IVIG-resistant Kawasaki Disease Research Articles

Combination of S100A12/TLR2 signaling molecules and clinical indicators in a new predictive model for IVIG-resistant Kawasaki disease

Although intravenous immunoglobulin (IVIG)-resistant Kawasaki disease (KD) presents with persistent inflammatory stimulation of the blood vessels and an increased risk of coronary artery dilatation. However, the pathogenesis of this disease is unclear, with no established biomarkers to predict its occurrence. This study intends to explore the utility of S100A12/TLR2-related signaling molecules and clinical indicators in the predictive modeling of IVIG-resistant KD. The subjects were classified according to IVIG treatment response: 206 patients in an IVIG-sensitive KD group and 49 in an IVIG-resistant KD group. Real-time PCR was used to measure the expression of S100A12, TLR2, MYD88, and NF-κB in peripheral blood mononuclear cells of patients, while collecting demographic characteristics, clinical manifestations, and laboratory test results of KD children. Multi-factor binary logistic regression analysis identified procalcitonin (PCT) level (≥ 0.845 ng/mL), Na level (≤ 136.55 mmol/L), and the relative expression level of S100A12 (≥ 10.224) as independent risk factors for IVIG-resistant KD and developed a new scoring model with good predictive ability to predict the occurrence of IVIG-resistant KD.

Efficacy and safety of infliximab in the treatment of Kawasaki disease: A systematic review and meta-analysis.

Infliximab is a monoclonal antibody specifically binding tumor necrosis factor-alpha and has been approved for the treatment of several inflammatory disorders. However, the efficacy of infliximab in primary treatment of Kawasaki disease (KD) or retreatment of intravenous immunoglobulin (IVIG)-resistant KD in children is controversial. Therefore, we conducted a meta-analysis to compare the efficacy of infliximab alone or in combination with IVIG to IVIG. Eligible randomized and non-randomized trials were retrieved by searching literature databases prior to May 31, 2023. Pooled odds ratio (OR) and 95% confidence interval (95% CI) were calculated for dichotomous variables, and mean difference (MD) with 95% CI was estimated for continuous variables. A total of 14 eligible studies comprising 1257 participants were included. In refractory KD, infliximab alone was associated with a higher effectiveness rate (OR = 4.48, 95% CI 2.67-7.52) and defervescence rate (OR = 5.01, 95% CI 2.99-8.37) and resulted in a 1.08-day-shorter duration of fever (95% CI 0.61-1.55, P < 0.001) and 1.36-day-shorter length of hospital stay (95% CI 0.65-2.08) compared with IVIG. Incidences of coronary artery lesions (CALs), newly developing CALs, and CAL regression did not differ between both groups. For initial treatment of KD, infliximab in addition to IVIG led to a nominally significant higher effectiveness rate (OR = 2.26, 95% CI 1.02-5.01) and a larger reduction of right coronary artery Z score (MD = -0.24, 95% CI -0.27 to -0.21) but did not show additional efficacy in improving other outcomes. The safety profile was similar between both groups. Conclusion: The meta-analysis demonstrates that infliximab alone is a well-tolerated and effective treatment for IVIG-resistant KD. The additional efficacy of infliximab to IVIG for initial treatment of KD is limited. More large and high-quality trials are needed to confirm the efficacy of infliximab, especially for intensification of primary treatment for KD. What is Known: • Infliximab is a novel monoclonal antibody specifically blocking tumor necrosis factor-alpha and is approved for treatment of several immune-mediated inflammatory disorders. • The efficacy of infliximab in treating children with Kawasaki disease is controversial. What is New: • Infliximab is an effective and safe treatment for children with refractory Kawasaki disease but adds limited efficacy to intravenous immunoglobulin for initial treatment of Kawasaki disease.

