Follow-Up Duration of Echocardiography in Patients with Kawasaki Disease with No Initial Coronary Aneurysms.

OBJECTIVE: To evaluate the optimal duration of echocardiographic follow-up in patients with Kawasaki disease without an initial coronary aneurysm. STUDY DESIGN: In this single-center, retrospective, observational study, we reviewed the results of follow-up echocardiography in children with Kawasaki disease enrolled in the Prospective Observational Study on Stratified Treatment with Immunoglobulin Plus Steroid Efficacy for Kawasaki Disease from a children's hospital. The main enrollment criterion was the absence of coronary aneurysms, defined as a maximum z-score (Zmax) ≥2.5, in the proximal right coronary artery and the proximal left anterior descending artery within 9 days from treatment initiation. The primary outcome was Zmax on follow-up echocardiography at up to 5 years. RESULTS: Among 386 patients, 106 (27.5%) received prednisolone with intravenous immunoglobulin for first-line therapy, and 57 (14.8%) showed a poor response. Echocardiography at 1 month detected 9 patients with a Zmax ≥2, including 3 (0.8%) with coronary aneurysms requiring additional antithrombotic treatment and observation. Of 7 patients (1.8%) with normal echocardiographic findings at 1 month but a Zmax ≥2 later, 2 were lost to follow-up and 5 experienced spontaneous resolution, but none of the 7 patients required any change in management. CONCLUSIONS: The optimal duration of echocardiographic follow-up may be 1 month in patients with no initial coronary aneurysms and a Zmax <2 at 1 month. Coronary artery abnormalities observed after 1 month are rare and mostly benign in this category of patients.

Risk factors of bacteremia in children hospitalized with community-acquired pneumonia: A nested case-control study.

OBJECTIVE: To assess the risk factors of bacteremia in children hospitalized with community-acquired pneumonia (CAP). STUDY DESIGN: The present, nested, case-control study enrolled a cohort of patients with CAP aged < 18 years who were hospitalized at Tokyo Metropolitan Children's Medical Center or Tama-Hokubu Medical Center between March 2010 and February 2018. Among the cohort with blood cultures (BCs), patients with bacteremia were identified and matched with five control patients based on their treatment facility, underlying disease, and age. Conditional logistic regression was used to calculate the odds ratios (ORs) of bacteremia for risk factor candidates. RESULTS: BCs were obtained for 2,383 (84%) of the 2,853 patients in the CAP cohort. Of those with BCs, 34 (1.4%) had bacteremia. S. pneumoniae and H. influenzae accounted for 26 (76%) and four (12%) instances of the bacteremia pathogens, respectively. Bacteremia occurred more frequently among patients hospitalized in the spring than during other seasons (P = 0.022). On multivariate analysis, the severity of pneumonia was not associated with bacteremia incidence (OR: 0.92 [0.30-2.85]) while a white blood cell count > 16,000/µL (OR: 5.90 [2.14-16.3]) was shown to be a significant risk factor. The OR of the need for a ventilator on admission day was significantly high (28.4 [3.02-1374]) on univariate analysis, but the subject pool was too small to determine its significance on multivariate analysis. CONCLUSIONS: The results of the present study supported BC collection in patients with leukocytosis and in those requiring ventilator use on admission.

Marked induction of matrix metalloproteinase-10 by respiratory syncytial virus infection in human nasal epithelial cells.

Respiratory syncytial virus (RSV) is an important pathogen of bronchiolitis, asthma, and severe lower respiratory tract disease in infants and young children. Matrix metalloproteinases (MMPs) play key roles in viral infection, inflammation and remodeling of the airway. However, the roles and regulation of MMPs in human nasal epithelial cells (HNECs) after RSV infection remain unclear. To investigate the regulation of MMP induced after RSV infection in HNECs, an RSV-infected model of HNECs in vitro was used. It was found that mRNA of MMP-10 was markedly increased in HNECs after RSV infection, together with induction of mRNAs of MMP-1, -7, -9, and -19. The amount of MMP-10 released from HNECs was also increased in a time-dependent manner after RSV infection as was that of chemokine RANTES. The upregulation of MMP-10 in HNECs after RSV infection was prevented by inhibitors of NF-κB and pan-PKC with inhibition of RSV replication, whereas it was prevented by inhibitors of JAK/STAT, MAPK, and EGF receptors without inhibition of RSV replication. In lung tissue of an infant with severe RSV infection in which a few RSV antibody-positive macrophages were observed, MMP-10 was expressed at the apical side of the bronchial epithelial cells and alveolar epithelial cells. In conclusion, MMP-10 induced by RSV infection in HNECs is regulated via distinct signal transduction pathways with or without relation to RSV replication. MMP-10 may play an important role in the pathogenesis of RSV diseases and it has the potential to be a novel marker and therapeutic target for RSV infection.

