Kawasaki disease was associated with higher IL-17A and IL-6, a cytokine profile similar to other autoimmune diseases. IVIG therapy resulted in increased expression of Treg-related FoxP3. IVIG resistance was associated with higher levels of IL-10 and IL-17A. Our findings provide further evidence that Kawasaki disease is an autoimmune-like disease.
BackgroundKawasaki disease (KD) is also known as multiple mucocutaneous lymph node syndrome of systemic vasculitis and is a leading cause of coronary artery lesions (CAL) in childhood. Intravenous immunoglobulin (IVIG) has been proven to effectively reduce the incidence of CAL, but the role and effect dose of aspirin in KD is still unclear. Moreover, overt bleeding and anemia are associated with the use of aspirin, and anemia is common in patients with KD. Thus, the aim of this study was conducted to compare the treatment efficacy, degree of anemia and inflammation, and changes in serum hepcidin in children who received a combination of high-dose aspirin and IVIG in the acute stage of KD, and those who received IVIG alone.Materials and MethodsKD patients from two medical centers were retrospectively analyzed from 1999–2009. All patients were initially treated with a single dose of IVIG (2 g/kg) as the standard care of treatment. In group 1, high-dose aspirin was prescribed (> 30 mg/kg/day) until the fever subsided, and then low-dose aspirin (3–5 mg/kg/day) was prescribed until all the inflammation signs had resolved. In group 2, low-dose aspirin was prescribed without high-dose aspirin. Laboratory data were collected for analysis in both groups.ResultsA total of 851 KD patients (group 1, N = 305, group 2, N = 546) were enrolled in this study. There were no significant differences between group 1 and group 2 in terms of gender (p = 0.51), IVIG resistance rate (31/305 vs. 38/546, p = 0.07), CAL formation (52/305 vs. 84/546, p = 0.67), and duration of hospitalization (6.3 ± 0.2 vs. 6.7 ± 0.2 days, p = 0.13). There were also initially no significant differences in total white blood cell count, hemoglobin level, platelet count, and CRP before IVIG treatment between groups (all p>0.1). After IVIG treatment, group 1 had significantly lower levels of hemoglobin (p = 0.006) and higher CRP (p<0.001) as well as a smaller decrease in CRP level (p = 0.012). Furthermore, there was also a higher serum level of hepcidin and a delayed decrease in hepcidin level after receiving IVIG in group 1 (p = 0.04 and 0.02, respectively).ConclusionsThese results provide evidence demonstrating that high-dose aspirin in the acute phase of KD does not confer any benefit with regards to inflammation and it does not appear to improve treatment outcomes. Therefore, high-dose aspirin is unnecessary in acute phase KD.
Capsule Summary 22Diagnosing Kawasaki disease (KD) currently relies on physicians' experience, 23 making it difficult to accurately diagnose KD. Using NGS, qPCR and machine 24 learning algorithm, we identified a miRNA-based biomarker panel with high 25 accuracy. 26 27 Kawasaki disease (KD) is an autoimmune disease preferentially attacking 32 children younger than five years old. Symptoms of KD include fever for at least 33 five days, oral mucosal inflammation, non-supportive conjunctivitis, 34 lymphadenopathy, edema of the extremities and a polymorphous rash. If left 35 untreated, almost 20-25% of the KD patients may develop severe coronary artery 36 aneurysms, making KD the leading cause of acquired heart disease in young 37 children in developed countries 1 . The successful detection of KD within the first 38 10 days of fever onset followed by treatment with high dose intravenous 39 immunoglobulin (IVIG) can greatly reduce the risk of severe coronary artery 40 lesions 1-3 . Therefore, early and successful detection is critical for treating KD. 41 So far, few cytokine-based biomarker platform was developed 4 . Therefore, the 42 detection of KD still mainly relies on the judgment of clinical physicians based on 43 patients' symptoms. However, infectious diseases by pathogens, may also result in 44 similar symptoms to those of KD, making it difficult to accurately diagnose KD and 45 leading to a delay in optimal and timely treatment of KD. 46 Previous studies showed that it is applicable to use blood miRNAs as disease 47 biomarkers 5-7 . So, we enrolled 70 fever control (FC, denoting non-KD patients with 48 fever) and 50 KD subjects (see Supplementary Methods). Among them, 37 FC and 49 31 KD subjects comprised the training set, used for developing KD biomarker panel 50 with NGS and/or qPCR assays. The remaining 33 FC and 19 KD subjects comprised 51 the blind test set, used for examining the performance of the developed KD 52biomarker panel. Table 1 shows that the most prevalent diagnosis of FC subjects was 53 upper or lower respiratory infection (28 and 27 patients, respectively). In KD 54 patients, bilateral conjunctivitis, oral mucosa changes and rash were the most 55 prevalent clinical features. 56We extracted RNA samples from white blood cells (see Supplementary 57 Methods). Then, we had two pooled FC and two pooled KD RNA libraries 58 sequenced with Illumina NGS platform, followed by miRSeq 8 analysis for 59 determining miRNA expression profiles (Supplementary Table 1). According to 60 miRSeq result, almost 80% of the initial reads belonged to clean read, the sequence 61 read with 3' adaptor recognized and trimmed. In addition, the majority of the clean 62 reads was 22-nt long (Supplementary Figure 1), reflecting high performance of the 63 sample preparation procedures and implying the dominance of miRNAs, which was 64 proven by Supplementary Figure 2. 65 To examine whether the FC and KD samples were distinguishable based on 66 miRNA expression profiles, we conducted clustering analysis. The heat map...
