Saito Kazuyoshi

BACKGROUND: Kawasaki disease (KD) onset has been suggested to be associated with infections and various environmental factors. However, research on whether the delivery type plays a role in KD development is limited. This study investigated whether cesarean section (CS) or vaginal delivery (VD) is associated with KD onset using a large administrative claims database in Japan. METHOD: We conducted a case-control study using the JMDC Claims Database from January 2005 to December 2021. Data on children born via CS or VD and their mothers were collected. KD patients were identified from the source population, and controls without KD were randomly selected based on sex, age and registration time, each matched to 4 controls using a risk-set sampling technique. We analyzed the association between delivery type and KD onset using multivariate conditional logistic regression, defining KD as the primary outcome based on specific criteria. RESULTS: Case-control matching created 3363 pairs of cases (n = 3363) and controls (n = 13,363). The proportions of CS, maternal age, Charlson Comorbidity Index, presence of older siblings and low birth weight infants were significantly different between the cases and controls. In the multivariate analysis, KD onset was associated with CS [odds ratio (OR): 1.12; 95% confidence interval (CI): 1.02-1.24], the presence of older siblings (OR: 1.11; 95% CI: 1.02-1.21), lower birth weight (1001-2500 g) (OR: 1.22; 95% CI: 1.04-1.43) and antibiotic use (OR: 1.12; 95% CI: 1.02-1.24). CONCLUSIONS: The risk of developing KD may be influenced by the delivery type (CS or VD), the presence of older siblings, low birth weight and antibiotic use.

UNLABELLED: Most cases of pulmonary arteriovenous malformation (PAVM) are associated with hereditary hemorrhagic telangiectasia (HHT). HHT is typically caused by loss-of-function gene mutations in the genes ENG, ACVRL1, or SMAD4, all participating in transforming growth factor β (TGF-β) family signaling pathways. We describe the case of an 11-year-old Japanese girl with PAVM, with no known family history of HHT or similar disease. She was found to carry a novel nonsense variant in SMAD9 (SMAD9-p. T267*), which we speculate contributed to her disease, because SMAD9 also participates in TGF-β family signaling pathways. SMAD9 mutations have been linked with pulmonary arterial hypertension (PAH), and, hence, mutations in SMAD9-as for ENG, ACVRL1, and SMAD4-may predispose to both PAH and HHT(-characteristic) disease features. The PAVM in our patient spread diffusely inside the lower lobe of the left lung, and coil embolization was considered difficult. Therefore, after feasibility assessment by performing a balloon occlusion test during cardiac catheterization, left lower lobectomy was performed. The patient's dyspnea recovered well postoperatively, and two years later an increase in left lung volume was observed and disease symptoms had not recurred. Thus, if PAVM spreads diffusely in a certain lung area, surgical treatment can be a viable option. LEARNING OBJECTIVE: SMAD9 gene mutations have been linked to pulmonary arterial hypertension (PAH). However, their associations with hereditary hemorrhagic telangiectasia (HHT) or pulmonary arteriovenous malformation (PAVM), which usually is HHT-associated, have not been reported previously. Our PAVM patient carrying a SMAD9 variant suggests that mutations in this gene, like in others participating in TGF-β family signaling pathways (like ENG, ACVRL1, and SMAD4), predispose to both PAH and HHT(-characteristic) disease features. Diffuse PAVM confined to a lung area may be treated by lobectomy.

Acute myocarditis (AM) is an inflammatory disease of the heart muscle that can progress to fulminant myocarditis (FM), a severe and life-threatening condition. The cytokine profile of myocarditis in children, especially in relation to fulminant myocarditis, is not well understood. This study aims to evaluate the cytokine profiles of acute and fulminant myocarditis in children. Pediatric patients diagnosed with myocarditis were included in the study. Cytokine levels were measured using a multiplexed fluorescent bead-based immunoassay. Statistical analysis was performed to compare patient characteristics and cytokine levels between FM, AM, and healthy control (HC) groups. Principal component analysis (PCA) was applied to cytokine groups that were independent among the FM, AM, and HC groups. The study included 22 patients with FM and 14 with AM patients. We identified four cytokines that were significantly higher in the FM group compared to the AM group: IL1-RA (p = 0.002), IL-8 (p = 0.005), IL-10 (p = 0.011), and IL-15 (p = 0.005). IL-4 was significantly higher in the AM group compared to FM and HC groups (p = 0.006 and 0.0015). PDGF-AA, and VEGF-A were significantly lower in the FM group than in the AM group (p = 0.013 and <0.001). Similar results were obtained in PCA. Cytokine profiles might be used to differentiate pediatric FM from AM, stratify severity, and predict prognosis. The targeted therapy that works individual cytokines might provide a potential treatment for reducing the onset of the FM and calming the condition, and further studies are needed.

UNLABELLED: This study aimed to identify the appropriate dose of aspirin to be prescribed to patients with acute Kawasaki disease (KD). Using a Japanese national inpatient database, we identified patients with KD treated with intravenous immunoglobulin between 2010 and 2021.The outcomes included the occurrence of coronary artery abnormalities and intravenous immunoglobulin resistance, length of hospital stay, and medical costs. Restricted cubic spline functions were performed to examine the association between aspirin dose and the outcomes. Data of 82,109 patients were extracted from the database. Non-linear associations were observed between aspirin dose and the outcomes. In comparison with an aspirin dose of 30 mg/kg/day, the odds ratio (95% confidence interval) for coronary artery abnormalities was 1.40 (1.13-1.75) at 5 mg/kg/day. An aspirin dose of ≥ 30 mg/kg/day did not significantly change the odds ratio for coronary artery abnormalities. Intravenous immunoglobulin resistance was significantly lower at a dose of 60 mg/kg/day or higher. CONCLUSION:  The results showed no significant association between aspirin escalation over standard-dose and coronary artery abnormalities in patients with acute KD. High-dose aspirin showed the potential to reduce hospital stay and medical costs without increasing complications. WHAT IS KNOWN: • Aspirin is used as a standard treatment together with intravenous immunoglobulin for acute Kawasaki disease (KD). However, few studies have shown the most effective dosage of aspirin to prevent coronary artery abnormalities (CAAs). WHAT IS NEW: • There was no significant association between aspirin dose escalation and CAAs in patients with acute KD.