Expression of Eosinophilic Subtype Markers in Patients with Kawasaki Disease.

PURPOSE: Eosinophils may rise to a higher level in the acute phase of Kawasaki disease (KD) both before and after intravenous immunoglobulin (IVIG) therapy. A substantial body of research was carried out on the association between KD and allergic diseases. Eosinophils play an important role in type 2 inflammation. Recent studies have shown that there are two distinct subtypes of eosinophils. In addition to their role in inflammation, lung-resident eosinophils (rEOS) also regulate homeostasis. Inflammatory eosinophils (iEOS) reflect type 2 inflammation in tissues. iEOS were considered the primary eosinophils in non-severe allergic asthma, while rEOS were thought to be the primary eosinophils in severe non-allergic eosinophilic asthma. This case-control study aimed to investigate the marker expression of eosinophilic subtypes in KD patients. MATERIALS AND METHODS: The marker expressions of eosinophilic subtypes in the leukocytes of patients with KD were evaluated by the recently established KDmarkers online tool, a web server including gene expression data. Finally, the results were validated with a quantitative reverse transcriptase polymerase chain reaction (RT-PCR). We analyzed the mRNA expression levels of SELL and IL10RA in leukocytes from KD patients and febrile children. RESULTS: Included in our screening tools were transcriptome arrays, which provided clues showing the importance of rEOS, whose role was identified by three genes (lower IL10RA, higher SELL, and SERPINB1 than controls). In contrast, the iEOS representative gene CD101 was not elevated in KD. It was found that the gene IL10RA, a marker of inflammatory eosinophilic leukocytes, was more highly expressed in the leukocytes of KD patients (n = 43) than febrile controls (n = 32), especially those without coronary artery lesions (CAL) (n = 26). Before treatment, SELL expression was higher in leukocytes of CAL patients (CAL, 1.33 ± 0.18, n = 39; non-CAL, 0.87 ± 0.12, n = 55; p = 0.012). SELL was significantly higher after half a year compared to febrile controls. CONCLUSIONS: To our knowledge, this is the first study to demonstrate that KD patients have increased SELL than febrile controls after 6 months of treatment. We present evidence here that dynamically different eosinophilic involvement exists between KD patients with and without CAL. The role of eosinophilic subtypes in KD patients warrants further investigation.

Identification of increased expression of activating Fc receptors and novel findings regarding distinct IgE and IgM receptors in Kawasaki disease.

BACKGROUND: Kawasaki disease (KD) is associated with expression and methylation of Fc gamma receptor genes. We characterized immunoglobulin A (IgA), IgE, IgG, and IgM receptor expression levels in KD. METHODS: Fc receptor expression levels were characterized using GeneChip Human Transcriptome Array 2.0 (HTA 2.0) with 18 KD patients, 18 non-febrile controls, and 18 febrile controls. Another 48 control individuals and 46 patients with KD were measured using pyrosequencing for the methylation levels. RESULTS: The mRNA expression levels of FCER1A and FCER2 were significantly lower in KD patients than in non-febrile controls and then rose following treatments with intravenous immunoglobulin (IVIG). Expression levels of FCER1G increased compared to the non-febrile subjects and then subsided after IVIG. FCER1A methylation was significantly lower among KD patients and even lower in KD patients with IVIG resistance. HTA analysis revealed higher mRNA levels of FCAR, FCGR1C, and FCGR2A in KD patients. FCMR mRNA expression levels were significantly lower in KD patients. FCMR expression levels rose after IVIG treatment. After IVIG, FCGR1A, B, and C decreased even lower than the febrile controls. CONCLUSION: This is the first study indicating that IgA, IgE, IgG, and IgM receptors are associated with KD. We highlighted potential biomarkers related to Fc receptors and their regulation.

Montelukast does not increase the risk of attention-deficit/hyperactivity disorder in pediatric asthma patients: A nationwide population-based matched cohort study.

BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) has been linked to pediatric asthma patients treated with montelukast. This study is the first to use a nationwide health insurance research database (NHIRD) to study whether asthmatic children using montelukast are at an increased risk of ADHD. METHODS: We used data from the Taiwan NHIRD, which is a longitudinal database of one million randomly selected subjects. The enrolled patients were followed up until 2013. Patients younger than and equal to 12 years old with new-onset asthma (ICD-9 CM code 493.X) diagnosed between 1997 and 2013 were enrolled. A multivariate Cox regression analysis was conducted to evaluate the association between montelukast treatment and the risk of ADHD (ICD-9-CM code 314.X). RESULTS: We enrolled a total of 54,487 asthmatic children younger than and equal to 12 years old who had at least one claim of inpatient admission or at least three claims of an ambulatory visit. Montelukast users and match controls were identified by matching age, gender, residence, the comorbidities including allergic rhinitis and atopic dermatitis, admission or emergency department visits due to asthma attack, and index date of starting montelukast in a 1:1 ratio, with 12,806 in the montelukast group and 12,806 in the non-montelukast group. The montelukast group had a similar risk of ADHD (n = 632, 4.94%) as the non-montelukast group (n = 610, 4.76%) [adjusted hazard ratio 1.04; 95% confidence interval, 0.93 to 1.17]. In children treated with montelukast, high cumulative days of montelukast use did not increase the risk of ADHD. CONCLUSION: This nationwide population-based cohort study reveals that asthma children treated with montelukast were not at an increased risk of developing ADHD. Nevertheless, validation of our retrospective survey requires further prospective study.

Low FCMR mRNA expression in leukocytes of patients with Kawasaki disease six months after disease onset.

BACKGROUND: Immunoglobulin (Ig) M plays an important role in immune regulation. FCMR-encoded FcµR is a receptor of IgM. Previous research has suggested that IgM levels may be involved in the coronary artery lesions of Kawasaki syndrome or Kawasaki disease (KD). In this study, we aimed to explore the roles of mRNA expressions of IgM receptors, particularly FCMR, in KD patients. FCMR encodes the Fc fragment of immunoglobulin M receptor. METHODS: We enrolled 60 KD patients and 55 non-KD controls. Whole-blood leukocytes were isolated, and the mRNA expression for FCMR was determined. Each mRNA consisted of a sample taken before intravenous immunoglobulin (IVIG) was administered (acute, KD1) and those taken at three weeks, six months, and one year later (KD3, KD4, KD5). Paired KD subjects were analyzed from both the acute and convalescent phases (n = 28). RESULTS: After six months and one year of treatment, KD patients still apparently have lower FCMR compared with controls (P = .004). FCMR expressions were downregulated in male patients with KD prior to IVIG administration (P = .044). The FCMR of paired KD patients who received IVIG treatments after six months was significantly lower than before undergoing IVIG treatment (P = .044). Expressions in the polymorphonuclear leukocytes were similar to those in the peripheral blood mononuclear cells. CONCLUSION: The unique data supported that FCMR is expressed by granulocytes at RNA levels in humans and demonstrated lower FCMR six months after the onset of KD. The findings remind us of the need to track the health of children with KD over the long term, even if we think patients have fully recovered.

Neutrophil-to-lymphocyte ratio and scoring system for predicting coronary artery lesions of Kawasaki disease.

BACKGROUND: Kawasaki disease (KD) causes coronary artery lesions (CAL) and is the leading cause of acquired heart disease in children. The aim of this study is to evaluate the risk factors and set-up a scoring system for predicting CAL of KD. METHODS: We retrospectively reviewed a total of 478 patients diagnosed with KD. We compared age, gender, laboratory data, and treatment response in two groups and developed a scoring system for predicting CAL. RESULTS: During the study period, 365 of these patients had complete medical records of coronary surveys by echocardiography. Anemia, hypoalbuminemia, C reactive protein (CRP), alanine aminotransferase, neutrophil count, and neutrophil/lymphocyte ratio (NLR) showed significant differences with CAL formation. We determined the cut-off value using a receiver-operating-characteristic (ROC) curve, and following multivariate logistic regression analysis, four independent risk factors demonstrated a significant difference with CAL formation, including CRP > 103 mg/L, NLR > 3.5, male gender, and intravenous immunoglobulin (IVIG) resistance. We established a score system based on the above evaluation, for which a ROC curve was performed, and a total score of ≥ 2 points showed a sensitivity of 60.8% and a specificity of 70.6%, with an area under the ROC curve of 0.696. CONCLUSIONS: Identifying children at risk is important in order to prevent CAL from developing. Four independent risk factors that can predict CAL formation were CRP > 103 mg/L, NLR > 3.5, male gender, and IVIG resistance. This first report incorporated NLR into score systems to predict CAL reinforces previously well-known risk factors for the CAL formation among KD patients.

