Hibiscus score: Developing and validating a predictive tool for intravenous immunoglobulin treatment resistance in Malaysian children with Kawasaki disease.

BACKGROUND: Children with intravenous immunoglobulin (IVIG) resistant Kawasaki disease (KD) are at higher risk of developing coronary artery (CA) aneurysm. Early identification of high-risk patients using a predictive tool would allow for earlier interventions to prevent cardiac complications. METHODS: Children with KD who were admitted to five selected hospitals in Malaysia between 2008 and 2018 and received 2 g/kg of IVIG within 10 days from the onset of illness were included. Predictors of IVIG resistance in KD were determined using multiple logistic regression analysis. An optimal cut-off point was set using receiver operative characteristic curve and a final multiple logistic regression analysis was performed entering these cut-off points. A new scoring system was constructed. RESULTS: A total of 276 patients were included. IVIG resistance occurred in 9.1 % of them. Total bilirubin [OR 7.37; 95 % CI (2.18, 24.83)], male sex [OR 0.34; 95 % CI (0.10, 1.19)], C-reactive protein (CRP) [OR 0.17; 95 % CI (0.02, 1.38)] and neutrophils [OR 0.25; 95 % CI (0.05, 1.21)] were found to be significant predictors for IVIG resistance. The findings led to the development of a new predictive tool called the Hibiscus score, which scored 1 point each for neutrophils ≥60 %, CRP ≥80 mg/L, and male sex, while total bilirubin ≥9.4 µmol/L scored 2 points. A cut-off point of ≥4 with this prediction score yielded a sensitivity of 78.9 % and specificity of 80.5 %, with area under the curve of 0.835 [95 % CI (0.752, 0.919)]. CA aneurysms occurred in 6.7 % of IVIG responders and 32 % of IVIG-resistant children (p < 0.001). CONCLUSION: The findings suggest that the Hibiscus score has a higher predictive power than the existing scoring systems for IVIG resistance in children with KD in Malaysia. However, external validation is required to enable its use to guide treatment decisions.

The role of serum lipid in predicting coronary artery lesions and intravenous immunoglobulin resistance in Kawasaki disease: a cohort study.

OBJECTIVE: To assess the predictive value of the serum lipid profile for initial intravenous immunoglobulin (IVIG) resistance and coronary artery lesions (CALs) in patients with Kawasaki disease (KD). METHODS: This retrospective cohort study enrolled patients with KD and divided them into IVIG-responsive and IVIG-resistant groups. They were also stratified based on the presence of CALs (CALs and non-CALs groups). Clinical, echocardiographic and biochemical values were evaluated. A subgroup analysis was performed on complete and incomplete KD. Predictors of initial IVIG resistance and CALs were determined by multivariate logistic regression analysis. RESULTS: A total of 649 KD patients were enrolled: 151 had CALs and 76 had initial IVIG resistance. Low-density lipoprotein cholesterol (LDL-C) was significantly lower in the IVIG-resistant group than in the IVIG-responsive group. LDL-C and apolipoprotein (Apo) B were significantly lower in the CALs group compared with the non-CALs group. Multivariate logistic regression failed to identify the serum lipid profile (LDL-C, Apo A or Apo B) as an independent risk factor for initial IVIG resistance or CALs in KD patients. CONCLUSION: KD patients might have dyslipidaemia in the acute phase, but the serum lipid profile might not be suitable as a single predictor for initial IVIG resistance or CALs.

Knowledge framework of intravenous immunoglobulin resistance in the field of Kawasaki disease: A bibliometric analysis (1997-2023).

BACKGROUND: Kawasaki disease (KD) is an autoimmune disease with cardiovascular disease as its main complication, mainly affecting children under 5 years old. KD treatment has made tremendous progress in recent years, but intravenous immunoglobulin (IVIG) resistance remains a major dilemma. Bibliometric analysis had not been used previously to summarize and analyze publications related to IVIG resistance in KD. This study aimed to provide an overview of the knowledge framework and research hotspots in this field through bibliometrics, and provide references for future basic and clinical research. METHODS: Through bibliometric analysis of relevant literature published on the Web of Science Core Collection (WoSCC) database between 1997 and 2023, we investigated the cooccurrence and collaboration relationships among countries, institutions, journals, and authors and summarized key research topics and hotspots. RESULTS: Following screening, a total of 364 publications were downloaded, comprising 328 articles and 36 reviews. The number of articles on IVIG resistance increased year on year and the top three most productive countries were China, Japan, and the United States. Frontiers in Pediatrics had the most published articles, and the Journal of Pediatrics had the most citations. IVIG resistance had been studied by 1889 authors, of whom Kuo Ho Chang had published the most papers. CONCLUSION: Research in the field was focused on risk factors, therapy (atorvastatin, tumor necrosis factor-alpha inhibitors), pathogenesis (gene expression), and similar diseases (multisystem inflammatory syndrome in children, MIS-C). "Treatment," "risk factor," and "prediction" were important keywords, providing a valuable reference for scholars studying this field. We suggest that, in the future, more active international collaborations are carried out to study the pathogenesis of IVIG insensitivity, using high-throughput sequencing technology. We also recommend that machine learning techniques are applied to explore the predictive variables of IVIG resistance.

