A registry study of Kawasaki disease patients with coronary artery aneurysms (KIDCAR): a report on a multicenter prospective registry study three years after commencement.

The long-term prognosis of patients with Kawasaki disease (KD) complicated by coronary artery aneurysms (CAA) is still unclear. The present, multicenter registry study aimed to study the factors associated with coronary events (CE) and determine an appropriate management method for patients with KD complicated with CAA. Patients with KD with onset after 2015 and with a medium-sized or large CAA having an actual diameter ≥ 4 mm or a Z-score ≥ 5.0 at 30 days and later after KD onset were included in the annual survey. The primary endpoint was the time-dependent incidence of CE. Associated factors were also examined. In total, 179 patients from 53 centers were enrolled and followed up for a median of 501 days. The median age at KD onset was 2.2 years, 137 patients were male (77%), 47 had incomplete KD (26%), and 36 had large CAA (20%). CE occurred in 13 patients (7%; 95% confidence interval: 4-12%); eight (62%) experienced CE within 1 year, and all the patients experienced a CE within 2 years. All but one patient received antiplatelet drugs and warfarin. Patients with a large CAA had significantly more CAA (2.8 vs. 1.7, p < 0.001), more cases of warfarin use (86% vs. 43%, p < 0.001), and were more likely to have CE (28% vs. 2%, p < 0.001) than those with a medium-sized CAA. On univariate Cox regression analysis, the factors significantly associated with CE were large CAA (hazard ratio (HR): 17.0), three or more CAA (HR: 23.3), and beaded CAA (HR: 15.9). Multivariable Cox regression analysis revealed that the only associated factor was a large CAA. CONCLUSION: Patients with a large CAA were more likely to have a CE within 2 years. Antithrombotic therapy with warfarin did not eliminate the CE risk, and better therapies are desirable. WHAT IS KNOWN: • Coronary artery aneurysms are a serious complication of Kawasaki disease, and coronary events are sometimes fatal. • In previous, retrospective studies in Japan, large aneurysms, male sex, and refractoriness to initial immunoglobulin therapy were considered risk factors for coronary events. WHAT IS NEW: • Of 179 patients with a medium sized or large aneurysm, 13 (7%) experienced coronary events, all of which occurred within 2 years of onset. Factors significantly associated with coronary events were large aneurysms, three or more aneurysms, and beaded aneurysms.

Factors affecting guardians' decision-making regarding the SARS-CoV-2 vaccine.

BACKGROUND: In Japan, the vaccination rate against the SARS-CoV-2 vaccine for children was low. Therefore, in this study we investigated the factors influencing guardians' decision-making regarding vaccination of their children. METHODS: From November 1, 2022 to March 31, 2023, pediatric clinics, departments, and midwifery clinics in Saitama Prefecture requested guardians of children under the age of 15 to complete an online questionnaire. RESULTS: Responses were obtained from 894 guardians of children aged 6 months to 15 years; 142 had had one of their children vaccinated at least once and 629 had not had any of their children vaccinated. Among guardians who had not had any of their children vaccinated, "the Age of children" was significantly younger (p < 0.001) and "Prevalence" (p < 0.001), "Free vaccination" (p < 0.001), and "Intentions of national and local governments" (p = 0.005) were selected as reasons significantly less frequently in comparison to guardians who had vaccinated their children. "Japanese adverse reactions" (p < 0.001), "Japanese effectiveness" (p < 0.001), "Adverse reactions" (p < 0.001), "History of adverse reactions" (p < 0.001), and "Reputation of friends" (p = 0.006) were selected significantly more frequently by guardians who had not had any of their children vaccinated. CONCLUSIONS: Guardians who had had one of their children vaccinated at least once emphasized the importance of prevalence and free vaccination. On the other hand, guardians who had not had any of their children vaccinated placed particular importance on adverse reactions and the Japanese data on effectiveness. To guide the decision-making of guardians, it is necessary to quickly collect and publish data on adverse reactions and effectiveness, particularly in Japanese individuals, so that citizens can decide whether to vaccinate themselves and their children.

Periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis syndrome: Clinical characteristics and treatment outcomes - a single center study in Japan.

