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Evidence indicates that corticosteroid therapy might be beneficial for the primary treatment of severe Kawasaki disease. We assessed whether addition of prednisolone to intravenous immunoglobulin with aspirin would reduce the incidence of coronary artery abnormalities in patients with severe Kawasaki disease. We did a multicentre, prospective, randomised, open-label, blinded-endpoints trial at 74 hospitals in Japan between Sept 29, 2008, and Dec 2, 2010. Patients with severe Kawasaki disease were randomly assigned by a minimisation method to receive either intravenous immunoglobulin (2 g/kg for 24 h and aspirin 30 mg/kg per day) or intravenous immunoglobulin plus prednisolone (the same intravenous immunoglobulin regimen as the intravenous immunoglobulin group plus prednisolone 2 mg/kg per day given over 15 days after concentrations of C-reactive protein normalised). Patients and treating physicians were unmasked to group allocation. The primary endpoint was incidence of coronary artery abnormalities during the study period. Analysis was by intention to treat. This trial is registered with the University Hospital Medical Information Network clinical trials registry, number UMIN000000940. We randomly assigned 125 patients to the intravenous immunoglobulin plus prednisolone group and 123 to the intravenous immunoglobulin group. Incidence of coronary artery abnormalities was significantly lower in the intravenous immunoglobulin plus prednisolone group than in the intravenous immunoglobulin group during the study period (four patients [3%] vs 28 patients [23%]; risk difference 0·20, 95% CI 0·12–0·28, p<0·0001). Serious adverse events were similar between both groups: two patients had high total cholesterol and one neutropenia in the intravenous immunoglobulin plus prednisolone group, and one had high total cholesterol and another non-occlusive thrombus in the intravenous immunoglobulin group. Addition of prednisolone to the standard regimen of intravenous immunoglobulin improves coronary artery outcomes in patients with severe Kawasaki disease in Japan. Further study of intensified primary treatment for this disease in a mixed ethnic population is warranted. Japanese Ministry of Health, Labour and Welfare.

Yoshihiro Onouchi and colleagues report the results of a genome-wide association study of Kawasaki disease. They identify three new risk loci, all mapping near genes previously implicated in adult-onset autoimmune diseases. We performed a genome-wide association study (GWAS) of Kawasaki disease in Japanese subjects using data from 428 individuals with Kawasaki disease (cases) and 3,379 controls genotyped at 473,803 SNPs. We validated the association results in two independent replication panels totaling 754 cases and 947 controls. We observed significant associations in the FAM167A - BLK region at 8p22-23 (rs2254546, P = 8.2 × 10 −21 ), in the human leukocyte antigen (HLA) region at 6p21.3 (rs2857151, P = 4.6 × 10 −11 ) and in the CD40 region at 20q13 (rs4813003, P = 4.8 × 10 −8 ). We also replicated the association of a functional SNP of FCGR2A (rs1801274, P = 1.6 × 10 −6 ) identified in a recently reported GWAS of Kawasaki disease. Our findings provide new insights into the pathogenesis and pathophysiology of Kawasaki disease.

