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.

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.

The state of play in tools for predicting immunoglobulin resistance in Kawasaki disease.

INTRODUCTION: Intravenous immunoglobulin (IVIG) resistance is an independent risk factor for the development of coronary artery lesions (CAL) in patients with Kawasaki disease (KD). Accurate identification of IVIG-resistant patients is one of the biggest clinical challenges in the treatment of KD. AREAS COVERED: In this review article, we will go over current IVIG resistance scoring systems and other biological markers of IVIG resistance, with a particular focus on advances in machine-based learning techniques and high-throughput omics data. EXPERT OPINION: Traditional scoring models, which were developed using logistic regression, including the Kobayashi score and Egami score, are inadequate at identifying IVIG resistance in non-Japanese populations. Newer machine-learning methods and high-throughput technologies including transcriptomic and epigenetic arrays have identified several potential targets for IVIG resistance including gene expression of the Fc receptor, and components of the interleukin (IL)-1ß and pyroptosis pathways. As we enter an age where access to big data has become more commonplace, interpretation of large data sets that are able take into account complexities in patient populations will hopefully usher in a new era of precision medicine, which will enable us to identify and treat KD patients with IVIG resistance with increased accuracy.

Combination of Hemoglobin-for-Age Z-Score and Plasma Hepcidin Identified as a Novel Predictor for Kawasaki Disease.

Kawasaki disease (KD) is a febrile coronary vasculitis that affects younger children and includes complications such as coronary artery aneurysm. KD diagnoses are diagnosed based on clinical presentations, a process that still poses a challenge for front-line physicians. In the current study, we developed a novel predictor using the hemoglobin-for-age z-score (HbZ) and plasma hepcidin to differentiate Kawasaki disease (KD) from febrile children (FC). There were 104 FC and 115 KD subjects (89 typical KD; 26 incomplete KD) for this study, and data were collected on the biological parameters of hemoglobin and plasma hepcidin levels. A receiver operating characteristic curve (auROC), multiple logistics regression, and support vector machine analysis were all adopted to develop our prediction condition. We obtained both predictors, HbZ and plasma hepcidin, for distinguishing KD and FC. The auROC of the multivariate logistic regression of both parameters for FC and KD was 0.959 (95% confidence interval = 0.937-0.981), and the sensitivity and specificity were 85.2% and 95.9%, respectively. Furthermore, the auROC for FC and incomplete KD was 0.981, and the sensitivity and specificity were 92.3% and 95.2%, respectively. We further developed a model of support vector machine (SVM) classification with 83.3% sensitivity and 88.0% specificity in the training set, and the blind cohort performed well (78.4% sensitivity and 100% specificity). All data showed that sensitivity and specificity were 81.7% and 91.3%, respectively, by SVM. Overall, our findings demonstrate a novel predictor using a combination of HbZ and plasma hepcidin with a better discriminatory ability for differentiating from WBC and CRP between children with KD and other FC. Using this predictor can assist front-line physicians to recognize and then provide early treatment for KD.

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.

Allergen Tests of Fruit Sensitization Involving Children with Allergic Diseases.

Fruit is a kind of plant food which is rich in nutrients and immune-regulating ingredients. A meta-analysis has demonstrated that fruits have a protective effects against asthma. On the other hand, clinical syndromes of allergic reactions to fruits manifest as an oral allergy syndrome. We aimed to investigate the patterns and associated factors of fruit allergen-specific IgE (sIgE) sensitization among patients with suspected clinical symptoms. Data were extracted from the Chang Gung Research Database. Fruit sensitization in Taiwan was evaluated using the presence of IgE antibodies against specific fruits. The overall prevalence of positive sIgE responses to fruit allergens in Taiwan, in order of decreasing importance, was pineapple, kiwi, banana, and papaya. Children aged 0-18 had a higher positive rate of allergic responses to pineapple, kiwi, banana, and papaya than adults over the age of 18. Positive specific IgE for kiwi, banana, or papaya was more frequent in younger than in older children and children with a higher total IgE of both logarithmic (log) and arithmetic values. The analysis of log IgE for pineapple positive vs. negative children determined an optimal cutoff value, log IgE 2.2, with both sensitivity (0.9) and specificity (0.5). Dermatitis was significantly more prevalent in children with positive IgE for pineapple, kiwi, banana, and papaya than negative specific IgE. The highest positive rate of sIgE against fruits was pineapple among children. Even in older children, the positive rate of pineapple allergens was high. IgE discriminates with and without sIgE for pineapple, with an optimal cutoff of 158.5 U/mL.

