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No studies have assessed differences between the Japanese and Z score criteria in the echocardiographic detection sensitivity of coronary artery (CA) abnormalities using large-scale data containing samples from multiple facilities engaged in daily clinical practices of Kawasaki disease (KD). We analyzed data from the 25th Japanese nationwide KD survey, which identified 30,415 patients from 1357 hospitals throughout Japan during 2017-2018. Hospitals were classified according to their use of Z score criteria. We assessed differences in hospital and patient background factors and compared the prevalence of CA abnormalities among groups using the Z score criteria. Multivariable logistic regression analyses were performed to evaluate differences in the detection sensitivity for CA abnormalities. The Z score criteria were more likely to be utilized in larger hospitals with more pediatricians and cardiologists. Even after controlling for potential confounders, detection sensitivities by the Z score criteria were significantly higher than by the Japanese criteria in patients with CA dilatations (adjusted odds ratio (95% confidence interval) 1.77 (1.56-2.01)) and aneurysms (1.62 (1.17-2.24)). No significant difference was found in patients with giant CA aneurysms. Compared with the Japanese criteria, the Z score criteria were significantly more sensitive for detecting patients with CA dilatations regardless of age, and for those with CA aneurysms only in patients aged ≤ 1 year. Our results indicate that differences in the detection sensitivity for CA abnormalities between the Z score and the Japanese criteria were dependent on the CA size and patient age.

Hyponatremia is a potential risk factor for the development of coronary artery lesions (CALs) identified after acute Kawasaki disease (KD). However, the serum sodium distribution corresponding to the reference intervals differs between infants ( 1 year of age) and older children. We hypothesized the association of serum sodium level with CAL complications differs between infants and older patients with KD.We analyzed 21,610 population-based patients who developed KD throughout Japan during 2013-2014. We performed multivariable logistic regression analyses to evaluate the association between serum sodium and CAL complications. Additionally, we stratified the serum sodium distribution associated with CAL complications by infants and older patients.CALs were identified in 158 (3.6%) infants and 302 (1.8%) older patients. Infants were more likely to develop CALs when within the normal sodium range compared with older patients (75% vs. 29%), whereas most older patients developed CALs with a sodium level lower than the reference interval. Serum sodium ≤ 130 mEq/L indicated significantly higher risk for development of CALs in both groups (adjusted odds ratio [95% confidence intervals] = 3.21 [1.65-6.25] in infants and 1.74 [1.18-2.57] in older patients).Serum sodium distribution associated with CAL complications differed greatly between infants and older patients. Older patients developed CALs with sodium levels lower than the reference interval; however, among infants, hyponatremia was not necessarily a risk factor for developing coronary artery lesion. When considering risk assessments for CALs using serum sodium levels, infants with KD should be distinguished from older patients. Key Points • Hyponatremia is a potential risk factor for the development of coronary artery lesions (CALs) among patients with Kawasaki disease. • However, the serum sodium distribution corresponding to the reference intervals differs between infants ( 1 year of age) and older children. • Most infants developed CALs within the normal sodium range, whereas older patients developed at a range lower than the reference interval. • These findings highlight that when considering risk assessments for CALs using serum sodium levels, infants should be distinguished from older patients.

The long-term prognosis of those with a history of Kawasaki disease (KD) is still unknown.Using a permanent registry system in Japan (koseki), 6,576 persons with a history of KD were followed up. The average follow-up period was 30 years. The endpoint was death.With a 99.5% follow-up rate, 68 deaths (48 males and 20 females) were observed. The overall standardized mortality ratio, of which reference was vital statistics in Japan, was not elevated. However, the observation according to the presence or absence of cardiac sequelae showed that the standardized mortality ratio for those with cardiac sequelae significantly elevated. Nine persons, all of whom were males, died of KD (including those cases where KD was suspected), but all deaths occurred in individuals who were under 30 years of age.This study revealed the long-term prognosis for KD, but almost all participants were younger than 40 years. Continuing follow up of this cohort is required to clarify whether a history of KD relates to the development of atherosclerosis when participants become middle aged or older.

Background Previous studies demonstrated that coronary artery lesions (CALs) resulting from Kawasaki disease (KD) can improve over time. However, limited information is available on sub-acute outcomes of CALs detected at admission during KD illness. Methods The nationwide Japanese KD survey contained substantial information on KD patients with CALs detected at admission and who received standard IVIG treatment within 10 days of disease onset. Coronary outcomes were evaluated by changes in CALs from admission to the first assessment at 30 days from disease onset in three categories: improved, unchanged, and progressed. Ordinal logistic regression analysis was performed to evaluate factors associated with the outcomes. Results Of 2024 patients with CALs detected at admission, improved, unchanged, and progressed outcomes were found in 1548 (76.5%), 390 (19.3%), and 86 (4.2%), respectively. Over 80% of patients with coronary artery (CA) dilatations had improved outcome. Independent factors associated with worse outcomes were larger-size CALs (adjusted ORs [95% CIs]: CA aneurysm = 5.13 [3.65-7.22] and giant CA aneurysms = 7.49 [3.56-15.72] compared with CA dilatation, respectively), age ≥ 60 months (1.45 [1.08-1.94] compared with 12-59 months), recurrent KD (1.57 [1.07-2.29]), parental history of KD (2.23 [1.02-4.85]), and delayed admission (8-10 days from disease onset: 1.76 [1.21-2.57] compared with 1-4 days). Conclusions KD patients with larger CALs, ≥60 months old, and with recurrent status or parental history may require more rigorous treatment. In addition, delayed admission may result in worse coronary outcome, indicating that prompt diagnosis and treatment are required.