Abstract Rationale To detect pulmonary arterial hypertension (PAH) at any early stage is a promising approach to optimize the outcome. Objectives To investigate the impact of school ECG-based screening on detecting idiopathic or heritable (I/H)-PAH in the general pediatric population. Methods This was a nationwide survey of patients with I/H-PAH newly diagnosed at 3 months to 18 years of age in Japan during 2005–2012. Measurements and Main Results Eighty-seven eligible patients (age range, 1–16 yr) were recruited. Among 68 (78%) patients diagnosed at greater than or equal to 6 years of age (the age of the first ECG-based screening), 28 (41%) were detected by the ECG-based screening (screening group) and 40 (59%) were recognized by their symptoms (n = 37) or coincidental occasions (n = 3; nonscreening group). In the screening group, the proportion of patients in World Health Organization functional class I/II at diagnosis was higher (96% vs. 60%; P < 0.001), plasma brain natriuretic peptide level was lower (149 ± 290 vs. 398 ± 559 pg/ml; P = 0.045), and 6-minute-walk distance was longer (420 ± 109 vs. 327 ± 104 m; P < 0.001) than the nonscreening group, despite similar values in mean pulmonary artery pressure (58 ± 17 vs. 61 ± 17 mm Hg; P = 0.42) and pulmonary vascular resistance index (18 ± 8 vs. 21 ± 11 Wood units ⋅ m2; P = 0.24) between groups. The proportion of patients on intravenous epoprostenol at the final visit was lower in the screening group than the nonscreening group (14% vs. 50; P = 0.004). Conclusions These findings suggest that the ECG-based screening detects a unique subpopulation of pediatric patients with I/H-PAH that is associated with already established pulmonary hypertension but without obvious right heart failure and warrants investigating the prognostic significance of this system.

Subjects who are heterozygous for ( ) gene mutations present various phenotypes that range from euthyroid to hyperthyrotropinemia. Similarly, heterozygous ( ) gene mutations result in variable phenotypes, such as transient congenital hypothyroidism, subclinical hyperthyrotropinemia, and euthyroid in children. Here, we describe an 8-year-old boy who had normal newborn screening results, but who developed nonautoimmune hypothyroidism at the age of 1 year and 8 months of age. He was heterozygous for previously reported mutation and heterozygous for a novel double mutant allele and . He needed levothyroxine (l-T4) replacement therapy to keep serum TSH levels within normal limits; l-T4 dose of 2.01–2.65 μg/kg/day corresponded to the dose taken by children homozygous for and by children with permanent congenital hypothyroidism. Therefore, the coexistence of a heterozygous mutation and a heterozygous mutation may have affected the severity of his hypothyroid condition.

Kawasaki disease (KD) is considered to be a kind of systemic vasculitis syndrome. It most frequently affects infants and young children and primarily invades medium-sized muscular arteries, including the coronary arteries. The etiology of KD is unknown, but epidemiological data suggest involvement of infectious agents, such as bacteria and viruses, in the onset of KD. In addition, host genetics underlie the disease’s pathogenesis. Histologically, coronary arteritis begins 6–8 days after KD onset, and inflammation of all layers of the artery rapidly ensues. The inflammation spreads completely around the artery, resulting in severe damage to structural components. Then, the artery begins to dilate. KD arteritis is characterized by inflammation consisting of marked accumulation of monocytes/macrophages. Aberrant activation of monocytes/macrophages is thought to be involved in the formation of vascular lesions. Inflammatory-cell infiltration persists until about the 25th day of the disease, after which the inflammatory cells gradually decrease in number. Lesions in all arteries are relatively synchronous, as they evolve from acute to chronic injury. If a giant aneurysm remains or vessel recanalization occurs after thrombotic occlusion of an aneurysm, remodeling of the vascular structure, sometimes including even reocclusion, continues even in the remote stage.

Background Aseptic meningitis is a serious adverse reaction to intravenous immunoglobulin (IVIG) therapy. We studied the clinical characteristics of patients with acute Kawasaki disease (KD) who developed IVIG-induced aseptic meningitis. Methods A retrospective analysis of the medical records of patients with KD who developed aseptic meningitis after IVIG treatment was performed. Results During the 10-year period from 2000 through 2009, among a total of 384 patients with Kawasaki disease, 4 (3 females and 1 male; age range, 19-120 months) developed aseptic meningitis after IVIG. All 4 developed aseptic meningitis within 48 hours (range, 25-40 hours) of initiation of IVIG. The analyses of cerebrospinal fluid (CSF) revealed elevated white blood cell counts (22-1,248/μL) in all 4 patients; a predominance of polynuclear cells (65%-89%) was noted in 3. The CSF protein level was elevated in only 1 patient (59 mg/dL), and the glucose levels were normal in all 4 patients. Two patients were treated with intravenous methylprednisolone; the other 2 children were observed carefully without any special therapy. All patients recovered without neurological complications. Conclusions In our patients with Kawasaki disease, aseptic meningitis induced by IVIG occurred within 48 hours after initiation of IVIG, resolved within a few days, and resulted in no neurological complications, even in patients who did not receive medical treatment.