Decreased DNA methyltransferases expression is associated with coronary artery lesion formation in Kawasaki disease.

Background: Kawasaki disease (KD) is the most common acute coronary vasculitis to occur in children. Although we have uncovered global DNA hypomethylation in KD, its underlying cause remains uncertain. In this study, we performed a survey of transcript levels of DNA methyltransferases and demethylases in KD patients. Materials and Methods: We recruited 145 participants for this study. The chip studies consisted of 18 KD patients that were analyzed before undergoing intravenous immunoglobulin (IVIG) treatment and at least 3 weeks after IVIG treatment, as well as 36 control subjects, using Affymetrix GeneChip® Human Transcriptome Array 2.0. An additional study of 91 subjects was performed in order to validate real-time quantitative PCR. Results: In our microarray study, the mRNA levels of DNMT1 and DNMT3A were significantly lower while TET2 was higher in acute-stage KD patients compared to the healthy controls. Through PCR validation, we observed that the expression of DNMT1 and TET2 are consistent with the Transcriptome Array 2.0 results. Furthermore, we observed significantly lower DMNT1 mRNA levels following IVIG treatment between those who developed CAL and those who did not. Conclusion: Our findings provide an evidence of DNA methyltransferases and demethylases changes and are among the first report that transient DNA hypomethylation is induced during acute inflammatory phase of Kawasaki disease.

Successful treatment in a child with enthesitis-related arthritis involving the sternoclavicular joint: a case report.

BACKGROUND: Although the sternoclavicular joint (SCJ) may be involved in ankylosing spondylitis, rheumatic arthritis, and Behçet's disease and participates in the systemic inflammatory process of arthritis, it is often neglected during routine rheumatologic clinical examinations. To the best of our knowledge, this is the first study to report etanercept treatment in juvenile idiopathic arthritis (JIA) with SCJ involvement. CASE PRESENTATION: In this study, we describe an unusual case of a child with juvenile idiopathic arthritis with an initial presentation of sternoclavicular mass. The patient (age, 14 years 10 months) presented with an insidious onset atraumatic swelling of the left SCJ and complained of right hip and bilateral ankle tenderness without an apparent cause. Initial ultrasonography indicated a heterogeneous mass in the left SCJ, while computed tomography identified mild swelling of the left SCJ with a thickened synovial lining, mild bone erosion, and some turbid fluid. The patient ultimately underwent left SCJ arthrotomy, during which tapping of the SCJ revealed 2 cc of yellowish fluid, inflammation and necrosis of tissues within the SCJ. A clear yellow joint fluid was aspirated, and testing revealed a negative culture result. The patient was diagnosed with JIA. The joint tenderness improved and erythrocyte sedimentation rate decreased after administering anti-tumor necrosis factor etanercept. An additional ultrasonography demonstrated that the initial imaging findings have been resolved. At the end of a 2-year follow-up period, the patient was completely symptom-free. CONCLUSIONS: JIA with SCJ involvement is an uncommon presentation in adolescents. Etanercept may be a beneficial treatment for SCJ involvement in patients with JIA. The upper limbs showed no signs of limited range of motion during the follow-up period. Further studies are warranted to elucidate the efficacy of etanercept in JIA with sternoclavicular joint involvement.

EFFICACY OF INTRAVENOUS IMMUNOGLOBULIN ALONE ON CORONARY ARTERY LESION REDUCTION IN KAWASAKI DISEASE.