Human Transcriptome Array Analysis Identifies CDR2 as a Novel Suppressed Gene for Kawasaki Disease.

Kawasaki disease (KD) is a febrile childhood vasculitis that involves the coronary arteries. Most previous studies have focused on the genes activated in the acute phase of KD. However, in this study, we focused on suppressed genes in the acute stage of KD and identified novel targets with clinical significance and potential prognostic value for KD patients. We enrolled 18 patients with KD, 18 healthy controls (HC), and 18 febrile controls (FC) for human transcriptome array analysis. Another 19 healthy controls, 20 febrile controls, and 31 patients with KD were recruited for RT-PCR validation of target mRNA expressions. The results of Human Transcriptome Array (HTA) 2.0 showed 461 genes that were significantly higher in KD and then normalized after IVIG, as well as 99 suppressed genes in KD. Furthermore, we identified the four genes in KD with the most downregulation, including BCL11B, DUSP2, DDX24, and CDR2, as well as the upregulation of their expression following IVIG administration. The mRNA expression of CDR2 by qRT-PCR was the most compatible with the pattern of the HTA2.0 results. Furthermore, we found higher DDX24 mRNA expression in KD patients with CAL when compared to those without CAL 3 weeks after IVIG administration. In summary, activated gene expression represented a majority in the immune response of KD. In this study, we identified CDR2 as a novel suppressed gene for Kawasaki disease via human transcriptome array analysis and DDX24 associated with CAL formation, which may contribute to further understanding of CAL pathogenesis in KD.

Pediatric Lupus Presenting as Pulmonary Hypertension, Myocarditis, and Massive Pericardial Effusion in an 11-Year-Old Girl: A Case Report and Literature Review.

Systemic lupus erythematosus (SLE) is an autoimmune disease that may cause vital organ damage. Although not rare for child-onset SLE to have cardiovascular or pulmonary involvement, myocarditis, and pulmonary hypertension are infrequent features and can be life-threatening. In this case report, we describe an 11-year-old girl with SLE who initially presented with fulminant myocarditis pulmonary hypertension, and massive pericardial effusion. Initial immunosuppressive therapy with methylprednisolone pulse therapy, and IVIG were administered, followed by cyclophosphamide, which was ultimately successful, with no residual pulmonary hypertension and no recurrence of myocarditis for over 3 years after the initial episode. Our case highlights the need for clinicians to be aware of systemic lupus erythematosus as a possible diagnostic entity in pediatric patients with severe myocarditis or pulmonary hypertension. Aggressive immunosuppressive therapy should be strongly considered in such cases, as it may lead to good short-term and long-term outcomes.

Number of Kawasaki Disease Admissions Is Associated with Number of Domestic COVID-19 and Severe Enterovirus Case Numbers in Taiwan.

Background: Non-pharmaceutical interventions (NPIs) introduced in response to the COVID-19 pandemic, including mask-wearing and social distancing, have changed the prevalence of circulating viruses in the community. Since viral infections represent a potential triggering factor for the development of Kawasaki disease (KD), we examined the relationship between KD admission rates and the number of COVID-19, severe influenza, and severe enterovirus infections both before and after the COVID-19 pandemic. Methods: We conducted a retrospective study using data obtained from the Chang Gung Research Database (including seven Taiwanese hospitals and more than 10,000 beds) and the Centers for Disease Control in Taiwan from January 2018 to December 2020. We recorded the number of KD admissions, as well as COVID-19, severe influenza, and severe enterovirus infections. Results: The numbers of KD admissions, severe enterovirus infections, and severe influenza infections were significantly lower from April to September 2020. The number of KD hospitalizations was positively correlated with the number of domestic COVID-19 cases (p = 0.001). A decrease in KD admission numbers was positively correlated with a decrease in severe enterovirus case numbers (p = 0.007). Conclusion: Our findings provide further evidence that viral infections may be an important trigger factor in the development of KD. Therefore, NPIs may not only prevent transmissible viral infections in children, but also decrease the risk of KD.

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.

DNA Methylation Array Identifies Golli-MBP as a Biomarker for Disease Severity in Childhood Atopic Dermatitis.