C-reactive protein to albumin ratio as a prognostic tool for predicting intravenous immunoglobulin resistance in children with kawasaki disease: a systematic review of cohort studies.

BACKGROUND: Intravenous immunoglobulin (IVIG) is the primary treatment for Kawasaki disease (KD). However, 10-20% of KD patients show no response to IVIG treatment, making the early prediction of IVIG resistance a key focus of KD research. Our aim is to explore the application of the C-reactive protein to albumin ratio (CAR) for predicting IVIG resistance in children with KD through meta-analysis. METHODS: Cochrane Library, PubMed, MEDLINE, EMbase, CNKI, WanFang, the Chinese Biomedical Database, and CQVIP were searched up to November 2023 for cohort studies on predicting IVIG-resistant KD using the CAR. Articles were selected based on pre-established inclusion and exclusion criteria after extracting literature data and assessing them using the QUADAS-2.0 tool for evaluating the accuracy of diagnostic tests. Stata 15.0 software was used for meta-analysis. RESULTS: Four Chinese and English literature reports were included in this meta-analysis. The results revealed the presence of a threshold effect and high heterogeneity among the included studies. The combined sensitivity for CAR predicting IVIG-resistant KD was calculated as 0.65 (95% CI 0.58-0.72), specificity as 0.71 (95% CI 0.57-0.81), and the area under the curve (AUC) as 0.70 (95% CI 0.66-0.74) using the random-effects model. The combined positive likelihood ratio was 2.22 (95% CI 1.35-3.65), the combined negative likelihood ratio was 0.49 (95% CI 0.35-0.69), and the diagnostic odds ratio was 5 (95% CI 2-10). CONCLUSION: CAR is an auxiliary predictive indicator with moderate diagnostic value that provides guidance in the early treatment of the disease, demonstrating a certain predictive value that warrants further investigation. However, CAR cannot yet be considered as a definitive diagnostic or exclusionary marker for IVIG-resistant KD. Therefore, multi-center, large sample, and high-quality long-term follow-up trials are warranted to confirm the current findings.

Values of prognostic nutritional index for predicting Kawasaki disease: a systematic review and meta-analysis.

Objective: This systematic review and meta-analysis aimed to evaluate the relationship between the prognostic nutritional index (PNI) and intravenous immunoglobulin (IVIG) resistance and coronary artery lesion (CAL) in Kawasaki disease (KD). Methods: The relevant literature was searched on PubMed, Embase, Cochrane Library, Web of Science, and Google Scholar up to August 5, 2023. A pooled sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), diagnostic odds ratio (DOR), and area under curve (AUC) were calculated to assess the predicted values of PNI in KD patients with IVIG resistance and CAL. Results: A total of 8 articles containing 10 studies involving 7,047 participants were included. The pooled results revealed a pooled sensitivity of 0.44 (0.25-0.65), a pooled specificity of 0.87 (0.73-0.94), a pooled PLR of 3.4 (2.0-5.9), a pooled NLR of 0.65 (0.48-0.87), a pooled DOR of 5.26 (2.76-10.02), and a pooled AUC of 0.75 (0.71-0.78) in the diagnosis of KD with CAL. The pooled results suggested that a pooled sensitivity was 0.69 (0.60-0.77), specificity was 0.76 (0.69-0.82), PLR was 2.9 (2.1-4.1), NLR was 0.40 (0.29-0.56), DOR was 7.27 (3.89-13.59), and AUC was 0.79 (0.75-0.82) in the diagnosis of KD with IVIG resistance. The combined results revealed the pooled sensitivity was 0.63 (0.58-0.67), specificity was 0.82 (0.80-0.83), PLR was 3.09 (1.06-8.98), NLR was 0.38 (0.07-2.02), DOR was 8.23 (0.81-83.16) in differentiating KD from febrile patients. These findings demonstrated low sensitivity and relatively high specificity of PNI for KD, KD-CAL, and IVIG-resistant KD. Conclusion: In conclusion, this study was the first systematic review and meta-analysis of the diagnostic value of PNI in KD with IVIG resistance and CAL. The results suggested that PNI could be used as biomarkers for distinguish KD, KD with CAL, and KD with IVIG resistance.

Predictors and a novel predictive model for intravascular immunoglobulin resistance in Kawasaki disease.

