Necrotic Change of Tunica Media Plays a Key Role in the Development of Coronary Artery Lesions in Kawasaki Disease.

BACKGROUND: Alarmins resulting from cell death or oxidative stress are involved in the development of Kawasaki disease (KD) vasculitis. In a previous study, we demonstrated the potential role of interleukin (IL)-33 as an alarmin in the development of KD vasculitis. Although edematous dissociation (necrotic change) of the tunica media is thought to be a major source of IL-33 in KD vasculitis, it has not yet been elucidated. METHODS AND RESULTS: We investigated the impact of IL-33 released from necrotic human coronary artery smooth muscle cells (HCASMCs) on human coronary artery endothelial cells (HCAECs) using a coculture assay. Subsequently, we evaluated the anti-inflammatory effects of anti-IL-33 and anti-suppression of tumorigenicity 2 (ST2) antibodies compared with conventional therapies of KD, such as high-dose IgG or anti-tumor necrosis factor (TNF)-α antibody. Primary necrosis of HCASMCs induced significant release of IL-33. In cocultures of necrotic HCASMCs with HCAECs, the necrotic HCASMCs significantly induced the production of various proinflammatory cytokines in the HCAECs. Anti-IL-33 and anti-ST2 antibodies exhibited unique inhibitory effects on the production of platelet-derived growth factor-BB or IL-12(p70) in HCAECs. CONCLUSIONS: There is potential involvement of edematous dissociation of the tunica media in the development of KD vasculitis. Furthermore, the distinctive anti-inflammatory effects of the anti-IL-33/ST2 axis drugs suggest novel therapeutic options for patients with refractory KD.

Congenital Pulmonary Lymphangiectasia Masked by Postoperative Pulmonary Venous Obstruction in an Infant with Total Anomalous Pulmonary Venous Connection.

Congenital pulmonary lymphangiectasia (CPL) is associated with fetal pulmonary venous obstructive physiology. The precise morbidity of CPL is unknown as CPL is generally fatal in neonates. Here, we report an infant with secondary CPL in total anomalous pulmonary venous connection (TAPVC). He developed severe pulmonary hypertension (PH) after corrective surgery for TAPVC. However, cardiac catheterization showed mild left pulmonary venous obstruction (PVO), which was deemed unnecessary for re-intervention. He died at 11 months-old due to an exacerbation of PH. Autopsy revealed medial hypertrophy of the pulmonary arteries, mild left PVO, and marked dilatation and proliferation of the pulmonary lymphatics which might have been involved in the PH, although CPL was not conclusively identified based on the previous biopsy findings. We should be aware of the possibility of CPL in addition to postoperative PVO when encountering patients with fetal pulmonary venous obstructive physiology. Furthermore, a cautious approach to the interpretation of lung biopsy results is warranted.

Successful Mitral Valve Replacement in an Infant with Neonatal Marfan Syndrome due to a Novel Missense Mutation of the FBN1 Gene.

Marfan syndrome is an autosomal dominant genetic disorder of the fibrous connective tissue caused by pathogenic mutations in the fibrillin-1 gene. Neonatal Marfan syndrome is a rare type of Marfan syndrome that is genotypically and phenotypically different from classical Marfan syndrome and has a poor prognosis. Most patients with neonatal Marfan syndrome die during infancy due to severe and rapidly progressive cardiovascular disorders. Here, we present a case of an 11-year-old girl with neonatal Marfan syndrome due to a novel missense mutation in exon 27 of the fibrillin-1 gene. Her condition was critical due to progressive mitral and tricuspid regurgitation. Mitral valve replacement, performed at the age of 6 months, improved her critical condition. Our case suggests that early mitral valve replacement may lead to better outcomes in patients with neonatal Marfan syndrome.

Pulmonary Hypertension Following Increased Dosing of Diazoxide in an Infant.

Diazoxide, a drug used to treat hyperinsulinemic hypoglycemia (HH), is associated with pulmonary hypertension (PH), as reported by the US Food and Drug Administration. However, no report has detailed the association between diazoxide dose and PH development. We report a case of an infant with HH, subsequently complicated by diazoxide-induced PH. When diazoxide was introduced, PH did not appear initially, but it developed during increased dosing. We monitored PH via regular echocardiography examinations. PH gradually improved with tapering of the diazoxide dose and disappeared after drug discontinuation. Our case suggests a diazoxide dose threshold might induce PH. Therefore, close echocardiography examinations should accompany diazoxide treatment.

Responses to Treatment According to the Cytokine Profiles of Pericardial Effusion in Two Children with Idiopathic Pericarditis.

Acute pericarditis is inflammation of the pericardium with or without pericardial effusion. In the pediatric population, most patients with acute pericarditis are diagnosed with idiopathic pericarditis. Herein, we present two children with idiopathic pericarditis who underwent immunological assessment of pericardial effusion for the first time. Both patients showed equally high levels of interleukin-6 in the pericardial effusion. However, they had different treatment responses, in accordance with the pericardial effusion and serum interleukin-10 concentrations. Our present cases suggest that interleukin-10 may be associated with the response to anti-inflammatory therapy in idiopathic acute pericarditis.