BACKGROUND: Periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome is an autoinflammatory disease occurring in children. Although PFAPA is the most common periodic fever syndrome found in children, there are only a few studies defining the clinical characteristics and the efficacy of treatment strategies among Japanese children. This study aimed to clarify the demographic characteristics and clinical features of patients with PFAPA syndrome and to evaluate treatment efficacy. METHODS: We retrospectively reviewed the clinical features of children with PFAPA who visited Saitama Children's Medical Center between January and December 2019. We also evaluated treatment strategies and their efficacy; abortive treatment with corticosteroids, prophylaxis with cimetidine or colchicine, and surgical management with tonsillectomy. RESULTS: A total of 100 Japanese children (61% male) with PFAPA were included. Median age of onset was 3 years, median duration of fever episodes was 5 days, and median interval between episodes was 4 weeks. The symptoms (frequencies) were pharyngitis (89%), exudate on tonsils (71%), cervical adenitis (50%), and aphthous stomatitis (49%). Approximately 37% of patients took prednisolone for aborting fever attacks, showing a 100% response; 93% were treated with cimetidine, showing an 79.6% response, and 18% were treated with colchicine, showing a 66.7% response. Only one patient underwent tonsillectomy. CONCLUSIONS: Among Japanese children with PFAPA, 28% of them were ≥5 years with a male predominance. Pharyngitis is the most frequent symptom associated with fever. Cimetidine is suitable for initial therapy because of its safety and efficacy.

Case Reports on Effect of Intratympanic Steroid Injection Therapy on Late-Onset Hearing Loss in Congenital Cytomegalovirus Infection.

BACKGROUND: One of the conditions or symptoms caused by congenital cytomegalovirus (cCMV) infection is late-onset hearing loss. This report examines the cases of two children exhibiting late-onset hearing loss after cCMV infection who showed improvement in hearing after undergoing intratympanic steroid injection therapy (IST). CASES: Case1 is girl aged 8 years and 10 months and case2 is girl aged 5 years and 1 month. Cytomegalovirus (CMV) was not detected in the blood or urine of either child at the time of hearing loss despite them having cCMV infection. FINDINGS: The hearing of both children improved as a result of IST on an outpatient basis. Case1 was given first session of IST in left ear immediately on the day of her visit and second session of IST in left ear 2 days later. Tendency for improvement in threshold on left side was observed (the differences were about 20 to 45 dB). Case2 was given a total of 2 sessions of IST on left ear, 3 days and 5 days after visiting the hospital. The test result of distortion product otoacoustic emissions changed from refer to pass. Tendency for improvement in threshold on left side was observed (the differences were about 5 to 25 dB). CONCLUSIONS: Bearing in mind that late-onset hearing loss in patients with cCMV may be caused by other factors besides CMV, consideration of IST as a possible treatment option is proposed.

Efficacy, safety, and pharmacokinetics of oral valganciclovir in patients with congenital cytomegalovirus infection.

OBJECTIVES: Valganciclovir (VGCV) has been shown to improve sensorineural hearing loss (SNHL) and neurological outcomes in patients with neonatal symptomatic congenital cytomegalovirus (cCMV) infection. However, reports on the pharmacokinetics, efficacy and safety of oral VGCV are limited. The aim of this study is to evaluate the pharmacokinetics of VGCV for use in the treatment of cCMV. METHODS: This was a single-center, retrospective observational study conducted at Saitama Children's Medical Center in Japan between 2012 and 2017. CMV DNA copy number, maximum plasma VGCV concentration (Cmax), and adverse events (ADEs) during treatment were evaluated. RESULTS: A total of 26 patients with cCMV who received VGCV were included in this study. The median age at VGCV initiation was 9.5 months (range 0-46). Twenty-one patients (81%) had SNHL at baseline. Of these, five patients (19%) presented with improved SNHL, and none experienced worsened SNHL during treatment. The mean VGCV Cmax was 3.5 µg/mL (range 2-5.3), with no significant variation among individual values, and the values were maintained during treatment. Furthermore, there were no correlations between the Cmax values and age, sex, SNHL improvement or ADEs. Neutropenia (<1000/mm3) was observed in six patients (23%); however, no serious ADEs occurred. CONCLUSIONS: VGCV prevented the progression of SNHL without serious ADEs due to its stable pharmacokinetics. This study provides safety and tolerability of VGCV for the treatment of cCMV patients.