The expression of autophagy markers in IVIG-resistant Kawasaki disease and the establishment of prediction model

BackgroundThe aim of this study was to find early predictors of Intravenous Immunoglobulin (IVIG)-Resistant Kawasaki Disease.MethodsPatients diagnosed with Kawasaki disease were enrolled in this study. Univariate analysis and multiple logistic regression were used to analyze the clinical characteristics and laboratory findings of patients in both groups before IVIG treatment. Independent predictors of Intravenous Immunoglobulin-Resistant Kawasaki Disease were analyzed, and a prediction model for children with Intravenous Immunoglobulin-Resistant Kawasaki Disease was constructed.ResultsA total of 108 children (67 males and 41 females) with IVIG-sensitive Kawasaki disease and 31 children (20 males and 11 females) with IVIG-resistant Kawasaki disease participated in this study. Compared with the IVIG-sensitive group, the duration of hospitalization, ALT, AST, GLB, r-GT, IgG, PCT, and ESR was elevated in the IVIG-resistant KD group, and ATG16L1, LC3II, BECN1, RBC, HGB, ALB, A/G, and CK were significantly lower (P < 0.05). mRNA expression of ESR, BECN1, and LC3II were independent risk factors for IVIG-resistant Kawasaki disease. A logistic regression model and scoring system were established, and the cut-off values of independent risk factors were derived from ROC curves: ESR ≥ 79.5 mm/h, BECN1 ≤ 0.645, LC3II ≤ 0.481. A new scoring system was established according to the respective regression coefficients as follows: ESR ≥ 79.5 mm/h (1 point), BECN1 ≤ 0.645 (1 point). LC3II ≤ 0.481 (2 points), 0–1 as low risk for IVIG non-response, and ≥ 2 as high risk. Applied to this group of study subjects, the sensitivity was 87.10%, specificity 83.33%, Youden index 0.70, AUC 0.9.ConclusionsAutophagy markers ATG16L1, BECN1, and LC3II are down-regulated in the expression of IVIG -resistant KD. ESR, BECN1, and LC3II mRNAs are independent risk factors for IVIG-resistant KD and may be involved in the development of IVIG-resistant KD. This study established a new model that can be used to predict IVIG-resistant KD, and future validation in a larger population is needed.

Predictive value of peripheral blood lymphocyte subsets for children with intravenous immunoglobulin-resistant Kawasaki disease

Based on peripheral blood lymphocyte subsets and common laboratory test indexes, this study aimed to construct a predictive scoring system for intravenous immunoglobulin (IVIG)-resistant Kawasaki disease (KD). Children hospitalized in Tianjin Children's Hospital from January 2021 to March 2023 were included in the study (185 cases of IVIG-sensitive KD and 41 cases of IVIG -resistant KD). Forty-six healthy children matched for age and gender were selected as controls. The relative percentage and absolute counts of peripheral lymphocyte subsets were measured by flow cytometry. Multivariate logistic regression was used to identify the predictive factors for IVIG-resistant KD and to construct a predictive scoring system for predicting IVIG-resistant KD. The multivariate logistic regression analysis showed that CD4+ T cell absolute count, natural killer cell absolute count, serum sodium level, globulin level, and total bilirubin level were identified as predictive factors for IVIG-resistant KD (P<0.05). The predictive scoring system based on these factors achieved a sensitivity of 70.7% and a specificity of 83.8% in predicting IVIG-resistant KD. Peripheral blood lymphocyte subsets can serve as predictive indicators for IVIG-resistant KD in children. The introduction of this indicator and the establishment of a scoring system based on it can provide a higher accuracy in predicting IVIG-resistant KD in children.

PTX3 promotes IVIG resistance-induced endothelial injury in Kawasaki disease by regulating the NF-κB pathway.

Intravenous immunoglobulin (IVIG) resistance leads to serious complications in Kawasaki disease (KD) with no effective treatment. This study aimed to investigate the effects of pentraxin 3 (PTX3) on human coronary artery endothelial cells (HCAECs). PTX3 levels were measured using quantitative real-time PCR (qRT-PCR), enzyme-linked immunosorbent assay, and western blotting. Cell viability was detected using the MTT assay. Biological functions were analyzed using CCK-8, EdU, flow cytometry, TUNEL, and qRT-PCR. The levels of factors of the NF-κB pathway were examined using western blotting. The results demonstrated that PTX3 expression was highest in patients and HCAECs with IVIG-resistance. Knockdown of PTX3 promoted proliferation and suppressed apoptosis and inflammation of IVIG-resistant HCAECs, whereas PTX3 overexpression produced the opposite results. Moreover, PTX3 activated the NF-κB pathway in IVIG-resistant HCAECs. A rescue study showed that PTX3 modulated biological behaviors by regulating the NF-κB pathway. Overall, our findings demonstrate that PTX3 promotes IVIG resistance-induced endothelial injury by activating the NF-κB pathway, suggesting that PTX3 may become a novel therapeutic target for patients with IVIG-resistant KD.