BACKGROUND: Early identification of intravenous immunoglobulin (IVIG) resistance contributes to better management of Kawasaki disease (KD). This study aims to establish an effective prediction model for IVIG resistance in the Chinese population. METHODS: A total of 658 eligible patients diagnosed with KD were enrolled in this study, with 461 in the training cohort and 197 in the validation cohort. The demographic characteristics and potential risk factors were compared between IVIG-responsive and resistant groups. Predictors were selected by the Akaike information criterion. The nomogram's performance was evaluated by calibration curve, decision curve analysis, and operating characteristic curve. RESULTS: White blood cell counts (WBC), neutrophil-lymphocyte ratio (N/L ratio), hematocrit (HCT), albumin (ALB), total bilirubin (TBIL), lactate dehydrogenase (LDH), and creatinine (Cr) were detected as predictors of IVIG resistance. A predictive nomogram incorporating these predictors was constructed using the training cohort. The calibration curve and decision curve analysis showed good discrimination and calibration of the proposed nomogram in both training and validation sets, and the area under the receiver operating characteristic curve (AUROC) in both sets was 75.8% and 74.2%, respectively. CONCLUSION: This study identified WBC, N/L ratio, HCT, ALB, TBIL, LDH, and Cr as predictors for IVIG resistance in patients with KD. The proposed novel nomogram with a high level of accuracy and reliability may benefit clinical decision-making upon treatment initiation.

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

Background: 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. Methods: 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. Results: 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. Conclusion: The nomogram can well predict IVIG resistance in KD. CAR was an important marker in predicting IVIG resistance in Kawasaki disease.

A simple scoring model based on machine learning predicts intravenous immunoglobulin resistance in Kawasaki disease.

INTRODUCTION: In Kawasaki disease (KD), accurate prediction of intravenous immunoglobulin (IVIG) resistance is crucial to reduce a risk for developing coronary artery lesions. OBJECTIVE: To establish a simple scoring model predicting IVIG resistance in KD patients based on the machine learning model. METHODS: A retrospective cohort study of 1002 KD patients diagnosed at 12 facilities for 10 years, in which 22.7% were resistant to initial IVIG treatment. We performed machine learning with diverse models using 30 clinical variables at diagnosis in 801 and 201 cases for training and test datasets, respectively. SHAP was applied to identify the variables that influenced the prediction model. A scoring model was designed using the influential clinical variables based on the Shapley additive explanation results. RESULTS: Light gradient boosting machine model accurately predicted IVIG resistance (area under the receiver operating characteristic curve (AUC), 0.78; sensitivity, 0.50; specificity, 0.88). Next, using top three influential features (days of illness at initial therapy, serum levels of C-reactive protein, and total cholesterol), we designed a simple scoring system. In spite of its simplicity, it predicted IVIG resistance (AUC, 0.72; sensitivity, 0.49; specificity, 0.82) as accurately as machine learning models. Moreover, accuracy of our scoring system with three clinical features was almost identical to that of Gunma score with seven clinical features (AUC, 0.73; sensitivity, 0.53; specificity, 0.83), a well-known logistic regression scoring model. CONCLUSION: A simple scoring system based on the findings in machine learning seems to be a useful tool to accurately predict IVIG resistance in KD patients.

Network meta-analysis of the efficacy and safety of different drug regimens in the treatment of children with Kawasaki disease / 中国药房

OBJECTIVE To evaluate the efficacy and safety of different drug regimens in the treatment of children with Kawasaki disease， and to provide evidence-based reference for clinical treatment. METHODS Retrieved from the Cochrane Library， Medline， Embase， CINAHL， Web of Science， ProQuest， Google Scholar， CNKI， Wanfang Data， Baidu academic database， World Health Organization International Clinical Trials Registration Platform and ClinicalTrials. gov， randomized controlled trials （RCTs） about intravenous immunoglobulin （IVIG）+glucocorticoid or cyclosporine or tumor necrosis factor-alpha （TNF-α） blocker （trial group） versus standard IVIG therapy （control group） were collected from the establishment of the database to Feb. 28th， 2023. After screening the literature， extracting data， and evaluating the quality of the literature， Stata 14.2 software was used for network meta-analysis. RESULTS Ten RCTs with a total of 1 323 participants involving six measures were included： standard IVIG therapy， glucocorticoid therapy，cyclosporine therapy， TNF- α blocker therapy， remedial glucocorticoid therapy and remedial TNF- α blocker therapy. Results of network meta-analysis showed that the incidence of coronary artery aneurysms （CAA） at 4-8 weeks was significantly lower in patients receiving glucocorticoid therapy than receiving standard IVIG therapy and TNF-α blocker therapy. The incidences of CAA at 4-8 weeks in children treated with remedial glucocorticoid therapy and remedial TNF- α blocker therapy were significantly higher than those treated with glucocorticoid therapy； there was no significant difference in the incidence of CAA at 4-8 weeks among other interventions （P＞ 0.05）； network meta-order of the incidence was glucocorticoid therapy＜cyclosporine therapy＜standard IVIG therapy＜remedial TNF-α blocker therapy＜remedial glucocorticoid therapy＜TNF-α blocker therapy. The incidence of initial IVIG resistance in children receiving cyclosporine therapy was significantly lower than those receiving standard IVIG therapy； there was no significant difference in the incidence of initial IVIG resistance among other interventions （P＞0.05）； network meta-order of the incidence was cyclosporine therapy＜glucocorticoid therapy＜TNF-α blocker therapy＜standard IVIG therapy. There was no significant difference in the incidence of ADR among different interventions （P＞0.05）； network meta-order of the incidence was remedial TNF-α blocker therapy＜TNF-α blocker therapy＜standard IVIG therapy＜glucocorticoid therapy＜cyclosporine therapy. CONCLUSIONS Glucocorticoid therapy at the initial treatment can significantly reduce the risk of CAA at 4-8 weeks in children with Kawasaki disease； cyclosporine has a significant effect on improving initial IVIG resistance， and the use of TNF-α blocker in the remedial stage may have the lowest incidence of adverse reactions.