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.

Mutations of BMPR2 and other TGF‐β superfamily genes have been reported in pulmonary arterial hypertension (PAH). However, 60–90% of idiopathic PAH cases have no mutations in these genes. Recently, the expression of NOTCH3 was shown to be increased in the pulmonary artery smooth muscle cells of PAH patients. We sought to investigate NOTCH3 and its target genes in PAH patients and clarify the role of NOTCH3 signaling. We screened for mutations in NOTCH3, HES1, and HES5 in 41 PAH patients who had no mutations in BMPR2, ALK1, endoglin, SMAD1/4/8, BMPR1B, or Caveolin‐1. Two novel missense mutations (c.2519 G>A p.G840E, c.2698 A>C p.T900P) in NOTCH3 were identified in two PAH patients. We performed functional analysis using stable cell lines expressing either wild‐type or mutant NOTCH3. The protein‐folding chaperone GRP78/BiP was colocalized with wild‐type NOTCH3 in the endoplasmic reticulum, whereas the majority of GRP78/BiP was translocated into the nuclei of cells expressing mutant NOTCH3. Cell proliferation and viability were higher for cells expressing mutant NOTCH3 than for those expressing wild‐type NOTCH3. We identified novel NOTCH3 mutations in PAH patients and revealed that these mutations were involved in cell proliferation and viability. NOTCH3 mutants induced an impairment in NOTCH3‐HES5 signaling. The results may contribute to the elucidation of PAH pathogenesis. We report the first case of NOTCH3 gene mutations in idiopathic pulmonary arterial hypertension (PAH) patients. This study helps to elucidate the pathogenesis of PAH from a new standpoint.

Pulmonary arterial hypertension (PAH) trial has mostly enrolled patients with World Health Organization functional class (WHO FC) III or IV. However, PAH is rapidly progressive in nature even in patients with less severe forms at diagnosis. Following the recent studies in Western population, here we assessed the efficacy of bosentan in Japanese patients with WHO FCII PAH. In this open-label trial, bosentan 125 mg twice daily was administered for 12 weeks in 16 patients, and a hemodynamic evaluation was performed. Treatment was continued for a further 12 weeks, where the effect on exercise capacity was assessed in 13 patients. In 16 patients, mean pulmonary arterial pressure decreased from 40.4 ± 10.4 to 35.6 ± 12.6 mmHg ( p  = 0.018) and cardiac index increased from 2.54 ± 0.73 to 2.96 ± 0.82 L/min/m 2 ( p  = 0.023). Thus, pulmonary vascular resistance decreased from 792 ± 565 to 598 ± 558 dyn·sec/cm 5 ( p  = 0.006). In 13 patients followed up for 24 weeks, 6-min walking distance increased from baseline at Week 12 ( p  = 0.003) and Week 24 ( p  = 0.011). All patients were mildly symptomatic at baseline with dyspnea index (Borg scale) of 2.50 ± 1.58 and the specific activity scale (SAS) of 5.0 ± 1.4 METs. These values remained unchanged throughout the study. These results suggest that bosentan treatment was beneficial for Japanese patients with WHO FC II PAH and treatment should be started in the early stage of the disease.

Key Clinical Message We successfully immunized the neonatal‐onset multisystem inflammatory disease (NOMID) patient with live‐attenuated vaccines for measles, rubella, varicella, and mumps and achieved sufficient antibody titer under canakinumab therapy without complications. We successfully immunized the neonatal‐onset multisystem inflammatory disease (NOMID) patient with live‐attenuated vaccines for measles, rubella, varicella, and mumps and achieved sufficient antibody titer under canakinumab therapy without complications.