieval of coils. Coils were successfully deployed in the other 30 patients, however, one patient developed persistent hemolysis that required surgical retrieval of the coils and closure. PDA was completely closed in the other 29 patients (clinical success rate, 91%). Thus, there were three major adverse events, while minor adverse events occurred in five patients. Univariate analysis did not identify any single factor that contributed to either major, minor, or total adverse events. However, all major adverse events occurred in patients under 6 months and less than 6 kg body weight with a minimum duct diameter of more than 3.5 mm. CONCLUSION: Transcatheter coil occlusion of PDA is feasible in selected patients younger than 1 year. A minimum diameter more than 3.5 mm in patients under 6 kg may be a risk factor for major adverse events.

[Cardiovascular and the other complication followed with Kawasaki disease].

Kawasaki disease (KD) was considered to be good prognosis in self-limited at first. But, sudden death followed KD has been reported. It became clear that KD produce the peculiar state of myocardial infarction in infants and young children. Now, KD took the place of the rheumatic fever and got the most important disease of acquired heart disease in childhood. Cardiovascular disorder is mainly included with the coronary arterial aneurysm. And aneurysm in an subaxial and iliac artery were complicated. Every organ flame in a whole body was produced with systematic vasculitis mainly on a medium size or small size artery of a whole body. We summarize about complications of a cardiovascular system and the other organs followed KD.

Metabolic properties of band heterotopia differ from those of other cortical dysplasias: a proton magnetic resonance spectroscopy study.

PURPOSE: To assess the biochemical properties of band heterotopia in comparison with other cortical developmental malformations (CDMs) by using proton magnetic resonance spectroscopy (1H-MRS). METHODS: We performed localized single-voxel 1H-MRS studies on 13 patients [five band heterotopia (BH), two focal cortical dysplasia (CD), two unilateral CD, one bilateral perisylvian dysplasia, three hemimegalencephaly]. CDMs other than BH were categorized as CD. Spectra were acquired from volumes of interest (VOIs) localized in the CD and in normal-appearing cortex on the contralateral side. In BH patients, the VOIs were the external cortex and the laminar heterotopia. For the BH study, spectra also were obtained from the cortex of age-matched normal volunteers. RESULTS: The spectra of CD lesions were characterized by significantly lower ratios of N-acetyl aspartate to creatine (NAA/Cr) and by higher choline to Cr (Cho/Cr) ratios than in the contralateral remote cortex (p = 0.01 and 0.01, respectively). The NAA/Cr and Cho/Cr ratios of the external cortex of BH were not significantly different from those of normal volunteers. The NAA/Cr ratio of the laminar heterotopia was not significantly different from that of the external cortex (p = 0.12) or normal volunteers (p = 0.60), whereas Cho/Cr was significantly higher in laminar heterotopias than in the external cortex (p = 0.04) or controls (p = 0.03). CONCLUSIONS: 1H-MRS can distinguish between the metabolic properties of BH and CD.