Background: Though Aspirin and intravenous immunoglobulin (IVIG) remain the standard treatments for Kawasaki Disease (KD) to minimize coronary artery damage, the duration and dosage of aspirin are inconsistent across hospitals. However, the lack of multi-center randomized trials prevents definitive answers to the impact of high-dose aspirin. Methods: This clinical trial was structured as a prospective, evaluator-blinded, multi-center randomized controlled trial with two parallel arms, aiming to assess the effectiveness of IVIG as a standalone primary therapy of KD in comparison to the combination of IVIG with high-dose aspirin therapy. KD patients were enrolled between September, 2016 and August, 2019. A final cohort of 134 patients were randomly assigned to the standard and test groups with 69 and 65 patients, respectively. The Standard group received IVIG (2 g/kg) along with aspirin (80-100 mg/kg/day) until fever subsided for 48 hours. The test group received IVIG (2 g/kg) alone. Following the initial treatment, both groups received a daily aspirin dose (3-5 mg/kg) for six weeks. The primary outcome measure was the occurrence of coronary artery lesions (CAL) at the 6-8 weeks mark. The secondary outcome is IVIG resistance. Results: The overall rate of CAL in test group decreased from 10.8% at diagnosis to 1.5% and 3.1% at 6 weeks and 6 months, respectively. The CAL rate of standard group declined from 13.0% to 2.9% and 1.4%, with no statistically significant difference (P>0.1) in the frequency of CAL between the two groups. Furthermore, no statistically significant differences were found for treatment (P>0.1) and prevention (P>0.1) effect between the two groups. Conclusions: This marks the first prospective multi-center randomized controlled trial comparing the standard treatment of KD using IVIG plus high-dose aspirin against IVIG alone. Our analysis indicates that addition of high-dose aspirin during initial IVIG treatment is neither statistically significant nor clinically meaningful for CAL reduction. Registration: URL: http://www.clinicaltrials.gov ; identifier: NCT02951234. What is New?: This study represents the first multi-center randomized controlled trial investigating the efficacy of high-dose aspirin or intravenous immunoglobulin (IVIG) during the acute stage of KD. This study assessed the impact of discontinuing high-dose aspirin (80-100 mg/kg/day) on the occurrence of CAL during the acute phase treatment of Kawasaki Disease.No significant differences were observed between high-dose aspirin plus IVIG treatment and IVIG alone treatment in terms of the frequency of abnormal coronary artery abnormalities. Additionally, our analysis revealed no statistically significant differences in either the treatment effect (the number of cases successfully treated) or prevention effect (the prevention of new cases) between these two treatments. What Are the Clinical Implications?: Comparison analysis indicated the non-inferiority between two groups with or without high-dose aspirin.Administering the standard 2 g/kg/day IVIG without high-dose aspirin (80-100 mg/kg/day) during the acute phase therapy for KD does not increase the risk of coronary artery lesions, which are a primary cause of morbidity and mortality in KD patients.Addition of high-dose aspirin during initial IVIG treatment is not statistically significant or clinically meaningful.

Evaluation of Formosa score and diagnostic sensitivity and specificity of four Asian risk scores for predicting intravenous immunoglobulin resistance in Kawasaki disease: a bivariate meta-analysis.

Background: In 2016, Lin et al. developed a prediction score of non-responsiveness to intravenous immunoglobulin (IVIG) in patients with Kawasaki disease (KD) (Lin et al., 2016). Various studies have attempted to validate the Formosa score, but inconsistent results have given us new opportunities and challenges. The aim of this meta-analysis is to explore the role of the Formosa score as a risk score in detecting IVIG-resistant KD patients and then compare the pooled sensitivity and specificity of four Asian risk scores, Egami, Formosa, Kobayashi, and Sano risk scores. Methods: A comprehensive search of Cochrane, Embase, and PubMed was conducted through 20 December 2021, using key terms relevant to the research question "What are the sensitivities and specificities of the four Asian predicting scores, Egami, Formosa, Kobayashi, and Sano, in Kawasaki disease patients with IVIG resistance?" The reference lists of the included studies were manually reviewed to identify pertinent references. A random-effects bivariate model was used to estimate the summary of sensitivity and specificity of the tools. Results: We found 41 relevant studies of the four Asian risk scores that were eligible to analyze for pooled accuracy. Eleven studies involving 5,169 KD patients reported the diagnostic performance of the Formosa score for the risk of IVIG resistance. The overall performance of the Formosa score was as follows: pooled sensitivity, 0.60 [95% confidence interval (CI), 0.48-0.70]; pooled specificity, 0.59 (95% CI, 0.50-0.68); and area under the hierarchical summary receiver operating characteristic curve, 0.62. The Formosa score exhibited the highest sensitivity 0.76 (95% CI, 0.70-0.82) for detecting IVIG-resistant KD patients among the 21,389 children included in the 41 studies. In terms of specificity estimates, Formosa had the lowest specificity of 0.46 (95% CI, 0.41-0.51). Conclusion: Patients at high risk for IVIG resistance may receive adjunctive treatment to reduce coronary lesions and thus also cardiovascular morbidity. Among all of the included studies, we found Formosa score to have the best sensitivity (0.76) but unsatisfactory specificity (0.46) for predicting IVIG resistance in Kawasaki disease. In the future, network meta-analysis should also incorporate the accuracy of the new scores after they have undergone a certain degree of validation around the world. Systematic Review Registration: https://www.crd.york.ac.uk/PROSPERO/, PROSPERO CRD42022341410.