Predicting immunoglobulin resistance in Kawasaki disease: an assessment of neutrophil to lymphocyte platelet ratio.

BACKGROUND: Kawasaki disease (KD) is an acute febrile illness of unknown etiology and predictors for intravenous immunoglobulin (IVIG) resistance have been widely explored in recent decades. Neutrophil to lymphocyte platelet ratio (NLPR) was reported to be associated with the outcomes in many diseases. However, its relationship with IVIG resistance has not be explored. METHODS: The medical data of patients diagnosed with KD in Children's Hospital of Soochow University between January 2019 and December 2020 were retrospectively reviewed and analyzed. Patients were trisected into three groups based on NLPR. Logistics regression was used to analyze the association between NLPR and IVIG resistance. Restricted cubic spine was used to exhibit the relationship. Sensitivity analysis and subgroup analysis were also carried out. RESULTS: A total of 803 patients were included in the present study (61.8% males; median age: 24 months). IVIG resistance occurred in 74 (9.2%) patients. Multivariable-adjusted analyses revealed higher NLPR (odds ratio [95% confidence interval]: 1.12 [1.00-1.24]) was an independent predictor of IVIG resistance, which was strengthened by sensitivity analyses. The association of NLPR and IVIG resistance was not modified by age, sex, CALs, or days of IVIG initiation ≤ 4. CONCLUSION: NLPR may be a valuable prognostic marker in KD patients with IVIG resistance.

Predicting Intravenous Immunoglobulin Resistance Among North American Children Hospitalized With Kawasaki Disease.

OBJECTIVE: The Kobayashi score (KS) is the most widely used tool for predicting intravenous immunoglobulin (IVIG) resistance in Kawasaki disease (KD). The KS has shown good sensitivity (86%) and specificity (68%) in Japanese children; however, its use is limited outside of Japan. No models accurately predict IVIG resistance of children with KD in the United States. We sought to develop and test a novel scoring system to predict IVIG resistance in hospitalized children with KD. METHODS: A retrospective chart review was conducted of all children diagnosed with KD from January 2000 to December 2015. Subjects were divided into 2 groups: IVIG susceptible or resistant. Variables that differed between the groups were identified and used to create a "new score" to predict resistance to IVIG. The new score was then compared with the KS and performance characteristics were determined. RESULTS: A total of 208 subjects were reviewed. White blood cell count, neutrophil percentage, age, and serum albumin were used in the new score with equal weighting. Overall, the new score achieved improved sensitivity (54% vs 26%) and similar specificity (69% vs 74%) compared with the KS in predicting IVIG resistance in hospitalized children diagnosed with KD. CONCLUSIONS: Predicting IVIG resistance in children diagnosed with KD remains challenging. The KS has low sensitivity in predicting IVIG resistance in children with KD in the United States. The new score resulted in improved sensitivity, but many children with true IVIG resistance may be missed. Further research is needed to improve IVIG resistance prediction.

Value of blood inflammatory markers for predicting intravenous immunoglobulin resistance in Kawasaki disease: A systematic review and meta-analysis.