Current knowledge of TNF-α monoclonal antibody infliximab in treating Kawasaki disease: a comprehensive review.

Kawasaki disease (KD), an autoinflammatory disease primarily affecting young children, characterized by consisting of acute systemic vasculitis and coronary artery involvement in severe cases. Intravenous immunoglobulin gamma (IVIG) combined with aspirin therapy is the first-line regimen for the prevention of coronary aneurysms in the acute phase of KD. The etiology and pathogenesis of KD are unclear, but its incidence is increasing gradually, especially in the cases of IVIG-naïve KD and refractory KD. Conventional therapies for refractory KD have unsatisfactory results. At present, infliximab (IFX), a human-murine chimeric monoclonal antibody that specifically blocks tumor necrosis factor-α (TNF-α), has made great progress in the treatment of KD. This review revealed that IFX infusion (5 mg/kg) could effectively modulate fever, reduce inflammation, improve arthritis, diminish the number of plasma exchange, decrease hospitalizations, and prevent the progression of coronary artery lesions. The adverse effects of IFX administration included skin rash, arthritis, respiratory disease, infusion reaction, hepatomegaly, and vaccination-associated complications. But the incidence of these adverse effects is low. The clear optimal application protocol of the application of IFX for either initial combination therapy or salvage therapy in KD is still under investigation. In addition, there are no effective biomarkers to predict IFX resistance. Further multicenter trials with large sample size and long-term follow-up are still needed to validate the clinical efficacy and safety of IFX for IVIG-resistant KD or refractory KD.

Approach to resistant IVIG Kawasaki disease in children

Kawasaki disease (KD) is an acute febrile illness of early childhood characterized by vasculitis of the medium-sized arteries. There is no diagnostic test for KD because the cause is unknown, so diagnosis relies on the recognition of the diagnostic clinical criteria. The most feared sequela of KD is development of coronary artery abnormalities, which occur in 20-25% of untreated children. IVIG reduces this risk in 2-5% when administrated within 10 days from the onset of fever. Here is reported the case of an infant which resulted resistant to 2 consecutive doses of IVIG. Glucocorticoids are recommended as an appropriate therapy in IVIG resistant Kawasaki disease.

A novel model for predicting intravenous immunoglobulin-resistance in Kawasaki disease: a large cohort study.

Predicting intravenous immunoglobulin (IVIG)-resistant Kawasaki disease (KD) can aid early treatment and prevent coronary artery lesions. A clinically consistent predictive model was developed for IVIG resistance in KD. In this retrospective cohort study of children diagnosed with KD from January 1, 2016 to December 31, 2021, a scoring system was constructed. A prospective model validation was performed using the dataset of children with KD diagnosed from January 1 to June 2022. The least absolute shrinkage and selection operator (LASSO) regression analysis optimally selected baseline variables. Multivariate logistic regression incorporated predictors from the LASSO regression analysis to construct the model. Using selected variables, a nomogram was developed. The calibration plot, area under the receiver operating characteristic curve (AUC), and clinical impact curve (CIC) were used to evaluate model performance. Of 1975, 1,259 children (1,177 IVIG-sensitive and 82 IVIG-resistant KD) were included in the training set. Lymphocyte percentage; C-reactive protein/albumin ratio (CAR); and aspartate aminotransferase, sodium, and total bilirubin levels, were risk factors for IVIG resistance. The training set AUC was 0.825 (sensitivity, 0.723; specificity, 0.744). CIC indicated good clinical application of the nomogram. The nomogram can well predict IVIG resistance in KD. CAR was an important marker in predicting IVIG resistance in Kawasaki disease.

Treatment of immunoglobulin-resistant kawasaki disease: a Bayesian network meta-analysis of different regimens.

