IVIG-resistant Group Research Articles

Evaluating the performance of egami, kobayashi and sano scores in predicting IVIG resistance in infant kawasaki disease

BackgroundThis study aimed to evaluate the effectiveness of Egami, Kobayashi and Sano scores in predicting intravenous immunoglobulin (IVIG) resistance in infant Kawasaki disease (KD), considering its unique clinical presentation.MethodsWe retrospectively analysed 143 infants aged < 12 months and diagnosed with KD at a single centre from 2019 to 2023. Patients were divided into IVIG-resistant and IVIG-responsive groups. Demographic, clinical and laboratory data were compared between the groups. The diagnostic performance of Egami, Kobayashi and Sano scores in predicting IVIG resistance was evaluated using sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and area under the receiver operating characteristic curve (AUC). Additionally, we developed a new scoring system based on significant predictors identified in our cohort.ResultsAmong 143 infants, 45 (31.5%) showed IVIG resistance. The IVIG-resistant group had a significantly higher rate of coronary artery lesions (15.6% vs. 5.1%, p = 0.036). Incomplete KD was observed in 61.5% of cases. Egami, Kobayashi and Sano scores exhibited low sensitivity (35.6%, 55.6% and 20%, respectively) and moderate specificity (77.6%, 63.3% and 95.9%, respectively) in predicting IVIG resistance. The AUC ranged from 0.583 to 0.674, indicating poor to fair discriminative ability. Our newly developed scoring system, based on total bilirubin and albumin levels, showed similar performance (AUC 0.633) to existing scores.ConclusionsExisting Japanese risk scoring systems and our newly developed score showed limited effectiveness in predicting IVIG resistance in infant KD. The high proportion of incomplete presentation and IVIG resistance in infants highlights the need for age-specific risk assessment and management. Further research is necessary to develop more sophisticated, dedicated prediction model for IVIG resistance in infants with KD.

Explorative case control study on the associations of serum vitamin D3, folic acid and vitamin B12 levels on Kawasaki disease and coronary artery lesions.

Kawasaki Disease (KD) is a pediatric vasculitic disorder characterized by systemic small vasculitis, notably coronary arteritis, with unclear pathogenesis. This explorative case-control study investigated the association between folic acid (FA), vitamin D3 (VD3), and vitamin B12 (VB12) levels and the different types of Kawasaki Disease, as well as the incidence of coronary artery lesions (CALs). In this explorative case control study, 365 KD children admitted to our hospital from January 1, 2022 to June 30, 2023 were included as the KD group. Simultaneously, 365 healthy children who received physical examination during the same period were included as the control group. The KD group was divided into typical KD group and incomplete KD group (IKD group), CALs group and non-CALS group, and IVIG sensitive group and IVIG resistant group. The children with CALs were divided into small tumor group, medium tumor group and large tumor group. Serum levels of FA, VB12, and VD3 were compared across all groups. Serum levels of FA and VD3 were significantly decreased in both the KD and CALs groups (p < 0.05), and both factors were identified as independent risk factors for KD and CALs. Similarly, reduced serum VD3 levels were observed in the IKD and IVIG-resistant groups (p < 0.05), with VD3 also being an independent risk factor for both IKD and IVIG resistance. Additionally, lower serum FA levels were noted in the group with large aneurysms (p < 0.05), establishing FA as an independent risk factor for aneurysm size. Serum levels of folic FA and vitamin VD3 were significantly reduced in children with KD. Furthermore, these reductions were more pronounced in children with IKD and CALs. This pattern suggests that lower FA and VD3 levels may increase the risk of more severe coronary lesions in KD patients. Therefore, monitoring these biomarkers could provide valuable insights for early clinical diagnosis and intervention.

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

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). 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. 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. 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.