Background: Previous studies have assessed the diagnostic accuracy of blood inflammatory markers like neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and C-reactive protein (CRP), and CRP to albumin ratio (CAR) to predict the resistant Kawasaki disease (KD). The aim of the current meta-analysis and systematic review is to compare the prognostic ability of these inflammatory markers to predict the resistance to IVIG in patients with Kawasaki disease. Methods: A systematic search of online academic databases and search engines such as EMBASE, PubMed Central, MEDLINE, Cochrane library, Google Scholar, and ScienceDirect was conducted for papers that report the diagnostic accuracy of inflammatory markers for resistant KD. Meta-analysis was performed using STATA software. Results: Twenty-two studies met the inclusion criteria. Pooled sensitivity and specificity of NLR as a predictor of resistant Kawasaki disease was 72% (95% CI: 62%, 80%) and 71% (95% CI: 63%, 78%), with AUC of 0.77 for PLR was 60% (95% CI: 50%, 69%) and 68% (95% CI: 61%, 75%), with area under the curve (AUC) of 0.69. Pooled sensitivity and specificity of CRP was 75% (95% CI: 68%, 81%) and 66% (95% CI: 55%, 76%), respectively, with an AUC value of 0.78. Pooled sensitivity and specificity of combined NLR and PLR was 58% (95% CI: 46%, 69%) and 73% (95% CI: 65%, 79%), respectively, with an AUC value of 0.72. Conclusion: Our study found that NLR, CRP, PLR, and combined NLR/PLR have a good prognostic value in patients with resistant Kawasaki disease, with moderate to high sensitivity and specificity. More research on the accuracy of these indexes in multiple combinations is needed. Systematic review registration: [https://www.crd.york.ac.uk/prospero/], identifier [CRD42022322165].

Serum ferritin as a crucial biomarker in the diagnosis and prognosis of intravenous immunoglobulin resistance and coronary artery lesions in Kawasaki disease: A systematic review and meta-analysis.

Background: Early identification and treatment are paramount for intravenous immunoglobulin (IVIG) resistance and coronary artery lesions (CALs) in patients with Kawasaki disease (KD). Unfortunately, there is no single crucial biomarker to identify these patients in a timely manner, which makes KD the most common cause of acquired heart disease in children in developed countries. Recently, many studies have focused on the association between serum ferritin (SF), IVIG resistance, and CALs in KD. We thus performed a systematic review and meta-analysis to ascertain the diagnostic and prognostic values of SF in predicting IVIG resistance and CALs in KD in the acute phase. Methods: The pooled sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), diagnostic odds ratio (DOR), and area under the receiver operating characteristic curve (AUC) were extracted from the data to evaluate the SF levels in KD. The hazard ratios (HRs) of related risk factors and their corresponding 95% confidence intervals (CIs) were applied to compute the pooled assessments of the outcomes. Results: A total of 11 eligible articles were included in this meta-analysis, including twenty studies for diagnosis and five studies for prognosis. In terms of diagnostic values, SF could identify KD patients in the overall studies with a relatively high pooled sensitivity, specificity, PLR, NLR, DOR, and AUC of 0.76 (95% CI: 0.69-0.82), 0.82 (95% CI: 0.76-0.88), 4.33 (95% CI: 3.07-6.11), 0.29 (95% CI: 0.22-0.38), 15.0 (95% CI: 9.00-25.00), and 0.86 (95% CI: 0.83-0.89), respectively. In studies comparing KD patients and controls, there were a relatively high pooled sensitivity, specificity, PLR, NLR, DOR, and AUC of 0.79 (95% CI: 0.72-0.84), 0.84 (95% CI: 0.79-0.91), 4.61 (95% CI: 3.27-6.51), 0.26 (95% CI: 0.20-0.34), 20.82 (95% CI: 11.83-36.64), and 0.89 (95% CI: 0.86-0.91), respectively. For the prognostic values, we found poor survival outcomes based on KD patients (HR = 1.31, 95% CI: 1.07-1.59, P = 0.008). Conclusion: Our meta-analysis suggests that SF may be used as a workable and critical biomarker for the diagnosis and prognosis of IVIG resistance and CALs in patients with KD. We also propose that maintaining the dynamic balance between iron, SF, and ferroptosis will be an important therapeutic strategy to reduce the morbidity of CALs. Systematic review registration: [https://www.crd.york.ac.uk/prospero/], identifier [CRD42022279157].

Sterile Pyuria in Kawasaki Disease: A Large Prospective Cohort Study.