Impact of Protein Binding Capacity and Daily Dosage of a Drug on Total Serum Bilirubin Levels in Susceptible Infants.

Hyperbilirubinemia is a common pathological condition in neonates. Free bilirubin can penetrate the blood-brain barrier (BBB), which can lead to bilirubin neurotoxicity. In the context of predicting the risk of bilirubin neurotoxicity, although the specificity and sensitivity of free bilirubin levels are higher than those of total serum bilirubin (TSB), free bilirubin is not widely monitored in clinical practice. The threshold TSB levels at which phototherapy must be administered have been established previously. However, TSB levels are not well correlated with neurodevelopmental outcomes. Currently, TSB levels are commonly used to guide phototherapy for neonatal hyperbilirubinemia. Some clinical drugs can displace bilirubin from its albumin-binding sites, and consequently upregulate plasma bilirubin. Daily dosages play a vital role in regulating bilirubin levels. A drug with both a high protein binding capacity and high daily dosage significantly increases bilirubin levels in infants. Premature or very low birth weight (VLBW) infants are vulnerable to the upregulation of bilirubin levels as they exhibit the lowest reserve albumin levels and consequently the highest bilirubin toxicity index. Because bilirubin is involved in maintaining the balance between pro-oxidant and antioxidant agents, the downregulation of bilirubin levels is not always desirable. This review provides insights into the impact of protein binding capacity and daily dosage of drugs on the bilirubin levels in susceptible infants.

Sex differences in vitamin D and behavioral profiles among children with allergic diseases.

Previous studies have suggested that vitamin D has a protective effect on allergic diseases, while an individual's sex may have a moderating effect on the relationship between vitamin D and allergic-related immunity. This study aimed to determine the role of vitamin D in children with coexisting allergic diseases in the context of sex differences and to explore the behavioral profiles of these patients. We recruited a total of 103 children with atopic diseases and divided them into four groups: males with one allergic disease (MA1, n = 20), males with two or more allergic diseases (MA2, n = 26), females with one allergic disease (FA1, n = 30), and females with two or more allergic diseases (FA2, n = 27). We measured serum calcium levels using the colorimetric method and serum 25-OH vitamin D total levels using electrochemiluminescence immunoassay. We found that MA2 had significantly lower vitamin D levels than MA1 and FA2. The levels of IgE were negatively correlated with vitamin D in females, whereas the levels of IgE were not significantly correlated with vitamin D in males. Furthermore, serum IgE was significantly correlated with children's adaptive skills, and different sexes were associated with different aspects of adaptive skills. Our findings suggest a protective role of vitamin D in the development of one allergic disease against the coexistence of allergic diseases in males, as well as extend the evidence for sex differences in immunity by demonstrating a sex-different correlation between IgE and vitamin D and the relationship between IgE and children's adaptive skills.

Echocardiography and laboratory outcomes of COVID-19 in children with a history of Kawasaki disease: a preliminary observation.