In this study, we investigated the changes in global methylation status and its functional relevance in childhood atopic dermatitis (AD). Differences in epigenome-scale methylation events in peripheral blood associated with childhood AD were screened using DNA methylation arrays of 24 patients with AD compared with 24 control subjects. Of the 16,840 differentially methylated CpG regions between AD and control subjects, >97% CpG loci revealed hypomethylation in patients with childhood AD. Among the globally hypomethylated loci, we identified two CpG clusters within the golli-mbp locus of the MBP gene, which was functionally enriched by subnetwork enrichment analysis as an orchestrator among associated genes. The differential hypomethylation of the top-ranked cg24700313 cluster in the golli-mbp locus was validated by pyrosequencing in an independent cohort of 224 children with AD and 44 control subjects. DNA methylation was found to be negatively correlated with disease severity but showed no significant correlation with IgE levels after age adjustment. The multivariate correlation analysis represents a higher score in AD intensity with significantly increased IgE levels and decreased methylation levels in cg27400313. We concluded that methylation loss in the golli-mbp locus is an epigenetic factor associated with disease severity of childhood AD.

Effect of breastfeeding for 6 months on disease outcomes in patients with Kawasaki disease.

BACKGROUND: Kawasaki disease (KD) is a systematic vasculitis that occurs predominantly in young children, and is the leading cause of acquired heart disease in children younger than five-years-old in developed countries. Although the etiology of KD is unknown, it is believed to be an inflammatory disease resulting from abnormal immune responses to possible environmental or infectious stimuli in genetically predisposed individuals. Breast milk contains numerous anti-inflammatory factors which may protect against allergic and autoimmune diseases. In this study we tried to examine the effect of breastfeeding for 6 months or more on disease outcomes in patients with Kawasaki disease. METHODS: A retrospective cohort study of 249 KD patients admitted from 1999- 2013 who were older than 6 months at time of diagnosis and had data regarding breastfeeding in the first 6 months of life. Demographic, clinical and laboratory data was collected by chart review. Continuous data was compared using Student's t-test and categorical variables were compared using Chi-square. Stepwise multivariate regression of all demographic factors was performed. RESULTS: Breastfeeding for 6 months or more was associated with a shorter total duration of fever (5.980± 1.405 Vs. 6.910 ± 2.573 days, p = 0.001) and a lower risk of developing persistent coronary artery lesions (CALs) (7.8% Vs. 20.2%, p-value = 0.039) on univariate analysis. Multivariate regression of all factors associated with CALs including breastfeeding for 6 months found that only the presence of CALs at baseline (ß-coefficient = 0.065, p < 0.001) and white blood count (ß-coefficient = 0.065, p = 0.018) remained significant after regression analysis. CONCLUSIONS: Breastfeeding for 6 months or more was associated with a shorter duration of fever and a lower risk of persistent CAL formation in patients with KD on univariate analysis, although this effect may be modest when other factors such as the presence of CALs at baseline and white blood cell count are also taken into consideration.

Increased Expression of Pyroptosis in Leukocytes of Patients with Kawasaki Disease.

BACKGROUND: Kawasaki disease (KD) is a form of febrile vasculitis that primarily occurs in children. It can cause inflammation of the coronary arteries, which leads to aneurysms. The pathogenesis of coronary arteries may be associated with apoptosis or pyroptosis mediated by caspases activity, but this idea has not been discussed much in KD. MATERIALS AND METHODS: We enrolled 236 participants in this study. In the Affymetrix GeneChip® Human Transcriptome Array 2.0 study, there were 18 KD patients analyzed prior to receiving intravenous immunoglobulin (IVIG) treatment, at least 3 weeks after IVIG treatment, and 36 non-KD control subjects. We also recruited 24 KD patients prior to receiving IVIG treatment, at least 3 weeks after IVIG treatment, and 24 non-KD control subjects for Illumina HumanMethylation450 BeadChip study. A separate cohort of 134 subjects was analyzed to validate real-time quantitative PCR. RESULTS: The mRNA levels of caspase-1, -3, -4, and -5 were significantly increased in KD patients compared with control subjects (p < 0.05). After administration of IVIG, the expression of these genes decreased considerably. Of particular note, the methylation status of the CpG sites of the caspase-4 and -5 genes demonstrated significant opposite tendencies between the KD patients and controls. Furthermore, compared with patients who responded to IVIG, refractory KD patients had a lower expression of the caspase-3 gene prior to IVIG treatment. CONCLUSION: Our study is the first to report the upregulation of pyroptotic caspase-1, -4, and -5 in peripheral leukocytes of KD patients. Moreover, the expression of caspase-3 may be associated with IVIG resistance in KD.