Background: Kawasaki disease (KD) is an acute systemic vasculitis and is becoming the leading cause of acquired cardiac disease in Children. Sterile pyuria is a known complication of KD. However, its associations with the inflammatory reaction severity, IVIG resistance as well as coronary artery lesions (CALs) in KD remain elusive. Aims: We aimed to analyze the clinical profiles of sterile pyuria in KD, to determine whether sterile pyuria is an indicator of the disease severity in patients with KD, and to assess the associations between sterile pyuria and IVIG resistance as well as CALs. Methods: We prospectively collected data from 702 patients with KD between January 2015 and June 2020. Profiles of patients with sterile pyuria (group A, n = 63) were compared to those of patients without sterile pyuria (group B, n = 639). The associations between sterile pyuria and IVIG resistance as well as CALs in KD were further determined by univariate and/or multivariate logistic regression analysis. Results: Sterile pyuria was observed in 9.0% of patients with KD, without predominance in age spectrum and gender. The levels of neutrophil percentages, alanine transaminase, total bilirubin, blood urea nitrogen, creatinine, the incidence of initial IVIG resistance, and rate of moderate/giant coronary artery aneurysms (CAAs) were significantly higher in group A than that in group B. Sterile pyuria was identified as an independent risk factor for initial IVIG resistance, yielding high specificity (92.7%) and low sensitivity (18.5%). However, sterile pyuria was not associated with repeated IVIG resistance and persistence of CALs in KD. Conclusion: The incidence of sterile pyuria is relatively low in KD patients. Patients with sterile pyuria in KD exhibited a more severe inflammatory burden and were more likely to develop the initial IVIG resistance and moderate/giant CAAs. The overall prognosis of KD patients with sterile pyuria was satisfactory.

Predictive role of sampling-time specific prognostic nutritional index cut-off values for intravenous immunoglobulin resistance and cardiovascular complications in Kawasaki disease.

BACKGROUND: Intravenous immunoglobulin (IVIG) resistance and cardiovascular complications prediction are pivotal topic of interests in Kawasaki disease (KD). The prognostic nutritional index (PNI) has been proposed to be valuable in predicting the severity of inflammatory status and prognosis in clinical circumstances, with limited data in KD. Therefore, we prospectively investigated the role of sampling-time specific PNI cut-off values in predicting initial IVIG resistance as well as cardiovascular complications in patients with KD for the first time. METHODS: A total of 755 patients with KD were prospectively recruited between January 2015 and December 2019. Patients with KD were subgrouped based on the presence of IVIG resistance or cardiovascular complications. The clinical and laboratory parameters were compared. Multivariate logistic regression analysis was performed to identify the independent risk factors for IVIG resistance and cardiovascular complications. The receiver operating characteristic (ROC) curve was further applied to assess the predictive values of PNI in IVIG resistance and cardiovascular complications. RESULTS: The lower level of PNI was identified as independent risk factors for initial IVIG resistance and cardiovascular complications. The discriminating cut-off values of the PNI for IVIG resistance, all cardiovascular complications, CALs, KDSS and myocarditis were 47.8, 52.2, 38.6, 48.2 and 52.0, with the corresponding sensitivities of 0.573, 0.679, 0.174, 0.750, 0.851, and specificities of 0.753, 0.549, 0.957, 0.679 and 0.576, respectively. After sampling time stratification, the sensitivities and specificities of the PNI obtained at the sixth day from fever onset for prediction of both IVIG resistance (0.778, 0.787) and all cardiovascular complications (0.667, 0.753) remarkably improved. CONCLUSION: PNI may serve as a promising predictor for KDSS in patients with KD. PNI obtained at sixth day from fever onset possess good predictive power for both IVIG resistance and all cardiovascular complications in KD.

Risk Factors for Resistance to Intravenous Immunoglobulin Treatment and Coronary Artery Abnormalities in a Chinese Pediatric Population With Kawasaki Disease: A Retrospective Cohort Study.

Background: The factors predicting high-risk Kawasaki disease (KD) remain unclear. Therefore, we aimed to determine the risk factors for resistance to intravenous immunoglobulin (IVIG) treatment and coronary artery aneurysm (CAA) development in a Chinese pediatric population with high-risk KD. Methods: We compared the performances of 11 scoring systems that have been reported to predict IVIG resistance among patients with KD hospitalized from January 2013 through August 2021. Patients were risk-stratified based on the optimal scoring system. The association of baseline characteristics with IVIG treatment resistance and CAA development was investigated within the high-risk group of KD. Results: In total, 346 pediatric patients with KD were included, of whom 63 (18.2%) presented with IVIG resistance. The Kobayashi score and five Chinese scoring system scores (Tang et al., Yang et al., Lan et al., Liping et al., and Wu et al.) were significantly higher in the IVIG non-responsive KD group than in the IVIG responsive KD group, and the results of the receiver operating characteristic (ROC) curves analysis were observed to be highest in the Xie Liping scoring system for IVIG resistance (area under the curve, 0.650). Especially, 87 (25.1%) patients comprised the high-risk KD group based on this optimal scoring system (≥5 points). IVIG resistance was significantly associated with the total bilirubin-to-albumin ratio (B/A ratio) [odds ratio, 7.427; 95% confidence interval (CI): 1.022-53.951]. The area under the ROC was 0.703 (95% CI: 0.586-0.821), and the cutoff point was 0.383, which indicated a sensitivity and specificity for predicting treatment resistance of 58% and 80%, respectively. The serum albumin level (odds ratio, 1.401; 95% CI: 1.049-1.869) and Z score of the left main coronary artery (odds ratio, 9.023; 95% CI: 1.070-76.112) were independent predictors of CAA development. Conclusions: In the Chinese pediatric population with KD, the Xie Liping scoring system is the most appropriate method for identifying high-risk patients, and IVIG resistance could be predicted based on the B/A ratio. Serum albumin level and Z score of the left main coronary artery at baseline were warning indicators for CAA development. More intensified or adjunctive therapies and close follow-up should be considered for high-risk patients with these risk factors.