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 setup 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 cutoff 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.
Kawasaki disease (KD) or Kawasaki syndrome is known as a vasculitis of small to medium-sized vessels, and coronary arteries are predominantly involved in childhood. Generally, 20–25% of untreated with IVIG and 3–5% of treated KD patients have been developed coronary artery lesions (CALs), such as dilatation and aneurysm. Understanding how coronary artery aneurysms (CAAs) are established and maintained in KD patients is therefore of great importance. Upon our previous genotyping data of 157 valid KD subjects, a genome-wide association study (GWAS) has been conducted among 11 (7%) CAA-developed KD patients to reveal five significant genetic variants passed pre-defined thresholds and resulted in two novel susceptibility protein-coding genes, which are NEBL (rs16921209 (P = 7.44 × 10−9; OR = 32.22) and rs7922552 (P = 8.43 × 10−9; OR = 32.0)) and TUBA3C (rs17076896 (P = 8.04 × 10−9; OR = 21.03)). Their known functions have been reported to associate with cardiac muscle and tubulin, respectively. As a result, this might imply their putative roles of establishing CAAs during KD progression. Additionally, various model analyses have been utilized to determine dominant and recessive inheritance patterns of identified susceptibility mutations. Finally, all susceptibility genes hit by significant genetic variants were further investigated and the top three representative gene-ontology (GO) clusters were regulation of cell projection organization, neuron recognition, and peptidyl-threonine phosphorylation. Our results help to depict the potential routes of the pathogenesis of CAAs in KD patients and will facilitate researchers to improve the diagnosis and prognosis of KD in personalized medicine.
BackgroundKawasaki disease (KD) is an autoimmune disease preferentially attacking children younger than five years worldwide. So far, the principal treatment to KD is the administration of Intravenous immunoglobulin (IVIG). Although DNA methylation plays important regulation roles in diseases, few studies investigated the regulation roles of DNA methylation in KD.MethodsIn this study, we focused not only on the DNA methylation alterations resulted from KD onset but also on DNA methylation alterations resulted from IVIG administration. To do so, we investigated the effects of KD’s onset and IVIG administration on CpG marker’s methylation alterations.ResultsWe first found that DNA methylation alterations reflecting disease onset or IVIG administration are contributed mainly by the CpG markers on autosomes. In addition, we also demonstrated that some CpG markers carry methylation alteration among samples, forcing the expression abundance of the downstream genes to be also altered and negatively correlated with methylation profile. Finally, compared with KD’s onset, IVIG administration brings stronger impact on methylation alteration. And, such alterations were conducted mainly by hyper-methylating CpG markers, forcing the corresponding genes to keep lower expression levels. Moreover, the genes regulated by the altered CpG markers with IVIG administration are enriched in the pathways associated with inflammatory immune response.ConclusionsIn summary, our result provides researchers with another way into the regulation mechanism through which IVIG represses excessive inflammatory responses.
An empirical equation for all age groups is developed. From this equation, particle deposition efficiency in the nasal airway can best be estimated with input data of particle size and pressure drop of the airway.
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