Background Some patients with Kawasaki disease (KD) develop cardiac sequelae, which increase the risk of subsequent ischemic heart events. Knowing the cumulative incidence (CI) of KD with cardiac sequelae may contribute to developing health policies to prevent subsequent ischemic events in these patients. Methods Study participants consisted of 254 984 patients aged 0-9 years with KD who were registered in nationwide surveys in Japan from 1991-2016. We calculated the incidence probabilities by dividing the number of patients with KD aged 0-9 years by the population used in vital statistics of each calendar year. We calculated the cumulative proportion of those not affected by KD, by multiplying each probability in patients aged from age 0-9 years. The CI of KD was obtained by subtracting this value from 1. We also calculated the number of patients in each birth cohort (BC). The same was done to calculate the CI of KD-related cardiac sequelae. Results The CIBC steadily increased from 0.005067 in males and 0.003668 in females in 1991 to 0.011431 in males and 0.0088253 in females in 2007. The CIBC of KD with cardiac sequelae decreased from 0.000478 in males and 0.000213 in females in 1997 to 0.000339 in males and 0.000169 in females in 2007. Conclusion The increasing CIBC of KD indicates an increased susceptibility to KD in accordance with birth year. The decreasing CIBC of cardiac sequelae suggests the efficacy of KD treatment.

BACKGROUND Platelet count is considered as a biomarker for the development of coronary artery abnormalities (CAAs) among Kawasaki disease (KD) patients. However, previous studies have reported inconsistent results. We addressed the controversial association of platelet count with CAAs using a large-scale dataset. METHODS A retrospective cohort study was conducted using KD survey data from Japan (2015-2016; n = 25,448). Classifying patients by intravenous immunoglobulin (IVIG) responsiveness, we described the trends in platelet count using the lowest and highest values along with the specific illness days. Multivariate logistic regression analysis was performed to evaluate the association between platelet count and CAAs, adjusting for relevant factors. RESULTS Platelet counts rapidly decreased from admission, reached the lowest count at 6-7 days, and peaked after 10 days. Platelet counts in IVIG non-responders decreased with a lower minimum value than IVIG responders, but subsequently rebounded toward a higher maximum. Compared with patients with normal platelet counts (150-450 × 10/L), patients with abnormally high platelet counts (>450 × 10/L) were more likely to have CAAs at admission (adjusted odds ratio: IVIG responders, 1.50 [95% confidence interval 1.20-1.87] and non-responders, 1.46 [1.01-2.12]). By contrast, IVIG non-responding patients whose counts were below normal (

Serum alanine aminotransferase (ALT) elevation is considered a risk factor for resistance to initial intravenous immunoglobulin (IVIG) treatment in patients with Kawasaki disease (KD). However, serum ALT levels change dramatically during acute KD illness. We tested the hypothesis that risk assessment for initial IVIG resistance based on serum ALT elevation may differ by examination day after KD onset.We analyzed 18,492 population-based patients who developed KD throughout Japan. First, we epidemiologically evaluated the serum ALT variation at 1‒10 days after disease onset. Second, we conducted multivariable logistic regression to determine the association between serum ALT level and initial IVIG resistance according to timing of initial hospital visit by stratifying the patients into an early group (1‒5 days after onset) and a late group (6‒10 days after onset).Serum ALT rapidly increased after KD onset, peaked at day 4 of illness, and then declined regardless of IVIG responsiveness. The adjusted odds ratio (OR) increased with increasing serum ALT in the early group (adjusted OR [95% CI]: 1.44 [1.25-1.66], 1.94 [1.65-2.28], and 2.22 [1.99-2.48] for serum ALT 50-99, 100-199, and ≥ 200 IU/L, respectively; reference ALT level: 1-49 IU/L). No significant association was observed in the late group.The findings indicate that risk assessment for initial IVIG resistance based on serum ALT level may only be reliable for patients with KD who visit hospitals during early illness, specifically 1-5 days after disease onset. Key Points Serum alanine aminotransferase level differed markedly according to examination days after Kawasaki disease onset. Serum alanine aminotransferase level declined toward normal range after day 5 of illness regardless of intravenous immunoglobulin responsiveness. Elevated serum alanine aminotransferase level was no longer a significant risk factor for initial intravenous immunoglobulin resistance when measured on delayed hospital visits. Risk assessment for initial intravenous immunoglobulin resistance based on serum alanine aminotransferase level may only be reliable for patients who visit hospitals during early illness, specifically 1-5 days after disease onset.

ImportanceGlobal studies have reported that the incidence of Kawasaki disease (KD) declined during the COVID-19 pandemic. These studies suggest that the global pandemic and its accompanying mitigation measures may provide an important opportunity to explore the hypothesis of a KD pathogenesis.ObjectiveTo compare changes in KD incidence in Japan before and after the start of the COVID-19 pandemic.Design, Setting, and ParticipantsThis cohort study was conducted using the data set from Japan’s 26th nationwide KD survey that obtained information on patients who were diagnosed with KD in Japan from January 1, 2019, through December 31, 2020.Main Outcomes and MeasuresKawasaki disease incidence rates were calculated by referring to the national population data in the vital statistics data for Japan.ResultsA total of 28 520 patients were identified (16 236 male individuals [56.9%]; median [IQR] age, 26 [14-44] months). A total of 17 347 patients were diagnosed with KD in 2019 and 11 173 were diagnosed in 2020, representing a 35.6% reduction in the number of patients diagnosed in 2020 compared with the previous year. Patient distributions for days of illness at the first hospital visit were almost identical in 2019 and 2020, suggesting that the decrease in KD incidence likely was not associated with pandemic-related delays in seeking treatment. The proportion of patients diagnosed with KD who were younger than 12 months was significantly larger in 2020 than in 2019 (21.6% vs 19.4%; P Conclusions and RelevanceIn this cohort study, the number of patients diagnosed with KD decreased by approximately one-third across Japan in 2020, with no indication that parents avoided a hospital visit. Differences in KD incidence reduction patterns before and after the initiation of COVID-19 pandemic mitigation measures were found in patients with KD aged younger than 12 months compared with those 24 months or older, suggesting a potential KD pathogenesis involving transmission among children.