This study aimed to gather evidence from clinical trials on the efficacy and safety of the available treatments for intravenous immunoglobulin (IVIG)-resistant Kawasaki disease (KD) in children. This work adopted the Newcastle-Ottawa scale to analyse the quality of the enrolled articles. A network meta-analysis was performed using clinical trials that compared drugs used to treat IVIG-resistant KD. Aggregate Data Drug Information System software v.1.16.5 was employed to analyse whether infliximab, second IVIG infusions, and intravenous pulse methylprednisolone (IVMP) were safe and effective. Ten studies, involving 704 patients with IVIG-resistant KD, were identified and analysed. Overall, infliximab exhibited remarkable antipyretic activity compared with the second IVIG infusions (2.46, 1.00-6.94). According to the drug rank, infliximab was the best option against IVIG-resistant KD. Regarding adverse effects, the infliximab group was more prone to hepatomegaly. A second IVIG infusion was more likely to result in haemolytic anaemia. IVMP treatment was more susceptible to bradycardia, hyperglycaemia, hypertension, and hypothermia. In addition, infliximab, IVMP, and the second IVIG infusions showed no significant differences in the risk of developing a coronary artery aneurysm (CAA). Infliximab was the best option against IVIG-resistant KD, and IVMP, infliximab, and second IVIG infusions have not significant differences of prevent CAA in patients with IVIG-resistant KD. Identifier: https://osf.io/3894y.

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.

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. 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. 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). 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. https://www.crd.york.ac.uk/PROSPERO/, PROSPERO CRD42022341410.

Successful Treatment with Infliximab in Intravenous Immunoglobulin-Resistant Kawasaki Disease with High Procalcitonin Level: A Case Report

Procalcitonin (PCT) is modulated by sepsis-related cytokines such as tumor necrosis factor (TNF)-α and interleukins. Therefore, TNF-α blockade, infliximab may be useful for intravenous immunoglobulin (IVIG)-resistant Kawasaki disease (KD) with high PCT level. We report a case of IVIG-resistant KD with elevated PCT level who was successfully treated with infliximab. This case report suggests that the treatment of infliximab may be useful for IVIG-resistant KD with high PCT level.

가와사키병과 선천면역

Kawasaki disease (KD) is a self-limited febrile illness diagnosed based on various clinical manifestations, including fever. The major complication of KD is systemic vasculitis, particularly involving the coronary artery. The etiology of KD is not clear, but the pathogenesis may be related to excessive activation of the immune system. Immune modulation for KD treatment, including intravenous immunoglobulin (IVIG), is based on the control of immune hyperactivation. Many studies have reported a genetic susceptibility to KD, which is related to immune cell activation (ITPKC, CAPS3, BLK, FCGR2A, etc.). The innate immunity of humans begins to recognize and react through pattern recognition receptors against pathogen-associated molecular patterns (PAMPs) or damage-associated molecular patterns (DAMPs). Among receptors, the nucleotide-binding domain and leucine-rich repeat-containing receptor (NLRP) or NOD-like receptor (NLRs) in the cytosol contribute to inflammation as a key component. Cytosolic protein complexes called inflammasomes, assembled by NLRP, activate proinflammatory caspase 1 and 11, which ultimately produce IL-1β and IL-18 or induce cell death. IL-1 serves as an initiator for the recruitment of immune cells and the inflammatory response. Systemic vasculitis, such as Behcet disease, may be related to IL-1 polymorphism, and the expression of NLRP3. Coronary arteritis in KD is associated with an innate immune response, including IL-1. The suggested evidence of innate immunity in KD is related to increased neutrophils and monocytes, high levels of γδT cells, macrophage infiltration in coronary arteries and skin, elevated DAMPs such as S100 or HMGB1, and is sometimes associated with hyperactive innate immunity. The gene of the IL-1 pathway may be related to IVIG-resistant KD, and a clinical trial with IL-1 antagonist is currently ongoing. Adjunctive therapy in KD consists of various strategies, including second IVIG, steroids, and TNF inhibitors. The rationale for adjunctive therapy is based on immune hyperactivation with hypercytokinemia or immune modulation. Further efforts are needed to understand innate immunity and KD, especially in IVIG-resistant cases.