Infected simple renal cyst due to Streptococcus pneumoniae rapidly diagnosed by the melting temperature mapping method: a case report.

BACKGROUND: Spontaneous infection of preexisting solitary renal cysts has been documented in adults but is extremely rare in children. To date, no cases of simple renal cysts infected with Streptococcus pneumoniae have been described. Recently, reports have described the diagnosis of bacterial infection using the 16 S rRNA gene as well as the accompanying antimicrobial stewardship for microorganisms that are difficult to culture and for culture-negative cases after preceding antibacterial administration. CASE PRESENTATION: A four-year-old Japanese girl who had a pleuroperitoneal shunt inserted to drain a right pleural effusion due to occlusion of the hepatic portion of the inferior vena cava at three years old visited our hospital due to fever and respiratory discomfort. She was incidentally found to have a right simple renal cyst 10 months before admission. The patient was suspected to have pneumonitis or catheter-related blood stream infection on chest X-ray, which showed right-side pleural effusion. She was diagnosed with invasive pneumococcal infection, as Streptococcus pneumoniae was detected from blood culture on admission. Transient improvements in her symptoms and decreases in the white blood cell count and C-reactive protein level were observed after effective antibiotic administration, but her respiratory condition deteriorated. Enhanced CT showed right renal cyst enlargement and enhancement and thickening of the surrounding wall. Using the melting temperature (Tm) mapping method, S. pneumoniae was rapidly detected directly from pus 4.5 hours after drainage. The specimen culture was negative, but the extracted 16 S rDNA sequence revealed 100 % identity for S. pneumoniae from the same specimen the subsequent day. We successfully performed optimal treatment and reduced medical cost based on the positive Tm mapping method result. CONCLUSIONS: We report the first case of a S. pneumoniae-infected simple renal cyst. The drainage culture was negative, but the Tm mapping method rapidly detected S. pneumoniae directly from the drainage. The Tm mapping method may have great impacts on rapid diagnosis and effective antimicrobial stewardship.

Pyogenic liver abscess due to hypervirulent Klebsiella pneumoniae in a 14-year-old boy.

A 14-year-old otherwise healthy boy presented with right-sided back pain following high fever. Abdominal computed tomography scan showed a large liver abscess. Klebsiella pneumoniae (KP) was rapidly identified from peripheral blood using the melting temperature mapping (Tm) method, which enables identification of pathogenic microorganisms within four hours after patient sample collection. He was diagnosed with pyogenic liver abscess (PLA) caused by KP on the day of admission. The KP was the hypervirulent (hv) clinical variant (string test positive, serotype K1, sequence type 23, rmpA and magA positive). After intravenous antibiotic therapy and drainage of the abscess, his condition resolved. The highlights of this case report are a healthy child with hypervirulent Klebsiella pneumoniae liver abscess in Japan and the new Tm mapping method for rapid and accurate identification of the pathogenic microorganism.

Infliximab for the Treatment of Refractory Kawasaki Disease: A Nationwide Survey in Japan.

OBJECTIVE: To assess the safety and efficacy of infliximab (IFX) for the treatment of patients with Kawasaki disease (KD). STUDY DESIGN: This was a nationwide survey of 274 Japanese institutions exploring how IFX was used to treat patients with KD. The patients' sex, age, treatment course, pre- and post-IFX therapy blood test results, coronary artery lesions (CALs), and adverse events (AEs) were evaluated. RESULTS: We analyzed 434 patients with KD who received IFX between March 2005 and November 2014. The median age at onset was 33 months (range 1-138), and 66 patients (15.2%) were under 1 year old. In all cases, IFX was administered as additional treatment. The median days of illness at the initiation of IFX was 9 days. In 275 patients (63.4%), IFX was administered as third-line treatment, and in 106 patients (24.4%), IFX was administered as fourth-line treatment. Single dose IFX 5 mg/kg was administered to 412 patients (94.9%). After IFX, 363 patients (83.6%) became afebrile within 2 days, and the white blood cell count, percentage of neutrophils, and serum C-reactive protein levels significantly decreased (P < .001), although 119 patients (27.4%) received additional treatment. Before IFX, 132 patients (30.4%) had already developed CALs. In patients without CALs before IFX, 31 patients (10.3%) newly developed CAL after IFX, whereas 32 patients (24.2%) with CAL before IFX showed increased CAL severity. Eighty AEs were observed in 69 patients (15.9%); however, serious AEs were few and reversible. CONCLUSIONS: IFX might be an effective and tolerable treatment for refractory KD.