Background Kawasaki disease (KD) is the most common cause of acquired pediatric heart disease in developed countries. The study aimed to summarize the epidemiologic characteristics, treatments, and cardiac complications of KD, using data from the nationwide survey in Japan. Methods The nationwide survey in Japan has been conducted biennially since 1970. The survey respondents were hospitals specializing in pediatrics and those with ≥100 beds and a pediatric department throughout Japan, where KD patients were eventually hospitalized. The most recent survey was completed in 2019, obtaining information for patients who developed KD during 2017–2018. Results The survey identified 32528 KD patients, which comprised 15164 (47%) in 2017 and 17364 (53%) in 2018. The highest annual incidence rate was recorded in 2018 (359 per 100,000 children aged 0–4 years). After 1982, patients with ≤4 principal KD signs increased, resulting in 6847 (21%) patients diagnosed during 2017–2018. Among 30784 patients who received initial intravenous immunoglobulin administration, 6061 (20%) did not respond. Within 30 days of KD onset, 9.0% of patients were diagnosed with cardiac complications, and consequently, 2.6% of patients developed cardiac sequelae after the acute illness. Conclusions The annual number of patients developing KD in Japan increased from 1970 through 2018, while the proportion of KD patients with cardiac complications decreased. Recent advances in KD treatments might have contributed to preventing the development of cardiac complications. Key messages We analyzed large-scale data and summarized the epidemiologic characteristics, treatments, and cardiac complications of KD in Japan.

Background Detection of coronary artery lesions (CALs) at initial echocardiography can aid in diagnosing Kawasaki disease (KD) and inform primary adjunctive treatments. We aimed to characterize patients with KD with CALs detected at initial echocardiography. Methods and Results We analyzed data from the nationwide Japanese KD survey that contained information on 103 222 population‐based patients diagnosed with KD across Japan during 2011 to 2018. Patients with CALs detected at initial echocardiography were assessed by age, day of illness, and number of principal KD signs (≥3). Multivariable logistic regression analysis was performed to evaluate factors independently associated with CAL detection. Overall, 3707 (3.6%) patients had CALs detected at initial echocardiography. Patients aged Conclusions Timely diagnosis could be beneficial for patients with KD. However, even when the hospital visit occurred early in the course of illness, patients with 3 or 4 principal KD signs, especially younger patients, were at higher risk of CAL detection at initial echocardiography.

A giant coronary artery (CA) aneurysm is a potentially fatal cardiac complication resulting from Kawasaki disease (KD). We aimed to identify epidemiologic characteristics and potential risk factors associated with giant CA aneurysms identified after acute KD. We analyzed 90,252 patients diagnosed with KD from 2011 to 2018, using data obtained in nationwide KD surveys conducted in Japan. Multivariable logistic regression analyses were performed to evaluate potential risk factors associated with subsequent giant CA aneurysm complications (defined as lumen size ≥ 8 mm), adjusting for all potential factors. Giant CA aneurysms were identified in 144 patients (0.16%) after acute KD. The annual prevalence ranged from 0.07 to 0.20% during the study period. In the multivariate analyses, male sex (adjusted odds ratio 2.09 [95% confidence interval 1.41–3.11], recurrent KD (1.90 [1.09–3.33]), IVIG administration at 1–4 days of illness (1.49 [1.04–2.15]) and ≥ 8 days after KD onset (2.52 [1.38–4.60]; reference, 5–7 days), detection of CA dilatations and aneurysms at initial echocardiography (4.17 [1.85–5.41] and 46.5 [28.8–74.8], respectively), and resistance to IVIG treatment (6.09 [4.23–8.75]) were significantly associated with giant CA aneurysm complications identified after acute KD. The annual prevalence of giant CA aneurysms identified after acute KD did not increase during the study period. Patients with larger CA abnormalities detected at initial echocardiography were independently associated with progression to giant CA aneurysm complications after acute KD regardless of the number of days from onset at treatment initiation.

BACKGROUND Randomized controlled trials previously provided different conclusions about the superiority of adding corticosteroids to initial intravenous immunoglobulin treatment for the prevention of coronary artery abnormalities in patients with Kawasaki disease (KD). To further assess this issue, we analyzed large‐scale data from nationwide KD surveys in Japan, where combination treatment (corticosteroids added to initial standard intravenous immunoglobulin treatment) has become commonly used for patients at high risk for KD. METHODS AND RESULTS Standard intravenous immunoglobulin treatment and combination treatment were compared using data from time periods with and without combination treatment. Outcome measures were coronary artery abnormalities and initial intravenous immunoglobulin treatment failure. Hospitals where ≥20% of patients received combination treatment were identified, and treatment and control groups were selected via matching by age, sex, illness day at initial treatment, and KD recurrence. Matched group selection and subsequent analyses were conducted 1000 times to minimize sampling bias and potential confounders (bootstrapping). From 115 hospitals, 1593 patients with KD in the treatment group and 1593 controls were selected for each of the 1000 sample iterations. The median proportion of patients who developed coronary artery abnormalities among the treatment group and controls were 4.6% (95% CI, 3.8%–5.8%) and 8.8% (95% CI, 7.5%–10.0%), respectively: an estimated risk ratio of 0.53 (0.41–0.67). A median of 14.1% (95% CI, 12.4%–15.9%) of the patients in the treatment group and 21.7% (95% CI, 19.8%–23.4%) in the controls had treatment failure: an estimated risk ratio of 0.65 (0.56―0.75). CONCLUSIONS Combination treatment reduced coronary artery abnormality risk by an estimated 47% and treatment failure by 35%. Multiple‐dose corticosteroids may provide benefit in selected patients at high risk for KD.