Uncovering Potential Novel Biomarkers in Immunoglobulin-Resistant Kawasaki Disease Using Bioinformatics Analysis

Intravenous immunoglobulin (IVIG)-resistant Kawasaki disease (KD) is a complicated disorder, which can induce multiple-system damage. The pathogenic factor inducing KD remains unclear. The present study focused on identifying potential novel biomarkers for IVIG-resistant KD using integrated analyses. Eight IVIG-resistant KD samples and twelve IVIG-sensitive KD samples were included in the GSE18606 dataset. A Linear Model for Microarray Data (LIMMA) identified 504 differentially expressed genes (DEGs), An IVIG-resistant KD sample was compared with an IVIG-sensitive KD sample to identify 17 modules through weighted gene co-expression network analysis (WGCNA). A common gene (CG) is the intersection of DEGs and genes in the most significant module. Analysis of functional enrichment revealed that CGs were mainly enriched in TNF signaling pathways and NF-kappa B signaling pathways. Ten of these genes were selected as hub genes because of their high degree of connectivity (KLF1, AHSP, HBQ1, HBA2, HBA1, EPB42, GYPB, UBB, KRT1 and BPIFB2).

Research on Early Identification Model of Intravenous Immunoglobulin Resistant Kawasaki Disease Based on Gradient Boosting Decision Tree.

To construct a predictive model for intravenous immunoglobulin (IVIG) resistant Kawasaki disease (KD) based on the gradient boosting decision tree (GBDT), so as to early identify children with IVIG resistance and actively take additional treatment to prevent adverse events. The case data of KD children hospitalized in the Pediatric Department of Lanzhou University Second Hospital from October 2015 to July 2020 were collected. All KD patients were divided into IVIG responsive group and IVIG resistant group. GBDT was used to explore the influencing factors of IVIG-resistant KD and to construct a prediction model. Then compared with previous models, the optimal model was selected. In the process of GBDT model construction, 80% of the data were used as the test set, and 20% of the data were used as the validation set. Among them, the verification set was used to adjust the hyperparameters in GDBT learning. The model performed best with a hyperparameter tree depth of 5. The area under the curve of the GBDT model constructed based on the best parameters was 0.87 (95% CI: 0.85-0.90), the sensitivity was 72.62%, the specificity was 89.04%, and the accuracy was 61.65%. The contribution degree of each feature value to the model was total bilirubin, albumin, C-reactive protein, fever time, and Na in order. The GBDT model is more suitable for the prediction of IVIG-resistant KD in this study area.

Distinctive serum lipidomic profile of IVIG-resistant Kawasaki disease children before and after treatment.

Kawasaki Disease (KD) is an acute inflammatory disorder associated with systemic vasculitis. Intravenous immunoglobulin (IVIG) is an effective therapy for KD, yet, about 20% of cases show IVIG resistance with persistent inflammation. The lipid profile in IVIG-resistant KD patients and the relationship between lipid characteristics and IVIG resistance remain unknown. In this study, serum samples from twenty KD patients with different IVIG responses (sensitive, intermediate, or resistant) were collected both before and after treatment, and lipidomic analysis was performed using high-performance liquid chromatography-mass spectrometry. As a result, before treatment, six lipid species were found as the most variant features, in which all the top decreased lipids in the IVIG-resistant group were lysophosphatidylcholine (LPC) and lysophosphatidylethanolamine (LPE), suggesting the potential to be IVIG-resistant markers in pretreatment diagnosis. During treatment, lipidomic changes showed a weaker response in the IVIG-resistant group. After treatment, LPC and LPE species exhibited lower in the IVIG-resistant group and negative correlation with the inflammatory markers, indicating that the unique metabolism may occur among IVIG-responsiveness. These results might contribute to diagnosing IVIG-resistant patients more accurately for alternative therapy and to a better understanding of how lipid metabolism is associated with IVIG sensitiveness/resistance in KD.

Risk-prediction models for intravenous immunoglobulin resistance in Kawasaki disease: Risk-of-Bias Assessment using PROBAST