Background: Infection with SARS-CoV-2 virus has been associated with cardiovascular sequelae including multisystem inflammatory syndrome (MIS-C) in children. Patients with a prior history of Kawasaki disease, may be more susceptible to changes in echocardiographic or laboratory findings after COVID-19. The objective of this study was to investigate the echocardiographic and laboratory findings in children with a prior history of Kawasaki disease after SARS-CoV-2 infection. Materials and methods: In this study, we performed a retrospective chart review of 41 children younger than 18 years old who were diagnosed with COVID-19 from April to August of 2022 and had a prior history KD. We included echocardiography and blood draw data obtained at the last outpatient follow-up at our hospital for KD, and within 4 months of SARS-CoV-2 infection. Echocardiographic data obtained from 82 age-matched and gender matched controls were also included for comparison. Results: We found that COVID-19 resulted in slightly higher RCA Z-scores within the first month after infection (mean ± SE, 1.20 ± 0.18 vs. 0.83 ± 0.18, p = 0.030), although this increase did not result in coronary artery dilatation, defined as a Z-score of at least 2.5. In addition, we found that degree of RCA dilatation after COVID-19 infection was negatively correlated with the change in monocyte percentage (Pearson's correlation coefficient-0.363, p = 0.020). Moreover, RCA Z-score changes were lower in patients who received at least one dose of mRNA COVID-19 vaccine when compared those who did not receive any (mean ± SE, -0.23 ± 0.16 vs. 0.39 ± 0.17, p = 0.031). Conclusion: In this pilot study we found that COVID-19 infection resulted in slightly higher RCA Z-scores in children with a prior history of KD, although not large enough to be classified as coronary aneurysms. While these changes could be the result of measurement imprecision or interobserver variation, further study of the cardiac outcomes of COVID-19 infection in children with a prior history of KD are needed in the future.

Basophils Predict Mite Sensitization in Patients with Kawasaki Disease.

Background: Patients with Kawasaki disease (KD) are at a significantly increased risk of allergic diseases. Immunoglobulin E (IgE) is an immunoglobulin that mediates allergic sensitization to various allergens and is related to various allergic diseases. However, few studies have analyzed specific IgE on allergy biomarkers after KD is diagnosed. Objective: This study aimed to investigate the pattern of specific IgE levels against food and inhalant allergens. Methods: This retrospective study was conducted in Taiwan to identify patients admitted with KD. A subset of 453 admitted KD children younger than or equal to five years of age with intravenous immunoglobulin (IVIG) was followed up at our clinic with available specific IgE data. Results: The most common allergens were Dermatophagoides farina or pteronyssinus, house-dust, and cockroach mix. Positive specific IgE for Dermatophagoides farina or pteronyssinus was less common in children diagnosed with KD who were two years old or younger (p = 0.028). KD patients with higher basophils before IVIG (p = 0.010 and 0.018 for two different mites) and higher C-reactive protein (CRP, p = 0.030 and 0.028) after IVIG were at higher risk of mite sensitization. Integrated mite sensitization demonstrated higher basophils before IVIG, age at KD diagnosis, and the male sex to be clinically meaningful after logistic regression models. Conclusions: This study is the first to suggest that specific IgE in KD patients may be correlated with age at KD diagnosis, as well as basophils. Further longitudinal prospective studies are warranted to clarify the unique profile of specific IgE in KD patients.

Perinatal Characteristics and the Sensitization to Cow Milk, Egg Whites and Wheat in Children up to 3 Years of Age.

Food sensitization in early life identifies children at risk of developing allergic diseases. We investigated the sensitization to cow milk (CM), egg whites, and wheat. Newborns and infants under 3 years of age with available specific immunoglobulin E (sIgE) data were identified. A retrospective survey was conducted using data from the Chang Gung Research Database. Perinatal characteristics, such as singleton or multiples in a single pregnancy, parity, meconium staining, maternal age, spontaneous delivery or cesarean section, meconium passage, weeks of gestation, birth length, body weight, head and chest circumferences, and season, were obtained. The data on sIgE were collected, and a logistic regression model was used to determine the odds of sensitization. Positive sIgE for CM and egg whites was more likely to occur in boys than in girls. Early-life egg white and wheat sensitization was associated with increased birth body length and weight. A multivariate analysis indicated an association between egg white sIgE positivity and logarithmic total IgE. Higher total IgE levels and younger age were associated with egg white sensitization, and elevated weight and length at birth were linked to food sensitization, particularly to egg whites and wheat.

Evaluation of Infective Endocarditis in Children: A 19-Year Retrospective Study in Taiwan.