ObjectiveTo investigate whether redness and crusting at the bacille Calmette-Guérin inoculation site (BCGitis), identified during acute illness owing to Kawasaki disease (KD), is an independent risk factor for development of cardiac complications.DesignRetrospective cohort study using data from the nationwide KD survey in Japan.SettingSurvey respondents included hospitals specialising in paediatrics and hospitals with ≥100 beds and a paediatric department throughout Japan.PatientsWe included 17 181 patients with KD across Japan during 2005–2006.Main outcome measuresBCGitis and cardiac complications resulting from KD.ResultsBCGitis was identified in 7549 (44%) patients with KD. Compared with patients without BCGitis, those with BCGitis were younger, more likely to be male, less likely to have recurrent status and visited a hospital and underwent initial intravenous immunoglobulin (IVIG) treatment earlier after KD onset. In the unadjusted model, patients with BCGitis were significantly less likely to have cardiac complications (crude OR 0.81, 95% CI 0.71 to 0.92). However, after including treatment factors (days of illness at initial IVIG and treatment responsiveness) in the adjusted model, the association was no longer significant (adjusted OR 0.89, 95% CI 0.77 to 1.03), indicating that BCGitis was not an independent factor associated with cardiac complication and might be confounded by treatment factors.ConclusionsBCGitis was identified in comparatively early illness stages of KD. Our findings indicated that BCGitis was not an independent factor associated with developing cardiac complications but was confounded by prompt initial IVIG administration, which might result in successful treatment and prevention of cardiac complications.

Background: Globally, few published studies have tracked the temporal trend of dioxin levels in the human body since 2000. This study describes the annual trend of dioxin levels in human breast milk in Japanese mothers from 1998 through 2015. Methods: An observational study was conducted from 1998 through 2015. Participants were 1,194 healthy mothers following their first delivery who were recruited annually in Japan. Breast milk samples obtained from participants were analyzed using gas chromatography and mass spectrometry for dioxins, including polychlorinated dibenzo-p-dioxins (PCDDs), polychlorinated dibenzofurans (PCDFs), and coplanar polychlorinated biphenyls (PCBs). Results: Mean age was 29.5 years, and 53% of participants were 20–25 years old. A declining trend in total dioxin levels was found, from a peak of 20.8 pg toxic equivalence (TEQ)/g fat in 1998 to 7.2 pg TEQ/g fat in 2014. Data from the last 5 years of the study indicated a plateau at minimal levels. In contrast, an increasing trend was found in the mean age of participants during the last 5 years. Although significantly higher dioxin levels were observed in samples from older participants, an upward trend in dioxin levels was not observed, indicating that dietary and environmental exposure to dioxins had greatly diminished in recent years. Conclusions: Dioxin levels in human breast milk may be approaching a minimum in recent years in Japan. The findings may contribute to global reference levels for environmental pollution of dioxins, which remains a problem for many developing countries.

BACKGROUND The etiology of Kawasaki disease (KD) is unknown. In Japan, the number of patients and incidence rate of KD has increased continuously since its discovery. The aim of this report was to analyze the latest nationwide epidemiological survey of KD in Japan. METHODS The 23rd nationwide survey of KD was conducted in 2015. To report on all patients diagnosed with KD in 2013 and 2014, a questionnaire was sent to hospitals with ≥100 beds containing pediatric departments, as well as specialized pediatric hospitals. RESULTS The number of KD patients reported was 15 696 in 2013 and 15 979 in 2014, resulting in an annual incidence rate of 302.5 and 308.0 per 100 000 population aged 0-4 years, respectively. The number of patients and incidence rate of KD in 2014 were the highest ever recorded in Japan. The number of patients diagnosed per month peaked in January, and a gradual increase in summer was also observed. Eight patients died of KD in 2013 and 2014. CONCLUSIONS The number of patients and incidence rate of KD in Japan continue to increase. Continued surveillance of epidemiological trends of KD is therefore required.

BACKGROUND Evidence suggests that seasonal variation in the onset of Kawasaki disease (KD) exists worldwide. Whether a seasonal component to successful i.v. immunoglobulin (IVIG) therapy exists in KD-positive children, however, is unknown. We addressed this question by focusing on patients with primary onset KD who were non-responsive to IVIG treatment, in the large nationwide Japanese KD survey datasets from 2009 to 2016. METHODS In these datasets, the IVIG therapy non-responders were defined as patients whose fever persisted ≥24 h or recurred ≤24 h after the end of the initial IVIG treatment (dosage, 2,000 mg/kg). Those who successfully responded to this treatment were defined as IVIG responders. The consecutive monthly trend of the proportion of IVIG non-responders was analyzed throughout the study period to investigate seasonal periodicity on Fourier analysis, and the monthly distributions of non-responders and responders were compared. RESULTS From a total of 113 691 KD-positive patients, 15.7% were IVIG non-responders, and 61% were male. The proportion of non-responders increased across each calendar year with fluctuation, and Fourier analysis indicated seasonal periodicity. The seasonality effect differed between responders and non-responders, with the proportion of responders tending to increase in autumn through winter, while the non-responders showed a decreasing trend in autumn. The seasonality effect tended to differ by sex. CONCLUSIONS The results indicate that the currently unknown etiological agents of KD might differ between IVIG responders and non-responders. In addition, immune reactivity against such agents possibly differs by sex in the IVIG non-responders.

IntroductionBased on data obtained before high-dose (2 g/kg) intravenous immunoglobulin (IVIG) therapy prevailed in Japan, children with a history of Kawasaki disease (KD) were highly susceptible to disease recurrence and more likely to develop cardiac sequelae. We aimed to examine the epidemiological features of cardiac complications among patients with recurrent KD following the widespread use of high-dose IVIG therapy.DesignTwo cohorts of patients with recurrent KD retrieved from Japanese nationwide surveys (previous cohort: 1989–1994; recent cohort: 2003–2012) were compared.ResultsOf 1842 patients with recurrent KD in the recent cohort, 3.5% and 5.2% developed cardiac sequelae at the initial and second episodes, respectively, which were markedly decreased compared with those (>10%, respectively) in the previous cohort. Multivariate analyses showed that the risk factors for cardiac sequelae at the second episode were similar between the cohorts. Patients with recurrent KD in both cohorts were more likely to have coronary aneurysms at the second episode than at the initial episode. However, when patients with coronary aneurysms at the initial episode were excluded from analyses, the difference in the proportions of coronary aneurysms between KD episodes disappeared in the recent cohort. Residual rates of previously formed coronary aneurysms were similar between the cohorts (approximately 50%).ConclusionThis study suggests that KD recurrence is no longer a risk factor for developing cardiac complications, unless cardiac sequelae appear at the initial episode. However, residual rates of previously formed coronary aneurysms remain high. Therefore, the importance of carefully managing coronary aneurysms associated with KD remains unchanged.