Live attenuated vaccine efficacy six months after intravenous immunoglobulin therapy for Kawasaki disease.

BACKGROUND: Due to the presence of maternal passive antibodies, the measles vaccine is ineffective if administered before age 12-15 months. The optimal timing for administering a live attenuated vaccine (LAV) after intravenous immunoglobulin therapy (IVIG) for Kawasaki disease (KD) has not been fully investigated. The recommended interval between vaccination and IVIG therapy for KD differs by country. The present study aimed to evaluate efficacy of LAV six months after IVIG therapy for KD in Japan. METHODS: The present, single-arm, prospective, interventional study included patients aged 6 months or older with no medical history of measles, rubella, varicella or mumps or vaccinations against these diseases. The subjects received these vaccinations for the first time at six months after IVIG therapy. Virus-specific IgG levels for each virus measured by EIA was examined at nine months after IVIG therapy. If the results were negative, the subjects received a booster vaccination at 12 months after IVIG therapy. The primary outcome was the prevalence of positivity for antibodies after the initial and booster vaccinations. RESULTS: The present study enrolled 32 subjects, 31% of whom were female, with an average age of 10.8 (standard deviation 2.8) months at IVIG therapy. At six months after IVIG therapy, 9% and 6% of the subjects were seropositive for measles and varicella titers, respectively, but were seronegative for the mumps and rubella titers. The seroconversion rate for measles, mumps, rubella, and varicella after the initial vaccination was 88%, 6%, 78%, and 16%, respectively. The seroconversion rate after a booster vaccination was 100% for measles and rubella, 97% for mumps, and 77% for varicella. CONCLUSIONS: The seroconversion rate was low for LAV at six months after a single dose of IVIG for KD, but seroconversion was achievable with a booster vaccination at 12 months. CLINICAL TRIAL REGISTRATION: UMIN-CTR, UMIN000007174, https://upload.umin.ac.jp/cgi-open-bin/ctr/ctr_view.cgi?recptno=R000008452.

Risk Factors of Coronary Artery Abnormalities and Resistance to Intravenous Immunoglobulin Plus Corticosteroid Therapy in Severe Kawasaki Disease: An Analysis of Post RAISE.

BACKGROUND: Coronary artery abnormalities (CAAs) still occur in patients with Kawasaki disease receiving intensified treatment with corticosteroids. We aimed to determine the risk factors of CAA development and resistance to intensified treatment in Post RAISE (Prospective Observational Study on Stratified Treatment With Immunoglobulin Plus Steroid Efficacy for Kawasaki Disease)-the largest prospective cohort of Kawasaki disease patients to date. METHODS: In Post RAISE, 2648 consecutive patients with Kawasaki disease were enrolled. The present study analyzed 724 patients predicted to be intravenous immunoglobulin (IVIG) nonresponders (Kobayashi score ≥5) who received intensified treatment consisting of IVIG plus prednisolone. The association between the baseline characteristics and CAA at 1 month after disease onset was examined. The association between the baseline characteristics and treatment resistance was also investigated. RESULTS: Maximum Z score at baseline ≥2.5 (odds ratio, 3.4 [95% CI, 1.5-7.8]), age at fever onset <1 year (odds ratio, 3.4 [95% CI, 1.6-7.4]), and nonresponsiveness to IVIG plus prednisolone treatment (odds ratio, 6.8 [95% CI, 3.3-14.0]) were independent predictors of CAA development. Nonresponsiveness to IVIG plus prednisolone was significantly associated with 8 baseline variables. Baseline total bilirubin (odds ratio, 1.4 [95% CI, 1.2-1.7]) was the only significant independent predictor other than the variables included in the Kobayashi score, enabling treatment resistance to be identified at diagnosis. The area under the ROC curve was 0.74 (95% CI, 0.69-0.79). At a cutoff point of 1.0, the sensitivity and specificity for predicting treatment resistance were 71% and 65%, respectively. CONCLUSIONS: In Post RAISE, younger age at fever onset, a larger maximum Z score at baseline, and nonresponsiveness to IVIG plus prednisolone were risk factors significantly associated with CAA development. Nonresponders were able to be identified at diagnosis based on the total bilirubin value. To prevent CAA, more intensified or adjunctive therapies using other agents, such as pulsed methylprednisolone, ciclosporin, infliximab, and Anakinra, should be considered for patients with these risk factors. Registration: URL: https://www.umin.ac.jp/ctr/; Unique identifier: UMIN000007133.