Nomogram to predict risk of resistance to intravenous immunoglobulin in children hospitalized with Kawasaki disease in Eastern China.

OBJECTIVE: We aimed to develop a nomogram to predict risk of resistance to intravenous immunoglobulin (IVIG) in children with Kawasaki disease in eastern China. METHODS: We retrospectively analysed the data of children with Kawasaki disease who received IVIG during hospitalisation at Soochow University Affiliated Children's Hospital. IVIG resistance was defined as recrudescent or persistent fever ≥36 h after the end of the IVIG infusion. Baseline variables were analysed using least absolute shrinkage and selection operator (LASSO) to identify the predictors of IVIG resistance, which were then used to construct a predictive nomogram. Calibration curve and area under the receiver operating characteristic curve (AUC) were used to evaluate the performance of the model. The predictive nomogram was validated on test sets of external data and prospective data. RESULTS: Between January 2015 and December 2020, 1293 Kawasaki disease patients were hospitalized in Soochow University Affiliated Children's Hospital. Among them, 72 (5.57%) showed IVIG resistance. LASSO identified haemoglobin, percentage of neutrophils, C-reactive protein level, platelet count, serum albumin, serum sodium, serum alkaline phosphatase, coronary artery damage, and complete Kawasaki disease as risk factors for IVIG resistance. The nomogram constructed using these factors showed satisfactory discriminatory power (AUC, 0.75), and sensitivity (0.74) and specificity (0.64). In the external data and prospective data, the AUC was 0.66 and 0.83, respectively, the sensitivity was 0.86 and 1, respectively, and the specificity was 0.49 and 0.60, respectively. CONCLUSIONS: The predictive nomogram constructed using nine factors associated with IVIG resistance in children with Kawasaki disease could be a useful tool for identifying patients likely to show IVIG resistance. This nomogram may help reduce the risk of coronary artery lesions.Key MessagesNone of the IVIG resistance scoring systems has shown consistently good performance in previous studies. Tools to predict the risk of IVIG resistance in eastern China are lacking.In our series, haemoglobin level, percentage of neutrophils, platelet count, coronary artery damage, incomplete Kawasaki disease, and CRP, serum albumin, serum sodium, and serum alkaline phosphatase levels were risk factors of IVIG resistance in hospitalized children in the eastern China cities of Suzhou and Fuzhou.We propose an easy-to-use nomogram to predict the risk factors of IVIG resistance in hospitalized children.

Association between serum miR-221-3p and intravenous immunoglobulin resistance in children with Kawasaki disease.

OBJECTIVES: Intravenous immunoglobulin (IVIG) resistance was a major cause of coronary artery lesions in children with Kawasaki disease (KD). However, the cause of IVIG resistance in KD remains unknown. miR-221-3p has been confirmed involved in cardiovascular diseases and rheumatoid arthritis. The purpose of this study was to investigate the association between miR-221-3p and IVIG resistance in children with KD. METHODS: Fifty-five KD patients and 29 healthy controls (HCs) were enrolled in this study. KD patients were divided into group of sensitive to IVIG (IVIG-response, n = 42) and group of resistant to IVIG (IVIG-resistance, n = 13), group of 10 KD patients with coronary artery lesions (CALs, KD-CALs) and group of 10 sex- and age-matched KD patients without CALs (KD-NCALs). Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) was used to detect the levels of miR-221-3p. RESULTS: Compared with the HCs group, miR-221-3p were significantly increased in the KD group (p < 0.05), and the IVIG-resistance group had higher levels of miR-221-3p than those in the IVIG-response group (p < 0.05). CRP (C-reactive protein), PCT (procalcitonin), NLR (neutrophil-lymphocyte ratio) were positively correlated with miR-221-3p in KD patients. In addition, the group of IVIG resistance had a higher level of Kobayashi Score (p < 0.001). The receiver operating characteristic curve showed that miR-221-3p had a better value for diagnosis IVIG resistance in children with KD than Kobayashi Score with the AUC of 0.811 (95% CI, 0.672-0.951), 0.793 (95% CI, 0.618-0.968), respectively. Additionally, miR-221-3p was elevated (p < 0.05) and showed an AUC value of 0.83 (95% CI, 0.648-1.000, p < 0.05) for the prediction of the complication of coronary artery abnormalities in the group of KD with CALs. CONCLUSIONS: miR-221-3p might be involved in the pathogenesis of KD and IVIG resistance and miR-221-3p can be used as a new potential biomarker to predict IVIG resistance in children with KD.