Few studies discuss the risk factors for acute cardiac lesions (within 30 days) resulting from Kawasaki disease (KD). We aimed to clarify the characteristics of patients with cardiac lesions within 30 days and determine the risk factors for acute cardiac lesion subtypes. Using the 23rd nationwide survey of KD in Japan, we analyzed data from patients with or without acute cardiac lesions resulting from KD (n = 31,380). We subdivided patients with acute cardiac lesions into three types: acute valvular lesions, coronary aneurysms, and giant coronary aneurysms (GCA), and calculated the odds ratios of potential risk factors for acute cardiac lesion subtypes. The prevalence of acute cardiac lesions was 8.6%, and these lesions were more prevalent among males than females (1.98:1). Male sex, age

Kawasaki disease (KD) is a systemic vasculitis of childhood involving coronary arteries. Treatment for intractable cases at a higher risk of cardiac sequelae remains controversial.Clinical outcomes of KD patients diagnosed in Yamaguchi prefecture, Japan between 2003 and 2014 were analyzed using the medical records from all 14 hospitals covering the prefecture. The study included 1487 patients (male:female, 873:614; median age at diagnosis, 24months).The proportion of initial intravenous immunoglobulin (IVIG)-resistant patients increased from 7% to 23% during this decade, although no patients died. Twenty-four patients developed coronary artery lesions (CALs) over one month after the KD onset. The incidence of CAL in patients who received corticosteroid during the disease course (10/37; 27.0%) was higher than that in those who did not (14/1450; 0.97%, p=2.0×10(-35)). Nine patients who responded to initial IVIG plus corticosteroids had no CAL. Conversely, IVIG-resistant patients with alternate corticosteroid therapy more frequently developed CAL than those without it (10/28; 35.7% vs. 5/194; 2.6%, p=8.9×10(-10)). Multivariate analyses indicated corticosteroid therapy (p0.0001), hyperbilirubinemia (p=0.0010), and a longer number of days before treatment (p=0.0005) as risk factors associated with CAL over a month after onset. The odds ratio of corticosteroid use increased from 18.3 to 43.5 if the cases were limited to initial IVIG non-responders and corticosteroid free-IVIG responders.IVIG-failure has recently increased. The incidence of CAL increased in intractable cases with prolonged corticosteroid use. Corticosteroid may not be alternate choice for IVIG-failure to reduce the risk of cardiac sequelae.

Aim We previously proposed the concept of caregiver daily impression (CDI) as a practical tool for emergency triage. We herein assessed how CDI varies by sex, education and career length by determining CDI scores as quantitative outcome measures. Methods We carried out a cross-sectional study using a self-reported questionnaire among caregivers in 20 long-term care facilities in Hyogo, Japan. A total of 10 CDI variables measured participants' previous experience of emergency transfers using a scale from 0–10. The resulting total was defined as the CDI score. We hypothetically considered that higher scores indicated greater caregiver focus. The CDI scores were compared by sex, education and career length using analysis of covariance. Results A total of 601 personal caregivers were evaluated (mean age 36.7 years; 36% men). The mean career length was 6.9 years, with the following groupings: 1–4 years (38%), 5–9 years (37%) and >10 years (24%). After adjustment for sex and education, the CDI scores for the variable, “poor eye contact,” significantly differed between caregivers with ≥10 and

Objective To report the epidemiologic characteristics, treatments, and cardiac complications of Kawasaki disease, using data from the nationwide survey in Japan. Study design The nationwide Kawasaki disease survey in Japan has been conducted biennially since 1970. The most recent survey was completed in 2019, obtaining information for patients who developed Kawasaki disease during 2017-2018. Survey respondents were hospitals specializing in pediatrics and those with ≥100 beds and a pediatric department throughout Japan, where patients with Kawasaki disease were eventually hospitalized. Results The survey identified 32 528 patients with Kawasaki disease, which consisted of 15 164 (46.6%) in 2017 and 17 364 (53.4%) in 2018. The highest annual incidence rate was recorded in 2018 (359 per 100 000 children aged 0-4 years). After 1982, patients with ≤4 principal Kawasaki disease signs gradually increased, resulting in 6847 (21.1%) patients diagnosed during 2017-2018. Among the 30 784 patients receiving initial intravenous immunoglobulin administration, 6061 (19.7%) did not respond. Within 30 days of Kawasaki disease onset, 9.0% of patients were diagnosed with cardiac complications, and 2.6% of patients developed cardiac sequelae after the acute illness. Conclusions The annual number of patients developing Kawasaki disease in Japan increased from 1970 through 2018, whereas the proportion of patients with Kawasaki disease with cardiac complications decreased in the most recent 2 decades. Early diagnosis of Kawasaki disease as well as advances in initial treatments could explain these findings.

Background Approximately 50 years have passed since Kawasaki disease (KD) was first reported. The KD nationwide survey began in 1970. Although >360 000 cases have already been reported in Japan, the cause is still unknown. In Japan, the number of patients and incidence rate of KD has continued to increase. It is necessary to examine the trend of the occurrence in the surveillance of KD. Methods The nationwide survey of patient incidence in 2015 and 2016 was conducted in 2017, as the 24th nationwide survey of KD. A questionnaire was sent to pediatric departments in hospitals with >100 beds and specialized pediatric hospitals, and was responded to by the attending pediatricians. Results The total number of patients in 2 years was 31 595, and the sex ratio (male/female) was 1.34. The incidence rate (/100 000 children aged 0-4 years/year) was 330.2 (371.2 in boys, 287.3 in girls) in 2015, and 309.0 (343.2 in boys, 273.2 in girls) in 2016. The number of patients by month peaked in January. The age-specific incidence rate according to sex was highest in children between 9 and 11 months of age, after which the incidence rate gradually decreased with advancing age. Conclusions We summarize the most recent nationwide survey of KD and consider the change in the epidemiologic picture.