Interleukin-33/ST2 Axis as Potential Biomarker and Therapeutic Target in Kawasaki Disease.

Kawasaki disease (KD) is an acute, self-limiting, febrile systemic vasculitis of unknown cause associated with the development of coronary artery lesions (CALs) during childhood. Damage-associated molecular patterns (DAMPs) from cell death and oxidative stress have been shown to be involved in the development of KD vasculitis. Interleukin (IL)-33 is released from damaged endothelial cells and acts as a DAMP. We studied whether IL-33 and its receptor (ST2) might be involved in KD pathogenesis. Serum levels of soluble ST2 (sST2) in KD patients were measured before their first therapy. Furthermore, we investigated the impact of IL-33 on human coronary artery endothelial cells (HCAECs). Serum levels of sST2 were significantly higher in KD patients with CALs than in those with normal coronary arteries. In vitro, IL-33 upregulated the expression of ST2L and increased production of sST2, IL-6, IL-8, and monocyte chemoattractant protein-1 in HCAECs in a time- and concentration-dependent manner. Moreover, IL-33 induced significantly greater production of IL-6 and IL-8 in HCAECs compared to the condition stimulated with isoconcentration of tumor necrosis factor-α. The results of the present study suggest that the IL-33/ST2 axis might be involved in the development of KD vasculitis. The IL-33/ST2 axis may be a therapeutic target for the treatment of KD.

Inositol phosphate kinase Vip1p interacts with histone chaperone Asf1p in Saccharomyces cerevisiae.

Histone eviction and deposition are critical steps in many nuclear processes. The histone H3/H4 chaperone Asf1p is highly conserved and is involved in DNA replication, DNA repair, and transcription. To identify the factors concerned with anti-silencing function 1 (ASF1), we purified Asf1p-associated factors from the yeast Saccharomyces cerevisiae by a GST pull-down experiment, and mass spectrometry analysis was performed. Several factors are specifically associated with Asf1p, including Vip1p. VIP1 is conserved from yeast to humans and encodes inositol hexakisphoshate and inositol heptakisphosphate kinase. Vip1p interacted with Asf1p as a dimer or in a complex with another protein(s). Deletion of VIP1 did not affect the interaction between Asf1p and other Asf1p-associated factors. An in vitro GST pull-down assay indicated a direct interaction between Asf1p and Vip1p, and the interaction between the two factors in vivo was detected by an immunoprecipitation experiment. Furthermore, genetic experiments revealed that VIP1 disruption increased sensitivity to 6-azauracil (6-AU), but not to DNA-damaging reagents in wild-type and ASF1-deleted strains. It is thought that 6-AU decreases nucleotide levels and reduces transcription elongation. These observations suggest that the association of Asf1p and Vip1p may be implicated in transcription elongation.

Safety and Feasibility of Infliximab Therapy in Children With Kawasaki Disease Who Received Live Vaccinations.

BACKGROUND: Kawasaki disease (KD) is an acute and febrile systemic vasculitis that occurs during childhood. Infliximab (IFX) is a chimeric monoclonal antibody that binds to tumor necrosis factor-α. Although IFX therapy is a useful option for refractory KD, vaccine-associated infections may develop after therapy. In Japan, IFX therapy is recommended after a duration of at least 3 months after live vaccinations or at least 6 months after Bacillus Calmette-Guérin (BCG) in children with KD. However, the appropriate duration between live vaccinations and IFX therapy is unclear. METHODS: We investigated children who developed KD within 3 months after live vaccinations or within 6 months after BCG. Clinical characteristics, side effects of therapies and efficacy of live vaccinations were retrospectively investigated. RESULTS: Forty-eight patients developed KD within 3 months of live vaccinations or within 6 months after BCG. Eight patients underwent IFX therapy. There were no apparent vaccine-associated infections. The patients who underwent IFX acquired protective IgG antibody titers in the 5 of 6 live vaccines. CONCLUSIONS: Safe and appropriate duration between live vaccinations and IFX therapy for KD patients could be shorter in the future, although more studies are warranted to establish the safe duration.

Use of Large Balloon Catheter to Treat Infants With Pulmonary Valve Stenosis.

Balloon pulmonary valvuloplasty is a safe and effective treatment for isolated pulmonary valve stenosis. Several balloon catheters are available for this procedure in neonates and infants. However, obtaining additional vascular access for the double-balloon technique in this population is troublesome, and tricuspid valve injury is a concern. We used a TMP PED balloon catheter to perform valvuloplasty in 2 infants with isolated pulmonary valve stenosis. This thin-walled, relatively large 12-mm balloon catheter can be delivered through a small-diameter sheath. In both cases, the transpulmonary pressure gradient was reduced without causing any valvular or vascular injuries. Neither patient had recurrent pulmonary valve stenosis. Together, these cases highlight the suitability and feasibility of using the 12-mm TMP PED balloon catheter for treating young infants with valvular stenosis.