BACKGROUND: Infective endocarditis (IE) is an important cause of morbidity and mortality in pediatric patients with heart disease. Little literature has explored differences in the presentation of endocarditis in children with and without heart disease. This study aimed to compare the clinical outcomes and determine the risk of in-hospital death in the study population. METHODS: Data were retrospectively collected from 2001 to 2019 from the Chang Gung Research Database (CGRD), which is the largest collection of multi-institutional electronic medical records in Taiwan. Children aged 0-20 years with IE were enrolled. We extracted and analyzed the demographic and clinical features, complications, microbiological information, and outcomes of each patient. RESULTS: Of the 208 patients with IE, 114 had heart disease and 94 did not. Compared to those without heart disease, more streptococcal infections (19.3% vs. 2.1%, p < 0.001) and cardiac complications (29.8% vs. 6.4%, p < 0.001) were observed in patients with heart disease. Although patients with heart disease underwent valve surgery more frequently (43.9% vs. 8.5%, p < 0.001) and had longer hospital stays (28.5 vs. 12.5, p = 0.021), their mortality was lower than that of those without heart disease (3.5% vs. 10.6%, p = 0.041). Thrombocytopenia was independent risk factor for in-hospital mortality in pediatric patients with IE (OR = 6.56, 95% CI: 1.43-40.37). CONCLUSION: Among pediatric patients diagnosed with IE, microbiological and clinical features differed between those with and without heart disease. Platelet counts can be used as a risk factor for in-hospital mortality in pediatric patients with IE.

Multimedia Mixed Reality Interactive Shared Decision-Making Game in Children with Moderate to Severe Atopic Dermatitis, a Pilot Study.

(1) Objective: Atopic dermatitis (AD) is a recurring skin disease that affects children's daily activities and sleep quality. Due to the limitations of children's understanding and ability to express themselves, shared decision making (SDM) is often made by guardians, which thus affects the acceptance and effectiveness of children's treatments. Previous studies have demonstrated that involving both children and parents in decision making may help improve treatment outcomes; thus, we designed a multimedia mixed reality (MR) interactive game of SDM for children with moderate to severe AD. (2) Methods: Research participants included 6-18-year-old patients with moderate to severe AD. This research consisted of the following steps: designing SDM; character setting and visual design; performing games; system modification and optimization; screen editing and dubbing; and user testing and questionnaires by the System Usability Scale (SUS). (3) Results: We completed the SDM design for children with moderate to severe AD. Four different treatments were biologics, oral immune-modulating drugs, phototherapy, and wet wrap. An animated PowerPoint slide showed the AD apple rolling around before treatments and the AD apple sleeping soundly after treatments. Instructions with video teaching for the four different treatments were played, and then, the MR was turned on so that the patients could help the AD apple in the metaverse to undergo these four treatments. A total of 12 moderate to severe AD patients and six control patients used the game, all aged between six and eighteen years old, with an average SUS score of 81.0 and a standard error of 2.1 points. Adjective ratings yielded a rating between good and excellent. The game showed acceptable usability. We found no statistically significant differences in SUS scores between patients with and without moderate to severe AD or between boys and girls nor significant associations between SUS and age or severity. The analysis identified that the two items with the lowest SUS scores were "I think that I would need the support of a technical person to be able to use this product" and "I needed to learn a lot of things before I could get going with this product". Both of these comments show the limitations of this game. (4) Conclusions: Overall, this study provides the first MR SDM game that has passed the SUS and can be used as an aid in clinical SDM.

The Impact of Onset Age on Eosinophils in Kawasaki Disease.

(1) Background: Kawasaki disease (KD) mainly affects children under the age of 5 years and eosinophilia in KD patients might be associated with the development of allergic diseases. We compared the age-adjusted Z-score (Z) of eosinophils and aimed to evaluate the impact of onset age on eosinophils in KD patients. (2) Methods: We divided 398 KD patients into seven age subgroups. Laboratory data and the age-adjusted Z-score of eosinophils during the phases of Kawasaki disease were analyzed. (3) Results: The absolute eosinophil count among all age groups showed significant differences in the post-intravenous immunoglobulin (IVIG) phase and throughout the course of KD with Z-score adjusted for age. Further analysis showed persistent elevation of the age-adjusted Z-score of eosinophils (Z-eosinophil) especially in the under six-month-old age subgroup. In addition, we divided the Z-eosinophil into two groups to find the relationship with coronary artery lesions (CALs). Patients with a higher eosinophil count than average age values had a higher risk of developing CALs, while those with a lower eosinophil count than average age values had a lower risk of having CALs. (4) Conclusions: These findings may provide information to clinicians to pay attention to allergic diseases during the follow-up of KD, especially for children who are younger than 6 months old at the onset of KD, and eosinophil count could be a crucial focus in KD.

Association between Serum Total and Specific Immunoglobulin E Levels and Body Height: A Cross-Sectional Study of Children and Adolescents.