Evidence suggests that seasonal variation in the onset of Kawasaki disease (KD) exists worldwide. Whether a seasonal component to successful i.v. immunoglobulin (IVIG) therapy exists in KD-positive children, however, is unknown. We addressed this question by focusing on patients with primary onset KD who were non-responsive to IVIG treatment, in the large nationwide Japanese KD survey datasets from 2009 to 2016.In these datasets, the IVIG therapy non-responders were defined as patients whose fever persisted ≥24 h or recurred ≤24 h after the end of the initial IVIG treatment (dosage, 2,000 mg/kg). Those who successfully responded to this treatment were defined as IVIG responders. The consecutive monthly trend of the proportion of IVIG non-responders was analyzed throughout the study period to investigate seasonal periodicity on Fourier analysis, and the monthly distributions of non-responders and responders were compared.From a total of 113 691 KD-positive patients, 15.7% were IVIG non-responders, and 61% were male. The proportion of non-responders increased across each calendar year with fluctuation, and Fourier analysis indicated seasonal periodicity. The seasonality effect differed between responders and non-responders, with the proportion of responders tending to increase in autumn through winter, while the non-responders showed a decreasing trend in autumn. The seasonality effect tended to differ by sex.The results indicate that the currently unknown etiological agents of KD might differ between IVIG responders and non-responders. In addition, immune reactivity against such agents possibly differs by sex in the IVIG non-responders.

The number of patients with food allergy in Japan is increasing year by year, although the precise prevalence of them is not clear. We aimed to determine the estimated number of people with food allergies in Japan and produce new methods of the investigation of them.We determined the number of people with food allergies using government data and statistics such as demographic statistic and the number of students.In infants, the number of patients with a food allergy was 800000 as per the self-reported prevalence; however, as per the physician's diagnoses, 300000-500000 of them had a food allergy. In students, the selfreported number was 600000, while 350000 cases were diagnosed by physicians. In adults, the consumer agency investigated the patients who visited the hospital with the immediate hypersensitivity. In this study, the participants were limited to patients who visited the hospital. This made the estimation of the overall prevalence of food allergy in Japan.For children, if we add the questionnaire to the existing study, which questions them regarding the symptoms of food allergy, the diagnosis by the physician, and the blood test, we can better investigate the prevalence of food allergies and changing pattern by the year. In adults, we propose that future investigations consisting of the National Health and Nutrition Survey and a comprehensive survey of living conditions should be conducted, because few studies have reported on food allergies.

Objectives To reveal the features of death and subsequent funeral services, we analyzed self-reported obituaries in The Shimotsuke, a local daily newspaper in Tochigi, Japan. In addition, the usefulness and disadvantages of such a database of deaths based on the obituaries were discussed.Method For a 5-year period, from January 2011 through December 2015, all the obituary columns in The Shimotsuke were computerized as a database and analyzed. Some results were compared with the vital statistics data in the corresponding period of time. Data analyzed were: dead persons' address (municipalities), name, sex, cause of death, age at death, date of death and funeral services, the chief mourner (Moshu), and so on.Results During the observed 5-year period, 69,793 deaths appeared in the columns, which were 67.6% of the all deaths in the vital statistics. No difference was observed in the proportions between the sexes in the published deaths in comparison with the vital statistics. In both sexes, the proportion was low in 0-9 years old, then high among 10-19 years, decreasing in 20s, and after then the proportion increased according to the age. The proportion was low in city areas, such as Utsunomiya and Oyama, and high in some cities and towns in the northern or eastern parts of Tochigi prefecture. The highest was in Motegi Town (88.0%), and the lowest was Nogi Town (38.0%), which is located in the southern-most part of the prefecture and is closest to the Tokyo metropolitan area. Almost all the funeral services were conducted within a week of the death, and no delays were observed to have been caused by the short supply of cremation services, which exists in large cities in Japan. In case where the chief mourner was a child, a parent, or a spouse of a child, the male sex was dominant. Analyses of death from senile decay, suicide, and homicide indicated that the accuracy of the published cause of death was low. The date of the funeral services was strongly influenced by superstitions in this country.Conclusions Observations of the self-reported obituaries in a local daily newspaper over five years revealed the situations of the deaths in the area that could not be observed using vital statistics. Despite limitations, the information was partially useful as a database.

Aims To propose a caregiver daily impression (CDI) rating instrument for personal caregivers of residents living in long-term care facilities (LTCF) to comprehensively evaluate residents' daily health condition, and to investigate whether the CDI reflects illness latency and severity in residents transferred emergently. Methods We carried out a retrospective review of facility care records from 20 LTCF in Hyogo, Japan. The participants were 169 LTCF residents with episodes of transfer to emergency hospitalization facilities during a 3-month period. We determined specific CDI variables by interviewing experienced LTCF caregivers, and then carried out a principal component analysis to determine the major parameter set. The generated components were incorporated into a regression model to investigate the association with hospitalization. Results The mean age was 87.9 ± 6.5 years, 68% were women and 28% of transfers resulted in hospitalization. The interview procedure identified 12 specific CDI variables, and the principal component analysis generated five distinct components: “change in feeding,” “change in emotion,” “disengaged or listless gaze,” “decrease in eye reactivity” and “change in movement.” By multivariate logistic regression, hospitalization was associated with “decrease in eye reactivity” (adjusted OR 1.78, 95% CI 1.07–2.97) and poor vital signs (adjusted OR 2.84, 95% CI 1.15–6.98), but not with body temperature (adjusted OR 1.29, 95% CI 0.52–3.21). Conclusions The CDI might reflect underlying illness severity beyond quantitative physical findings. Once the CDI can be appropriately validated, quantified and linked to physical findings, it could be used by caregivers for daily resident assessments and as a practical triage tool in emergency situations. Geriatr Gerontol Int 2016; 16: 612–617.