10-year follow-up of congenital cytomegalovirus infection complicated with severe neurological findings in infancy: a case report.

BACKGROUND: Congenital cytomegalovirus (cCMV) infection leads to sensorineural hearing loss (SNHL) and neurodevelopmental delays. However, the long-term outcomes of cCMV infection with severe neurological manifestations in infancy remain unclear. CASE PRESENTATION: The patient was a one-month-old girl visited owing to abnormalities in neonatal hearing screening. Central nervous system involvement including intracranial calcification and extensive white matter abnormalities was identified. Right SNHL (50 dB) was detected by auditory brain response (ABR) testing. The cause of her hearing loss was determined to be cCMV infection by polymerase chain reaction (PCR) using a dried blood spot. At 1.5 months of age, the patient was treated with intravenous ganciclovir (GCV) for 5 weeks followed by oral valganciclovir (VGCV) for an additional 6 weeks. Cytomegalovirus (CMV) loads in her urine continued to be detected until she was 10 years old. Fortunately, during this time, her right hearing loss did not deteriorate, and her left hearing remained normal. Furthermore, the extensive abnormal areas of white matter observed at 1 month of age mostly disappeared by the time the patient was 9 years old. Her neurodevelopmental score was normal, and motor milestones were not delayed as of 10 years of age. CONCLUSIONS: Here, we report the 10-year follow-up of a patient with cCMV who showed normal neurodevelopment, no progression of hearing loss, and ameliorating magnetic resonance imaging (MRI) findings, despite having various complications and severe neurological findings during infancy.

Clinical features of Stevens-Johnson syndrome and toxic epidermal necrolysis.

BACKGROUND: Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are rare, but these conditions are associated with high mortality. There have been few reports of SJS and TEN in children. The aim of this study was to evaluate the clinical features and outcomes of SJS and TEN in a group of Japanese children. METHODS: We retrospectively reviewed pediatric cases of SJS and TEN, from 2000 to 2015. RESULTS: We identified 12 pediatric cases of SJS and three of TEN. Six (all SJS) were caused by infection, and eight of the cases (SJS, n = 5; TEN, n = 3) were drug induced. Respiratory complications were the most common in terms of organ involvement, followed by hepatitis and gastrointestinal symptoms. Thirteen patients were treated with systemic corticosteroids, and two patients were treated with supportive therapy only. Concomitant with corticosteroid, four patients were given i.v. immunoglobulin. One patient with severe TEN was treated with systemic corticosteroids combined with plasmapheresis and cyclosporine. None of the present patients died. One patient with TEN had severe sequelae, with bronchiolitis obliterans and ocular involvement. CONCLUSIONS: SJS/TEN are rare, but are associated with severe complications. General pediatricians need to have up-to-date information regarding these conditions. The present study provides insights into the confirmation of the risk of SJS/TEN as well as the treatment of these diseases.

Losartan attenuates the coronary perivasculitis through its local and systemic anti-inflammatory properties in a murine model of Kawasaki disease.

BACKGROUND: Kawasaki disease is a common systemic vasculitis that leads to coronary artery lesions. Besides its antihypertensive effects, losartan can modulate inflammation in cardiovascular disease. We examined whether losartan can attenuate coronary inflammation in a murine model of Kawasaki disease. METHODS AND RESULTS: Five-wk-old C57/BL6J male mice were intraperitoneally injected with Lactobacillus casei cell wall extract to induce coronary inflammation and divided into four groups: placebo, intravenous immunoglobulin (IVIG), losartan, and IVIG+losartan. After 2 wk, mice were harvested. The coronary perivasculitis was significantly attenuated by losartan but not by IVIG alone, and further dramatic attenuation by IVIG+losartan was observed. The frequency of Lactobacillus casei cell wall extract-induced myocarditis (80%) was markedly lowered by losartan (22%) and IVIG+losartan (0%). Furthermore, interleukin (IL)-6 mRNA was markedly attenuated by IVIG+losartan. Serum levels of IL-6, TNF-α, MCP-1, and IL-10 after Lactobacillus casei cell wall extract injection were slightly decreased by IVIG or losartan. Moreover, IL-1ß, IL-10, and MCP-1 levels were significantly decreased by IVIG+losartan. CONCLUSION: The addition of losartan to IVIG strongly attenuated the severity of coronary perivasculitis and the incidence of myocarditis, along with suppressing systemic/local cytokines as well as the activated macrophage infiltration. Therefore, losartan may be a potentially useful additive drug for the acute phase of Kawasaki disease to minimize coronary artery lesions.