BackgroundThe prediction model of intravenous immunoglobulin (IVIG) resistance in Kawasaki disease can calculate the probability of IVIG resistance and provide a basis for clinical decision-making. We aim to assess the quality of these models developed in the children with Kawasaki disease.MethodsStudies of prediction models for IVIG-resistant Kawasaki disease were identified through searches in the PubMed, Web of Science, and Embase databases. Two investigators independently performed literature screening, data extraction, quality evaluation, and discrepancies were settled by a statistician. The checklist for critical appraisal and data extraction for systematic reviews of prediction modeling studies (CHARMS) was used for data extraction, and the prediction models were evaluated using the Prediction Model Risk of Bias Assessment Tool (PROBAST).ResultsSeventeen studies meeting the selection criteria were included in the qualitative analysis. The top three predictors were neutrophil measurements (peripheral neutrophil count and neutrophil %), serum albumin level, and C-reactive protein (CRP) level. The reported area under the curve (AUC) values for the developed models ranged from 0.672 (95% confidence interval [CI]: 0.631–0.712) to 0.891 (95% CI: 0.837–0.945); The studies showed a high risk of bias (ROB) for modeling techniques, yielding a high overall ROB.ConclusionIVIG resistance models for Kawasaki disease showed high ROB. An emphasis on improving their quality can provide high-quality evidence for clinical practice.Impact statementThis study systematically evaluated the risk of bias (ROB) of existing prediction models for intravenous immunoglobulin (IVIG) resistance in Kawasaki disease to provide guidance for future model development meeting clinical expectations.This is the first study to systematically evaluate the ROB of IVIG resistance in Kawasaki disease by using PROBAST. ROB may reduce model performance in different populations.Future prediction models should account for this problem, and PROBAST can help improve the methodological quality and applicability of prediction model development.

Expression of interleukin-17A in serum of children with intravenous immunoglobulin-resistant Kawasaki disease and its clinical significance

To study the expression of interleukin-17A (IL-17A) in the serum of children with intravenous immunoglobulin (IVIG)-resistant Kawasaki disease (KD) and its clinical significance. A total of 143 children with KD who were hospitalized in Wuhan Children's Hospital, Tongji Medical College, Huazhong University of Science and Technology, from June 2021 to June 2022 were enrolled in this prospective study, among whom 115 had IVIG-sensitive KD and 28 had IVIG-resistant KD. After matching for sex and age, 110 children with acute respiratory infectious diseases (fever time ≥5 days but without KD) were enrolled as the control group. The enzyme-linked immunosorbent assay was used to measure the serum level of IL-17A. The levels of white blood cell count (WBC), neutrophil count (NE), platelet count, erythrocyte sedimentation rate, and C-reactive protein (CRP) were measured. The receiver operating characteristic curve was plotted to analyze the value of WBC, NE, CRP, and IL-17A in the prediction of IVIG-resistant KD. The multivariate logistic regression analysis was used to evaluate the predictive factors for resistance to IVIG in children with KD. Before IVIG treatment, the KD group had a significantly higher serum level of IL-17A than the control group (P<0.05), and the children with IVIG-resistant KD had a significantly higher serum level of IL-17A than those with IVIG-sensitive KD (P<0.05). The receiver operating characteristic curve analysis showed that WBC, NE, CRP, and IL-17A had an area under the curve of 0.718, 0.741, 0.627, and 0.840, respectively, in the prediction of IVIG-resistant KD. With serum IL-17A ≥44.06 pg/mL as the cut-off value, IL-17A had a sensitivity of 84% and a specificity of 81% in the prediction of IVIG-resistant KD. The multivariate logistic regression analysis showed that a high serum level of IL-17A was a predictive factor for resistance to IVIG in children with KD (OR=1.161, P=0.001). Serum IL-17A levels are elevated in children with IVIG-resistant KD, and serum IL-17A level (≥44.06 pg/mL) may have a predictive value for resistance to IVIG in children with KD.

A nomogram for predicting immunoglobulin-resistant Kawasaki disease in children.

This case-control study focused on the establishment and internal validation of a risk nomogram for intravenous immunoglobulin (IVIG)-resistant Kawasaki disease (KD) using the Kawasaki Disease Database. The Kawasaki Disease Database is the first public database for KD researchers. A prediction nomogram for IVIG-resistant KD was constructed using multivariable logistic regression. Then, the C-index was used to assess the discriminating ability of the proposed prediction model, a calibration plot was drawn to evaluate its calibration, and a decision curve analysis was adopted to assess its clinical usefulness. Bootstrapping validation was performed for interval validation. The median ages of IVIG-resistant and -sensitive KD groups were 3.3 and 2.9 years, respectively. Predicting factors incorporated into the nomogram were coronary artery lesions, C-reactive protein, percentage of neutrophils, platelets, aspartate aminotransferase, and alanine transaminase. Our constructed nomogram exhibited favorable discriminating ability (C-index: 0.742; 95% confidence interval: 0.673-0.812) and excellent calibration. Moreover, interval validation achieved a high C-index of 0.722. The as-constructed new IVIG-resistant KD nomogram that incorporated C-reactive protein, coronary artery lesions, platelets, percentage of neutrophils, alanine transaminase, and aspartate aminotransferase may be adopted for predicting the risk of IVIG-resistant KD.