Background The number of patients and incidence rate of Kawasaki disease (KD) are increasing in Japan. We have therefore characterized the latest epidemiological information on KD. Methods The 22nd nationwide survey of KD, which targeted patients diagnosed with KD in 2011 and 2012, was conducted in 2013 and included a total of 1983 departments and hospitals. In order to report on all patients with KD during the 2 survey years, we targeted hospitals of 100 beds or more with pediatric departments, or specialized pediatric hospitals. Results From a total of 1420 hospitals and departments (71.6% response rate), 26 691 KD patients were reported (12 774 in 2011 and 13 917 in 2012; 15 442 males and 11 249 females). The annual incidence rates were 243.1 per 100 000 population aged 0 to 4 years in 2011 and 264.8 in 2012. The number of cases of KD recorded in 2012 was the highest ever reported in Japan. The incidence rate of complete cases was also the highest ever reported in Japan and contributed to the increase in the rate of total cases in recent years. The number of patients diagnosed per month peaked in January, and additional peaks were noted during summer months, although these peaks were lower than those seen in winter. Age-specific incidence rate showed a monomodal distribution with a peak in the latter half of the year in which patients were born. Conclusions The number of patients and the incidence rate of KD in Japan continue to increase. A similar trend has also been seen for patients with complete KD.

Transnasal endoscopy is widely used in screening for upper gastrointestinal lesions because of less associated pain. Nasal bleeding is the most severe adverse effect, but specific risk factors have not been identified. The aim of this study is to identify risk factors for nasal bleeding during transnasal endoscopy. Nasal bleeding occurred in 160/3035 (5.3%) of patients undergoing transnasal endoscopy as part of health checkups. Patient data were retrospectively evaluated including anthropometric, medical, and life-style parameters with multiple logistic regression analysis. Multiple logistic regression revealed that nasal bleeding was significantly associated with age in decades [odds ratio/10 years 0.78, 95% confidence interval (CI) 0.63–0.97, p = 0.027], female gender (2.15, 95% CI 1.48–3.12, p

Background Although the incidence rates of Kawasaki disease (KD) in Japan have been determined in nationwide surveys, the cumulative incidence, that is, the proportion of those with a history of KD in the general population of 10-year-olds, is currently unknown. The aim of this study was therefore to assess the cumulative incidence of KD in Japan. Methods Using the age- and sex-specific incidence rate of KD in Japan from the results of the nationwide surveys, incidence probabilities, that is, the age-specific number of KD patients divided by the population used in the vital statistics, and cumulative proportions of those not affected by KD up to the end of 9 years of age, were calculated. The cumulative incidence was then defined as 1 minus the cumulative proportion. The observed age classes were 0, 1, 2, 3, 4, and 5-9 years. All data were calculated by sex. Results The cumulative incidence was 0.004833 for boys and 0.003474 for girls in 1991, but was 0.015284 and 0.012145 in 2014, respectively. According to these figures, 15.284 per 1,000 boys and 12.145 per 1,000 girls have been affected by KD by the age of 10 years. The birth-cohort cumulative incidences had similar trends. Conclusions More than 10 persons in 1,000 have a history of KD at age 10 years in Japan.

Background Tissue type plasminogen activator (tPA) functions as a fibrinolytic factor in the blood and has unique roles in the nervous system. However, the role of tPA in the olfactory epithelium (OE) is still unclear. Generally, surgical ablation of the olfactory bulb (bulbectomy) triggers degeneration followed by regeneration of OE. In this experimental study, we investigated the role of tPA in OE regeneration. Methods Wild-type (WT) mice and tPA-knockout (tPA−/−) mice were subjected to bulbectomy. Reverse-transcription polymerase chain reaction (RT-PCR), in situ hybridization, and immunohistochemical examination was done to detect tPA expression in the olfactory bulb and OE. Cellular proliferation and apoptosis was also monitored in the OE. Results Before bulbectomy, tPA was found to be expressed in the olfactory bulb and OE. OE degenerated to a similar extent in both strains between 0 and 3 days after bulbectomy. However, OE was thicker and contained more cells in tPA−/− mice than in WT mice at 7 days after bulbectomy. Moreover, the number of apoptotic bodies was reduced and the number of proliferating cells was increased in the OE of tPA−/− mice compared to WT mice, after bulbectomy. Transmission electron microscopy revealed continuous degeneration of the OE for up to 7 days after bulbectomy in WT mice. In contrast, we observed some intact olfactory vesicles and almost normal supporting cells in the OE of tPA−/− mice, at 7 days after bulbectomy. Conclusion The current findings show that the tPA-plasmin system plays an inhibitory role in the regulation of regeneration in the OE.

Objective:This study aimed to investigate the function of tissue plasminogen activator in the olfactory epithelium of mice following neural injury.Method:Transmission electron microscopy was used to study the changes in the morphology of the olfactory epithelium 1–7 days after surgical ablation of the olfactory bulb (bulbectomy).Results:Prior to bulbectomy, a uniformly fine material was observed within some regions of the olfactory epithelium of mice deficient in tissue plasminogen activator. At 2–3 days after bulbectomy, there were degenerative changes in the olfactory epithelium. At 5–7 days after bulbectomy, we noted drastic differences in olfactory epithelium morphology between mice deficient in tissue plasminogen activator and wild-type mice (comparisons were made using findings from a previous study). The microvilli seemed to be normal and olfactory vesicles and receptor neuron dendrites were largely intact in the olfactory epithelium of mice deficient in tissue plasminogen activator.Conclusion:The tissue plasminogen activator plasmin system may inhibit the regeneration of the olfactory epithelium in the early stages following neural injury.