Postural change for supine position does not disturb toddlers' nap.

This study examined whether forced postural change from prone to supine during toddlers' nap, a preventative measure taken in Japan for sudden unexplained death in childhood (SUDC), disturbs toddlers' sleep. When the "Back to Sleep" campaign (BSC) was introduced to Japan in 1996, its recommendations were also applied to infants aged 1 year old and over with the expectation that the BSC recommendations may also contribute to a decrease in the occurrence rate of SUDC. Since then, Japanese nurseries have routinely conducted sleeping position checks and positional adjustments of toddlers every 5-10 min during naps. A total of 52 toddlers (age 18.4 ± 3.3 months, means ± SD) were continuously monitored for 8 h during daytime at nursery schools for wake-sleep status and body position (prone, supine and lateral) with actigraphs and 3-orthogonal-axis accelerometers. Out of the 52 toddlers, 24 toddlers adopted prone positions during naps, which were adjusted by nursery staff back to supine. When nursery staff manually changed the toddlers position from prone to supine, the toddlers either did not wake or woke only briefly (3.1 ± 4.9 min) and returned to sleep soon after the positional change. Our study indicates that manual change of toddlers' sleeping position from prone to supine, a potential SUDC prevention method, does not disturb toddlers' sleep during their naps.

Brainstem monoamine pathology of neonatal hypoxic-ischemic brain damage: a model of acute stage of neonatal asphyxia.

Neonatal hypoxic-ischemic encephalopathy (HIE) is one of the most severe perinatal diseases and leads to high mortality and sometimes severe neurological sequelae. At the acute stage of HIE, it is thought to be the damage of catecholaminergic system in the brainstem. And then, HIE reflects mental development throughout the norepinephrine and serotonin systems, which mainly originates in the brainstem. Therefore, we studied both systems in the brainstem of neonatal HIE model rats with tyrosine hydroxylase (TH) and tryptophan hydroxylase (TpH) immunohistochemistry and a high-performance liquid column (HPLC) to measure norepinephrine and serotonin and their metabolism. As a result, the TH-positive and TpH-positive cell numbers significantly decreased 2 days after hypoxic-ischemic (HI) insult (n=10). However, 7 days after insult (n=10), the TH-positive and TpH-positive cell numbers had recovered in most regions. HPLC demonstrated a significant difference in the norepinephrine concentration 2 days after HI insult, but not in the other monoamines.

Nebulized hypertonic saline in infants hospitalized with moderately severe bronchiolitis due to RSV infection: A multicenter randomized controlled trial.

INTRODUCTION: The efficacy of nebulized hypertonic saline (HS) therapy for shortening hospital length of stay (LOS) or improving bronchiolitic symptoms remains controversial. Most studies enrolled small numbers of subjects and did not consider the role of respiratory syncytial virus (RSV), the most common cause of acute bronchiolitis. Our aim was to evaluate the efficacy and safety of nebulized HS therapy for acute bronchiolitis due to RSV in moderately ill hospitalized infants. MATERIALS AND METHODS: This was an open-label, multicenter, randomized controlled trial comparing a nebulized HS treatment group with a normal saline (NS) group. The subjects, 128 infants with bronchiolitis due to RSV, were admitted to five hospitals in Tokyo, Japan. Three-percent HS or NS was administered via bronchodilator four times daily post-admission. The primary outcome was LOS, defined as the time until the patients fulfilled the discharge criteria, namely, absence of fever, no need for supplemental oxygen, and adequate feeding. Survival analysis was conducted in accordance with the intention-to-treat principle. RESULTS: The baseline characteristics were similar between the two groups. There was no significant overall difference in LOS between the groups (4.81 ± 2.14 days in HS vs 4.61 ± 2.18 days in NS; P = 0.60). Survival analysis by log-rank test also showed no significance (P = 0.62). Multivariate adjustment did not significantly alter the results. The treatment was well-tolerated, with no adverse effects attributable to the use of HS. CONCLUSIONS: Nebulized HS therapy did not significantly reduce LOS among infants with bronchiolitis due to RSV.