Ultrasound evaluation of endothelial dysfunction in immunoglobulin-resistant children with acute Kawasaki disease.

Given the evidence that brachial artery flow-mediated dilation (FMD) is declined in children later after the onset of Kawasaki disease (KD), we hypothesized that indicators that detect the situation of the endothelium are useful parameters that can accurately reflect subclinical dysfunction in resistant patients and assist in differentiating patients with KD at a higher risk of IVIG resistance, which may be valuable in better understanding how to protect patients from endothelial and thrombotic complications. Fifty IVIG-resistant KD children, 120 IVIG-responsive KD children, 35 febrile children with acute upper respiratory infection, and 50 healthy controls were recruited, and indicators reflecting endothelial inflammation, including flow-mediated dilation (FMD), were measured. Receiver operating characteristic (ROC) curve analysis was utilized to determine the threshold values of these indicators of IVIG resistance. Multiple logistic regression analysis was performed to determine whether FMD was an independent predictor of IVIG-resistant patients. In comparison with the lab data, PCT, Na + , and FMD exhibited AUCs of 0.727, 0.653, and 0.698 (P < 0.05), respectively, in predicting IVIG resistance in KD through ROC analysis. PCT > 1.69ng/ml, Na + < 133.2mmol/l, and FMD < 5.79% were independent predictors of IVIG resistance in KD (OR 4.257, 3.516, 3.563, 95% CI 1.549 ~ 11.700, 1.277 ~ 9.680, 1.299 ~ 9.772, P < 0.05). More severe endothelial dysfunction, especially lower FMD, was present in IVIG-resistant patients than in IVIG-responsive patients. It is a helpful diagnostic tool that provides supportive criteria to detect KD patients at a higher risk of IVIG resistance when FMD < 5.79% in children. Key Points • IVIG-resistant KD patients have more severe endothelial dysfunction than IVIG-sensitive patients. • FMD < 5.79% may indicate an increased risk of IVIG resistance in children with Kawasaki disease.

Predictors for Intravenous Immunoglobulin Resistance in Patients with Kawasaki Disease.

Background Between 10 and 20% of Kawasaki disease (KD) patients are resistant to treatment with initial intravenous immunoglobulin (IVIG) and have a high risk of developing coronary artery lesions. Some studies have been conducted to identify predictive factors. However, the results are controversial. This study aims to identify the risk factors for IVIG-resistant KD patients in a Chinese population. Methods We performed a retrospective analysis of medical records of consecutive KD patients from two medical centers in South China from January 2015 to December 2017. A total of 1281 KD patients were eligible for inclusion in this study and maintained follow-up for over 12 months. The KD patients were divided into two groups based on IVIG response. Clinical characteristics and laboratory variables were compared between the two groups. Multivariate logistic regression analysis was performed to identify the risk factors of IVIG resistance in KD patients. Results Of the 1281 KD patients, 141 (11.0%) cases who were IVIG resistant to adjunctive therapies for primary treatment were classified as group 1. The remaining patients were in group 2 (n = 1140), classified as the control group. There was a significant difference in male to female ratio and the length of hospital stay between the two groups (P < 0.05). Group 1 had a higher white blood cell count (P=0.01) and C-reactive protein level (P < 0.01) before IVIG treatment than in group 2. Group 1 had a significantly higher white blood cell count and percentage of neutrophils after the IVIG infusion than in group 2 (P < 0.001). In addition, the mean values of C-reactive protein level and neutrophil percentage before and after treatment difference comparison were significantly different. Multivariate analysis showed that patients presenting with coronary artery lesions in the acute phase and a C-reactive protein level >100 mg/L at diagnosis were associated with IVIG resistance in KD. During the 12-month follow-up period, group 1 had an obviously higher incidence of coronary artery lesions than group 2, and the difference between the groups was statistically significant (P < 0.001). Conclusions Patients presenting with coronary artery lesions in the acute phase and elevated C-reactive protein levels before IVIG treatment might be a useful and important value for predicting IVIG resistance in KD. Risk assessment based on coronary artery lesions and C-reactive protein levels prior to the treatment may improve the outcome of IVIG resistance.