Utility of Soluble CD163 in the Clinical Management of Patients With Kawasaki Disease.

Objective: Intravenous immunoglobulin (IVIG) therapy is a useful first-line treatment for Kawasaki disease (KD); however, 10-20% of patients fail to respond and require additional IVIG. Soluble CD163 (sCD163) is considered a biomarker for macrophage activation. There are no reports measuring serum sCD163 in KD patients. This study aimed to explore its possible utility in the clinical management of patients with KD. Methods: Eighty-seven patients with well-defined KD were retrospectively enrolled together with 19 healthy individuals with comparable ages. KD patients were classified into three groups, Group A (initial IVIG responders), Group B (additional IVIG responders), and Group C (additional IVIG non-responders). Serum sCD163 together with complete blood counts, C-reactive protein, d-dimer, albumin, aspartate aminotransferase (AST), and alanine aminotransferase (ALT) were measured before the initial IVIG treatment in all cases, and afterward in a fraction of cases. Results: Serum sCD163 in KD patients before initial IVIG was generally much higher than the control group. The median (interquartile range) of sCD163 was as follows: Control 446 (385-521) ng/mL; Group A, 699 (478-1,072); Group B, 1,349 (1,116-1,390); and Group C, 665 (544-1,094). In general, sCD163 showed close positive correlation with ALT and AST, but none with other markers. Among the KD groups, Group B showed the highest sCD163: Group B vs. A: p = 0.0003; B vs. C: p = 0.035). Serum sCD163 was significantly increased after IVIG in Group A, while no change occurred in others. Conclusion: The serum sCD163 levels could be a useful biomarker in the clinical management of KD, especially for predicting responsiveness to IVIG.

Circulating endothelial glycocalyx components as a predictive marker of coronary artery lesions in Kawasaki disease.

BACKGROUND: Kawasaki disease (KD) is acute and self-limited vasculitis caused by unknown origin, and the critical complication in KD patients is coronary artery lesions (CALs). The endothelial glycocalyx is a network of membranes luminally covering the endothelium. This study aimed to evaluate the clinical utility of serum glycocalyx components as biomarkers of predicting the onset CALs in KD. METHODS: Seventy subjects with complete type KD, 18 subjects as febrile control (FC), and 15 subjects as afebrile controls (AC) were enrolled. Medical, demographic, echocardiography, and laboratory data from the medical records were retrospectively analyzed. Serum syndecan-1 and hyaluronan levels prior to intravenous immunoglobulin (IVIG) therapy were measured at the acute phase, immediately after IVIG, the subacute phase, and the time of discharge at the convalescent phase. RESULTS: Serum syndecan-1 and hyaluronan levels were higher in the KD group than in the AC and FC groups at all three phases. Further, these levels were compared between KD patients with and without the development of CALs. Serum syndecan-1 and hyaluronan levels at the acute phase were significantly elevated in KD patients with the CALs than in those without CALs. Serum hyaluronan, not syndecan-1, was determined as the most contributory parameter to predict CALs by a multiple logistic analysis. CONCLUSIONS: Circulating syndecan-1 and hyaluronan can be useful biomarkers to predict the development of CALs in KD.

Non-androgen secreting adrenocortical carcinoma in preadolescence: a case report and literature review.

Adrenocortical carcinoma (ACC) is a rare malignancy in childhood. Affected children with ACC mostly present with virilization, but not the pure form of Cushing's syndrome. A 9-year-old Japanese girl was hospitalized, because of the unstable emotions and excessive weight gain. She was diagnosed as having Cushing's syndrome and a left adrenal tumor. The adrenalectomy led to the pathological diagnosis of ACC without metastasis. There was no mutation of PRKACA in the tumor-derived DNA, or p53 in peripheral blood-derived DNA. Testosterone and dehydroepiandrosterone sulfate (DHEA-S) levels were normal throughout the clinical course. On the other hand, these levels were elevated in all five reported cases of preadolescent ACC children with isolated Cushing's syndrome. The exceptional secretory behavior of ACC gave a diagnostic precaution of the rare pediatric cancer.

Two infants with tuberculid associated with Kawasaki disease.

Bacille de Calmette et Guerin (BCG) is the only licensed tuberculosis vaccine to prevent severe tuberculosis. The adverse events of BCG vaccination, including local reactions, lymphadenitis, osteomyelitis, tuberculid, and disseminated infection, have been reported. Two infants presented erythema at the inoculation site of BCG after the resolution of Kawasaki disease (KD). They received BCG vaccination 1 week and 6 weeks before the KD onset, respectively. Intravenous immunoglobulin improved the KD activity, however the skin rash of BCG inoculation site extended to the face and extremities days 24 and 10 after the KD onset, respectively. Both bacteriological study and interferon-γ release assay were negative for Mycobacterium tuberculosis infection. These patients were diagnosed as having tuberculid after KD. The skin lesions gradually disappeared without antibiotic therapy over 2 months. The development of tuberculid in these patients might be associated with the remnant immune activation of KD.