A Machine Learning Model to Predict Intravenous Immunoglobulin-Resistant Kawasaki Disease Patients: A Retrospective Study Based on the Chongqing Population.

Objective: We explored the risk factors for intravenous immunoglobulin (IVIG) resistance in children with Kawasaki disease (KD) and constructed a prediction model based on machine learning algorithms. Methods: A retrospective study including 1,398 KD patients hospitalized in 7 affiliated hospitals of Chongqing Medical University from January 2015 to August 2020 was conducted. All patients were divided into IVIG-responsive and IVIG-resistant groups, which were randomly divided into training and validation sets. The independent risk factors were determined using logistic regression analysis. Logistic regression nomograms, support vector machine (SVM), XGBoost and LightGBM prediction models were constructed and compared with the previous models. Results: In total, 1,240 out of 1,398 patients were IVIG responders, while 158 were resistant to IVIG. According to the results of logistic regression analysis of the training set, four independent risk factors were identified, including total bilirubin (TBIL) (OR = 1.115, 95% CI 1.067-1.165), procalcitonin (PCT) (OR = 1.511, 95% CI 1.270-1.798), alanine aminotransferase (ALT) (OR = 1.013, 95% CI 1.008-1.018) and platelet count (PLT) (OR = 0.998, 95% CI 0.996-1). Logistic regression nomogram, SVM, XGBoost, and LightGBM prediction models were constructed based on the above independent risk factors. The sensitivity was 0.617, 0.681, 0.638, and 0.702, the specificity was 0.712, 0.841, 0.967, and 0.903, and the area under curve (AUC) was 0.731, 0.814, 0.804, and 0.874, respectively. Among the prediction models, the LightGBM model displayed the best ability for comprehensive prediction, with an AUC of 0.874, which surpassed the previous classic models of Egami (AUC = 0.581), Kobayashi (AUC = 0.524), Sano (AUC = 0.519), Fu (AUC = 0.578), and Formosa (AUC = 0.575). Conclusion: The machine learning LightGBM prediction model for IVIG-resistant KD patients was superior to previous models. Our findings may help to accomplish early identification of the risk of IVIG resistance and improve their outcomes.

Prediction of repeated intravenous immunoglobulin resistance in children with Kawasaki disease.

BACKGROUND: Repeated intravenous immunoglobulin (IVIG) resistance prediction is one of the pivotal topics in Kawasaki disease (KD). Those non-responders of repeated IVIG treatment might be improved by an early-intensified therapy to reduce coronary artery lesion and medical costs. This study investigated predictors of resistance to repeated IVIG treatment in KD. METHODS: A total of 94 children with IVIG-resistant KD treated at our hospital between January 2016 and August 2020 were retrospectively analyzed. According to the therapeutic effect of a second dose IVIG treatment, the children were divided into repeated IVIG-responsive group and repeated IVIG-resistant group, and the clinical and laboratory data were compared. Predictors of repeated IVIG resistance and the optimal cut-off value were determined by multiple logistic regression analysis and receiver operating characteristic (ROC) curve analysis. RESULTS: The Pre-IVIG laboratory data showed the percentage of neutrophils (N%) and levels of serum procalcitonin (PCT), N-terminal pro-brain natriuretic peptide (NT-proBNP) were significantly higher in repeated IVIG-resistant group compared with repeated IVIG-responsive group, while levels of serum sodium and albumin (ALB) were significantly lower (P < 0.05). The post-IVIG laboratory values of N% and C-reactive protein (CRP) were significantly higher in the repeated IVIG-resistant group compared with repeated IVIG-responsive group, while hemoglobin and ALB were lower (P < 0.05). Pre-IVIG PCT and post-IVIG CRP exhibited AUC of 0.751 and 0.778 respectively in predicting repeated IVIG resistance in KD. Pre-IVIG PCT > 1.81ng/ml (OR 4.1, 95 % CI 1.4 ~ 12.0, P < 0.05) and post-IVIG CRP > 45 mg/L (OR 4.6, 95 % CI 1.3 ~ 16.2, P < 0.05) were independent predictors of repeated IVIG resistance in KD. CONCLUSIONS: Our study illustrates the serum PCT level before initial IVIG treatment and CRP after initial IVIG could be used to predict repeated IVIG resistance in KD.