Transmission electron microscopy was used to study the responses of the supporting cells of the olfactory epithelium at 1-5 days after surgical ablation of the olfactory bulb (bulbectomy). In intact olfactory epithelium, lamellar smooth endoplasmic reticulum and rod-shaped mitochondria were distinctly observed in the supporting cells. On the first day after bulbectomy, bending of the microvilli and an increase in the smooth endoplasmic reticulum were observed. Cristae of the mitochondria became obscure, and the density of the mitochondrial matrix decreased. On the second day after bulbectomy, the number of microvilli decreased, broad cytoplasmic projections that contained cytoplasmic organelles protruded into the luminal side, and the mitochondria were swollen. On the fifth day after bulbectomy, microvilli seemed to be normal and some cells had large cytoplasmic projections that protruded toward the lumen of the nasal cavity. Within the cytoplasmic projections of the supporting cells, a large lamellar and reticular-shaped smooth endoplasmic reticulum was evident. Mitochondria exhibited almost normal morphology. The current findings demonstrate that morphological changes occur in the supporting cells after bulbectomy. This new evidence hypothesizes that these changes represent events that contribute to the regeneration of the olfactory epithelium after bulbectomy.

Since 1987, no study has reported the municipal-level geographical clustering of Kawasaki disease (KD) in Japan. Therefore, the aim of the present study was to identify the temporal and municipal-level geographical clustering of KD.The annual incidence rates of KD for each municipality were calculated using nationwide data from 73 758 patients with KD (2007-2012). To determine whether temporal and municipal-level clustering existed, we calculated the correlations of the annual incidence rates for each municipality during the study years, and compared these rates with those of the adjacent municipalities. Spatial scanning analysis was used to identify the geographical clusters for each year, and the incidence rates in those clusters were compared with the rates in the surrounding region.The annual national incidence rate of KD, adjusted for the prefecture-specific response rate, was 322.45 patients per 100 000 children aged 0-4 years. The correlation between the annual incidence rates during 2 consecutive years was significantly positive (coefficients, 0.149-0.428). On spatial scanning analysis, the most likely clusters were in the Tokyo metropolitan area during 2007-2010 and 2012, and in Kumamoto prefecture during 2011.Kawasaki disease exhibits temporal and municipal-level clustering.

We previously proposed the concept of caregiver daily impression (CDI) as a practical tool for emergency triage. We herein assessed how CDI varies by sex, education and career length by determining CDI scores as quantitative outcome measures.We carried out a cross-sectional study using a self-reported questionnaire among caregivers in 20 long-term care facilities in Hyogo, Japan. A total of 10 CDI variables measured participants' previous experience of emergency transfers using a scale from 0-10. The resulting total was defined as the CDI score. We hypothetically considered that higher scores indicated greater caregiver focus. The CDI scores were compared by sex, education and career length using analysis of covariance.A total of 601 personal caregivers were evaluated (mean age 36.7 years; 36% men). The mean career length was 6.9 years, with the following groupings: 1-4 years (38%), 5-9 years (37%) and10 years (24%). After adjustment for sex and education, the CDI scores for the variable, "poor eye contact," significantly differed between caregivers with ≥10 and5 years of experience (scores of 5.0 ± 3.1 and 4.0 ± 2.7, respectively). The CDI scores for variables related to eyes tended to increase with experience, whereas other CDI scores decreased. Male caregivers focused on residents' eyes significantly more than did female caregivers.We found that the CDI variable, "poor eye contact," is influenced by career length. Caregivers with more experience attach more importance to their impression of residents' eyes than do those with less experience. Sex-related differences in CDI might also exist. Geriatr Gerontol Int 2016; 17: 410-415.

To propose a caregiver daily impression (CDI) rating instrument for personal caregivers of residents living in long-term care facilities (LTCF) to comprehensively evaluate residents' daily health condition, and to investigate whether the CDI reflects illness latency and severity in residents transferred emergently.We carried out a retrospective review of facility care records from 20 LTCF in Hyogo, Japan. The participants were 169 LTCF residents with episodes of transfer to emergency hospitalization facilities during a 3-month period. We determined specific CDI variables by interviewing experienced LTCF caregivers, and then carried out a principal component analysis to determine the major parameter set. The generated components were incorporated into a regression model to investigate the association with hospitalization.The mean age was 87.9 ± 6.5 years, 68% were women and 28% of transfers resulted in hospitalization. The interview procedure identified 12 specific CDI variables, and the principal component analysis generated five distinct components: "change in feeding," "change in emotion," "disengaged or listless gaze," "decrease in eye reactivity" and "change in movement." By multivariate logistic regression, hospitalization was associated with "decrease in eye reactivity" (adjusted OR 1.78, 95% CI 1.07-2.97) and poor vital signs (adjusted OR 2.84, 95% CI 1.15-6.98), but not with body temperature (adjusted OR 1.29, 95% CI 0.52-3.21).The CDI might reflect underlying illness severity beyond quantitative physical findings. Once the CDI can be appropriately validated, quantified and linked to physical findings, it could be used by caregivers for daily resident assessments and as a practical triage tool in emergency situations. Geriatr Gerontol Int 2016; 16: 612-617.

Chronic sinusitis with eosinophils easily recurs after endoscopic sinus surgery. The condition is usually complicated by asthma, and many eosinophils are present in the sinus mucosa. One conservative treatment method is the administration of glucocorticoids locally or systematically. To evaluate the efficacy and tolerability of intranasal fluticasone propionate for the treatment of chronic sinusitis with eosinophils, seven patients with chronic sinusitis with eosinophils were treated over a 12-week period using a fluticasone propionate aqueous nasal spray (800 microg per day in each nostrilz). The Symptons of 7 patients, especially nasal discharge and nasal obstructions, improved and an expanded air space was observed on paranasal CT images. The percent of drug systemically available after intranasal administration varied by less than 1% for intranasal fluticasone propionate. Therefore, even if intranasal fluticasone propionate is administerved at double the usual dose, it is unlikely to cause systemic side effects. Fluticasone propionate aqueous nasal spray at double the usual dose is effective for the treatment of chronic sinusitis with eosinophils.