A retrospective study: Acute rheumatic fever and post-streptococcal reactive arthritis in Japan.

BACKGROUND: Acute rheumatic fever (ARF) and post-streptococcal reactive arthritis (PSRA) are immune-mediated consequences of group A streptococcal pharyngitis. ARF has declined in developed nations. No prevalence survey of PSRA has been conducted. This study evaluated the incidence and characteristics of ARF and PSRA in Japanese children. METHODS: From 2010 to 2015, ARF and PSRA were evaluated using clinical data retrospectively collected by chart review from 528 hospitals. RESULTS: From 323 hospitals (61% response rate), 44 cases of ARF and 21 cases of PSRA were reported. Patients with ARF and/or PSRA were mainly from large cities in Japan. The mean age of ARF occurrence was 8.5 years, and the ratio of female/male patients was 16:28. Major manifestations in the acute phase included carditis, 27 cases (61.4%); polyarthritis, 22 cases (50%); erythema marginatum, 7 cases (15.9%); Sydenham chorea, 3 cases (6.8%); and subcutaneous nodules, 1 case (2.3%). Twenty-one (58.3%) patients had migratory arthritis. During the follow-up period, 6 patients (13.6%) showed mild carditis. For PRSA, the mean age was 8.2 years, and the ratio of female/male patients was 12:9. Six (28.6%) patients had monoarthritis, and 4 (19%) patients had migratory arthritis. No patient had carditis. CONCLUSIONS: Although ARF and PSRA are rare in the Japanese pediatric population, substantial numbers of patients with both conditions were identified in this study. We observed a high incidence of arthritis and carditis in ARF patients. No PSRA case was complicated with carditis. General pediatricians need to have updated information about ARF and PSRA, even in industrialized countries.

Clinical analysis and outcome of interstitial lung disease complicated with juvenile dermatomyositis and juvenile polymyositis.

OBJECTIVES: The aim of this study was to determine the clinical phenotype and outcome of interstitial lung disease (ILD) complicated with juvenile dermatomyositis (JDM) or juvenile polymyositis (JPM). METHODS: This was a single-center retrospective study. From 1984 to 2015, we retrospectively reviewed 29 patients who were diagnosed with JDM/JPM, among whom eight cases were ILD and 21 were non-ILD. The clinical features and laboratory findings included chest computed tomography (CT) images that were compared between the patients with ILD and non-ILD. RESULTS: Eight cases (27.6%) were complicated with ILD. The mean age was 6.3 years, and 75% of the patients were women. We found that high fever, arthralgia, muscle weakness, and high serum Krebs von den Lungen-6 (KL-6) level were significantly associated with the presence of ILD (p < 0.05). Two patients were positive for the anti-Jo-1 antibody, and two other patients were positive for the anti-MDA5 antibody. Three cases were identified as rapidly progressive (RP)-ILD. The chest CT images of the ILD patients appeared to show ground glass opacity (GGO) with a lower lobe predominance, reticulation, and traction bronchiectasis consolidation. Three patients with RP-ILD showed random subpleural GGO with/without consolidation patterns. Further, three patients with RP-ILD died of respiratory failure (p < 0.01). CONCLUSION: ILD is one of the most serious complications of JDM/JPM. In the early phase of ILD, high levels of serum KL-6 can be detected, regardless of the respiratory symptoms. Additionally, RP-ILD can be predicted based on the presence of anti-MDA5 antibodies and the chest CT findings, including random subpleural GGO with/without consolidation patterns.