Combined effects of body position and sleep status on the cardiorespiratory stability of near-term infants.

The purpose of this study was to determine the effects of body position (prone, supine and lateral) together with sleep status (wake and sleep) on the cardiorespiratory stability of near-term infants. A total of 53 infants (gestational age at birth 33.2 ± 3.5 weeks; birth weight 1,682 ± 521 g; gestational age at recording 38.6 ± 2.1 weeks; weight at recording: 2,273 ± 393 g) were monitored for 24 hours for clinically significant apnea (>15 seconds), bradycardia (<100 bpm), and oxygen desaturation (SpO2 < 90%) in alternating body positions (prone, supine and lateral) by cardiorespiratory monitors and 3-orthogonal-axis accelerometers. Sleep status of the infants was also continuously monitored by actigraphs. No apnea was observed. During wake, severe bradycardia was most frequently observed in the lateral position while, during sleep, severe bradycardia was most frequently observed in the supine position. Desaturation was most frequently observed in the supine and lateral positions during both wake and sleep. Our study suggests that the cardiorespiratory stability of infants is significantly compromised by both body position and sleep status. During both wake and sleep, prone position induces the most stable cardiorespiratory functions of near-term infants.

Efficacy and safety of intravenous immunoglobulin plus prednisolone therapy in patients with Kawasaki disease (Post RAISE): a multicentre, prospective cohort study.

BACKGROUND: The RAISE study showed that additional prednisolone improved coronary artery outcomes in patients with Kawasaki disease at high risk of intravenous immunoglobulin (IVIG) resistance. However, no studies have been done to test the steroid regimen used in the RAISE study. We therefore aimed to verify the efficacy and safety of primary IVIG plus prednisolone. METHODS: We did a multicentre, prospective cohort study at 34 hospitals in Japan. We included patients diagnosed with Kawasaki disease according to the Japanese diagnostic criteria, and excluded those who were treated at other hospitals before being transferred to a participating hospital. Patients who were febrile at diagnosis received primary IVIG (2 g/kg per 24 h) and oral aspirin (30 mg/kg per day) until the fever resolved, followed by oral aspirin (5 mg/kg per day) for 2 months after Kawasaki disease onset. We stratified patients using the Kobayashi score into predicted IVIG non-responders (Kobayashi score ≥5) or predicted IVIG responders (Kobayashi score <5). For predicted non-responders, each hospital independently decided whether to add prednisolone (intravenous injection of 2 mg/kg per day for 5 days) to the primary IVIG treatment, according to their respective treatment policy, and we further divided these patients based on the primary treatment received. The primary endpoint was the incidence of coronary artery abnormalities determined by two-dimensional echocardiography at 1 month after the primary treatment in predicted non-responders treated with primary IVIG plus prednisolone. Coronary artery abnormalities were defined according to the criteria of the Japanese Ministry of Health and Welfare and of the American Heart Association (AHA). This study is registered with the University Hospital Medical Information Network Clinical Trials Registry, number UMIN000007133. FINDINGS: From July 1, 2012, to June 30, 2015, we enrolled 2628 patients with Kawasaki disease, of whom 724 (27·6%) were predicted IVIG non-responders who received IVIG plus prednisolone as primary treatment. 132 (18·2%) of 724 patients did not respond to primary treatment. Among patients with complete data, coronary artery abnormalities were present in 40 (incidence rate 5·9%, 95% CI 4·3-8·0) of 676 patients according to the AHA criteria or in 26 (3·8%, 2·5-5·6) of 677 patients according to the Japanese criteria. Serious adverse events were reported in 12 (1·7%) of 724 patients treated with primary IVIG plus prednisolone; two of these patients had hypertension and bacteraemia that was probably related to prednisolone. One patient died possibly due to severe inflammation from the Kawasaki disease itself. INTERPRETATION: Primary IVIG plus prednisolone therapy in this study had an effect similar to that seen in the RAISE study in reducing the non-response rate and decreasing the incidence of coronary artery abnormalities. A primary IVIG and prednisolone combination therapy might prevent coronary artery abnormalities and contribute to lowering medical costs. FUNDING: Tokyo Metropolitan Government Hospitals and the Japan Kawasaki Disease Research Center.