Background: The atopy rate in children has increased significantly. Atopy and growth are connected in a multifactorial manner and are important health issues for children around the world. The principal research question in this cross-sectional investigation concerned the association between serum total, specific immunoglobulin E (IgE) levels, and body height (BH)/weight (BW)/body mass index (BMI). Methods: A total of 993 subjects were enrolled for analysis retrospectively with allergic diseases and aged from 6 months to 18 years during the years 2015−2016. A complete panel of 36 allergen-specific IgE was taken from each participant using the MAST allergen test as well as their BH, BW, BMI, and total IgE levels. Results: There was a statistically significant positive association between the total IgE levels with BH (N = 348) and BW (N = 623) in the preschool age group (<6 years old, p-values of 0.009 and 0.034, respectively). In the preschool group, the total IgE levels showed a positive association with house dust (p < 0.001), cockroach mix (p < 0.001), Dermatophagoides farina (p < 0.001), and Dermatophagoides pteronyssinus (p < 0.001). After performing a general linear model followed by a backward selection of variables with age, sex, specific IgE, and total IgE, egg white sensitization demonstrated a significant negative association with BH (p = 0.009), and Dermatophagoides farina sensitization showed a significant positive association with BH (p = 0.006). The analysis showed that, in this model, the level of total IgE was not associated with BH. Conclusions: The results of this study indicate that the level of total IgE was not associated with BH in the preschool age group. Future studies are needed to replicate the results in outcome with follow-up allergic cohorts.

Multiple intravenous antibiotics usage is associated with intravenous immunoglobulin resistance in Kawasaki disease.

BACKGROUND: Kawasaki disease (KD) is a form of systemic vasculitis that primarily affects children under the age of 5 years old. Antibiotics are often prescribed for KD patients even before a diagnosis is made due to their prolonged fever and elevated inflammatory markers. Therefore, the purpose of this study was to investigate the impact of antibiotics usage on the disease outcome of KD. METHODS: We carried out a retrospective chart review of children between 2005 and 2017 for initial immunoglobulin (IVIG) treatment of KD. KD children with initial IVIG treatment more than 10 days after the onset of symptoms were excluded. RESULTS: In total, 280 children were eligible for this study, among which 209 had been treated with antibiotic(s) and 71 had not been. The IVIG resistance rates were 5.6% (4/71), 8.9% (10/112), and 21.6% (21/97) in non-users, single-drug users, and multiple-drug users, respectively (r = 0.205, p = 0.003). The IVIG resistance rate of the multiple antibiotics drug users in KD patients was significantly higher than the other two groups. Furthermore, the likelihood of IVIG resistance was found to increase with elevated C-reactive protein (CRP) values (1.010/unit, p < 0.001) but not with total white blood cell (WBC) count (p = 0.466). CONCLUSION: The probability of IVIG resistance increases with elevated CRP values and the use of multiple IV antibiotics, thus indicating that physicians should be prudent in administering multiple IV antibiotics when treating assumed infections in KD children.

CD36 is Associated With the Development of Coronary Artery Lesions in Patients With Kawasaki Disease.

Kawasaki disease (KD) is an autoimmune-like vasculitis of childhood involving the coronary arteries. Macrophages require scavenger receptors such as CD36 to effectively clear cellular debris and induce self-tolerance. In this study, we hypothesized that CD36 plays an important role in the immunopathogenesis of KD, by aiding in the clearance of plasma mitochondrial DNA, and by amplifying the immune response by activating the inflammasome pathway via AIM2. Fifty-two healthy controls, 52 febrile controls, and 102 KD patients were recruited for RT-PCR of target mRNA expression and plasma mitochondrial DNA. Blood samples were obtained 24 hours prior and 21 days after the administration of intravenous immunoglobulin (IVIG) therapy. Patients with acute KD had higher plasma levels of cell-free mitochondrial DNA (ND1, ND4, and COX1), and higher mRNA expressions of CD36 and AIM2 when compared to both healthy and febrile controls. A greater decrease in both CD36 and AIM2 mRNA expression after IVIG therapy was associated with the development of coronary artery lesions. Coronary artery lesions were associated with a larger decrease of CD36 expression following IVIG therapy, which may indicate that prolonged expression of the scavenger receptor may have a protective effect against the development of coronary artery lesions in KD.