Treatment of Kawasaki Disease: A Network Meta-Analysis of Four Dosage Regimens of Aspirin Combined With Recommended Intravenous Immunoglobulin.

Aspirin was once believed to reduce the mortality of Kawasaki disease (KD) due to its effect on the thrombotic occlusion of coronary arteries. However, conflicting evidence has been found regarding aspirin treatment and its benefit in patients with acute KD. We compared the efficacy of different aspirin doses in acute KD. A literature search of PubMed, EMBASE, and Cochrane databases was conducted to identify studies comparing different doses of aspirin for acute KD. The primary outcome of interest was coronary artery lesions (CAL). We used random-effects network meta-analysis. Six retrospective studies, including 1944 patients receiving aspirin in doses of 0, 3-5, 30-50, or 80-100 mg/kg/day, were selected. The risks of CAL were not significantly different for the various doses of aspirin compared to the placebo: odds ratio (OR) was 1.10 [95% confidence interval (CI): 0.70-1.71] for patients with aspirin 3-5 mg/kg/day; OR = 1.23 (95% CI: 0.67-2.26) for aspirin 30-50 mg/kg/day, and OR = 1.59 (95% CI: 0.74, 3.421) for 80-100 mg/kg/day. The P-score ranged from 0.76 for placebo to 0.19 for aspirin 80-100 mg/kg/day. The different doses of aspirin exhibited no significant difference with regard to the efficacy of CAL or with the secondary outcomes of intravenous immunoglobulin resistance or hospital stays for acute KD. Therefore, we found that treatment without any aspirin is not inferior to other doses of aspirin and can also slightly reduce the risk of CAL.

Long-Term Hypermethylation of FcγR2B in Leukocytes of Patients with Kawasaki Disease.

The Fc gamma receptor family contains several activating receptors and the only inhibitory receptor, FcγR2B. In this study, we investigated the dynamic methylation change of FcγR2B in different stages of Kawasaki disease (KD). We enrolled a total of 116 participants, which included patients with febrile diseases as controls and KD patients. Whole blood cells of KD patients were collected prior to intravenous immunoglobulin (IVIG) treatment (KD1), three to seven days after IVIG (KD2), three weeks after IVIG treatment (KD3), six months after IVIG (KD4), and one year after IVIG treatment (KD5). In total, 76 KD patients provided samples in every stage. Leukocytes of controls were also recruited. We performed DNA extraction and pyrosequencing. FcγR2B methylation levels were higher in KD3 compared to both the controls and KD1. A significantly higher methylation of FcγR2B was found in KD5 when compared with KD1. FcγR2B methylation levels in the IVIG-resistant group were lower than those in the IVIG-responsive group at KD1-3 (p = 0.004, 0.004, 0.005 respectively). This study is the first to report the dynamic change of FcγR2B methylation and to demonstrate long-term hypermethylation one year after disease onset. Hypomethylation of FcγR2B is associated with IVIG resistance.

Desquamation in Kawasaki Disease.

(1) Background: Desquamation is a common characteristic of Kawasaki disease (KD). In this study, we analyzed patients' varying desquamation levels in their hands or feet, in correlation with clinical presentation, to assess the relationship. (2) Methods: We retrospectively reviewed children with KD. We analyzed their age, laboratory data before intravenous immunoglobulin (IVIG) treatment and coronary artery abnormalities (CAA) based on the desquamation level of their hands and feet. We classified the desquamation level from 0 to 3 and defined high-grade desquamation as grade 2 and 3. (3) Results: We enrolled a total 112 patients in the study. We found the hands' high-grade desquamation was positively associated with age and segmented neutrophil percentage (p = 0.047 and 0.029, respectively) but negatively associated with lymphocyte and monocyte percentage (p = 0.03 and 0.006, respectively). Meanwhile, the feet's high-grade desquamation was positively associated with total white blood cell counts (p = 0.033). Furthermore, we found that high-grade hand desquamation had less probability of CAA formation compared with that of a low grade (7.1% vs. 40.8%, p = 0.016). (4) Conclusions: This report is the first to demonstrate that the desquamation level of hands or feet in KD is associated with different coronary artery abnormalities and laboratory findings.