International comparison of sudden unexpected death in infancy rates using a newly proposed set of cause-of-death codes.

BACKGROUND: Comparing rates of sudden unexpected death in infancy (SUDI) in different countries and over time is difficult, as these deaths are certified differently in different countries, and, even within the same jurisdiction, changes in this death certification process have occurred over time. AIMS: To identify if International Classification of Diseases-10 (ICD-10) codes are being applied differently in different countries, and to develop a more robust tool for international comparison of these types of deaths. METHODS: Usage of six ICD-10 codes, which code for the majority of SUDI, was compared for the years 2002-2010 in eight high-income countries. RESULTS: There was a great variability in how each country codes SUDI. For example, the proportion of SUDI coded as sudden infant death syndrome (R95) ranged from 32.6% in Japan to 72.5% in Germany. The proportion of deaths coded as accidental suffocation and strangulation in bed (W75) ranged from 1.1% in Germany to 31.7% in New Zealand. Japan was the only country to consistently use the R96 code, with 44.8% of SUDI attributed to that code. The lowest, overall, SUDI rate was seen in the Netherlands (0.19/1000 live births (LB)), and the highest in New Zealand (1.00/1000 LB). SUDI accounted for one-third to half of postneonatal mortality in 2002-2010 for all of the countries except for the Netherlands. CONCLUSIONS: The proposed set of ICD-10 codes encompasses the codes used in different countries for most SUDI cases. Use of these codes will allow for better international comparisons and tracking of trends over time.

Kawasaki disease complicated by mild encephalopathy with a reversible splenial lesion (MERS).

We reported four patients (2 to 10 years) with Kawasaki disease complicated by clinically mild encephalitis/encephalopathy with a reversible splenial lesion (MERS). All were treated with γ-globulin (2 to 6 g/kg) after the diagnosis of Kawasaki disease, the fever being alleviated between day 6 and 25. One of two patients exhibiting a poor response to γ-globulin had a cardiac aneurysm as a sequela. Their neurological manifestations (delirious behavior and drowsiness), laboratorial hyponatremia, and radiological abnormalities completely disappeared. It is important for pediatricians to acknowledge that MERS can be observed in patients with Kawasaki disease, especially in older children, and that they might be at high risk for cardiac abnormalities.

Comparison of serum cortisol concentrations in preterm infants with or without late-onset circulatory collapse due to adrenal insufficiency of prematurity.

A recent survey found that approximately 4% of very low birth weight infants in Japan were treated with glucocorticoids postnatally for circulatory collapse thought to be caused by late-onset adrenal insufficiency. We identified 11 preterm infants with clinical signs compatible with this diagnosis (hypotension, oliguria, hyponatremia, lung edema, and increased demand for oxygen treatment) and matched them for gestational age with 11 infants without such signs. Blood samples were obtained for cortisol and its precursors from the patient group before the administration of hydrocortisone, and from the control group during the same postnatal week. All samples were analyzed using a gas chromatography-mass spectrometry system. Cortisol concentrations did not differ between the two groups (6.6 +/- 4.5 vs 3.4 +/- 2.7 microg/dL); however, the total concentration of precursors in the pathway to cortisol production was significantly higher in the patient group (72.2 +/- 50.3 vs 25.0 +/- 28.5 microg/dL; p < 0.05). We conclude that the clinical picture of late-onset adrenal insufficiency in preterm infants is not a result of an absolute deficiency of cortisol production, but may be a result of a limited ability to synthesize sufficient cortisol for the degree of clinical stress.