Serum amyloid A as a biomarker for immunoglobulin resistance in Kawasaki disease

Background Intravenous immunoglobulin (IVIG) resistance is of prime importance in Kawasaki disease (KD). In this study, we examined the value and mechanism of serum amyloid A (SAA) level in predicting IVIG resistance in patients with KD. Methods SAA levels were measured in 497 consecutive patients with KD before IVIG therapy in the training set. The patients were divided into two groups (IVIG-responsive and IVIG-resistant) according to the American Heart Association (AHA) definition of IVIG resistance. Demographic, echocardiographic, and laboratory data were also retrospectively analyzed and tabulated to predict IVIG resistance. The predictive value of SAA was validated on test sets of prospective data. Cytokine microarrays were analyzed from 4 patients with resistant to IVIG, 4 patients with responsive to IVIG and 4 healthy volunteers. Results During the training set, 409 patients with KD were enrolled, of whom 43 (10.5%) were resistant to initial IVIG treatment and 47 (11.49%) had coronary artery lesions (CALs). Serum levels of SAA were higher in the IVIG resistant group compared to the IVIG responsive group, (380.00 [204.40–547.25] vs 230.85 [105.40–490.00] mg/L; p = .008). The values of total bilirubin, C-reactive protein, neutrophils, alanine aminotransferase, aspartate aminotransferase, interleukin-6(IL-6), and procalcitonin were significantly higher in the IVIG-resistant group than in the IVIG-responsive group (p < .05); however, the lymphocytes, platelets, serum sodium levels, and duration of fever before IVIG therapy were significantly lower (p < .05). There was no significant difference in SAA levels between patients with KD with and without CALs. Binary logistic regression analysis showed that SAA (p = .008), neutrophils (p < .001), total bilirubin (p = .001), platelet count (p = .004), and serum sodium level (p = .019) were independent factors influencing IVIG resistance. The optimal cutoff value of SAA for IVIG resistance prediction was 252.45 mg/L, with a corresponding clinical sensitivity of 69.8% and specificity of 54.4%. Based on receiver operating characteristic (ROC) curve analyses, the area under the curve (AUC) of combined detection with these five indicators was 0.800, clinical sensitivity was 69.8%, and specificity was 76.2%. In the prospective data, the sensitivity, specificity, and accuracy of SAA for identifying IVIG resistance KD were 77.8%,69.0%, and 70.0%, respectively. Compared with IVIG- responsive group and healthy children, the levels of IL-6 was upregulated significantly in IVIG-resistant group through cytokine microarrays. Conclusions SAA may be a potential biomarker for predicting IVIG responsiveness to KD, Combined detection of SAA levels, total bilirubin, neutrophil count, platelet count, and serum sodium levels is superior to that of any other single indicator for predicting IVIG resistance in KD. And elevated SAA may accompany with IL-6 in KD patients, its use in clinical practice may be helpful for treatment management.

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.

Association between Rab31/rs9965664 polymorphism and immunoglobulin therapy resistance in patients with Kawasaki disease.

Kawasaki disease (KD) is an acute febrile systemic vasculitis affecting infants and young children. A high dose of intravenous immunoglobulin (IVIG) is the first-line strategy for patients with KD to reduce persistent inflammation and the risk of coronary artery aneurysm (CAA) formation. Unfortunately, 10-20% of the patients showed no response to the treatment and were defined as resistant to IVIG. Rab31 has been reported to regulate innate immunity in several human diseases. However, whether single nucleotide polymorphism (SNP) in Rab31 gene could predispose to IVIG therapy response in KD was uncovered. Rab31/rs9965664 polymorphism was genotyped in 1,024 Chinese patients with KD through TaqMan assay. The odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to assess the strength of association between Rab31/rs9965664 polymorphism and IVIG therapeutic effects. Our results showed that Rab31/rs9965664 AA/GA genotype was significantly associated with an increased risk of IVIG resistance compared to GG genotype (GA vs. GG: p = 0.0249; AA vs. GG: p = 0.0016; AA/GA vs. GG: p = 0.0039; and AA vs. GG/GA: p = 0.0072). Moreover, the KD individuals carrying the rs9965664 A allele displayed lower Rab31 protein levels, and the expression level of Rab31 in the IVIG-resistant group was decreased significantly when compared to that observed in the response group. A mechanical study demonstrated that Rab31 modulated IVIG response through NLRP3 and p38 pathways. These results suggested that Rab31/rs9965664 polymorphism might be associated with an increased risk of IVIG resistance in southern Chinese patients with KD. The possible mechanism is that Rab31 regulates the NLRP3 pathway negatively to inhibit IVIG response.

Evaluation of laboratory predictors for intravenous immunoglobulin resistance and coronary artery aneurysm in Kawasaki Disease before and after therapy

ObjectivesWe aimed to evaluate the clinical and laboratory characteristics of patients with Kawasaki disease (KD) before and after therapy.MethodsPatients with KD were divided into different groups according to their responsiveness to initial intravenous immunoglobulin (IVIG) treatment and coronary status. The clinical and laboratory parameters before and after therapy were compared. Multivariate analysis was performed to identify the independent risk factors, and the receiver operating characteristic (ROC) curve was applied to assess and compare the prediction ability of risk factors and their fluctuations.ResultsOf the 153 patients included in the study, 41 (26.8%) had IVIG resistance and 37 (24.2%) had developed CAA. After stratifying by therapy response, the two groups differed in the levels of total bilirubin (TSB), albumin, and sodium, neutrophil-to-lymphocyte count ratio (NLR), platelet-to-lymphocyte count ratio (PLR), TSB-to-albumin (B/A) ratio, and prognostic nutritional index (PNI) before IVIG, and in the white blood cell count (WBC), neutrophil count, levels of hemoglobin, C-reactive protein (CRP), alanine aminotransferase (ALT), and albumin, NLR, PNI, capillary leakage index (CLI), and systemic immune-inflammation index (SII) after IVIG. Multivariate analysis revealed that the B/A ratio before IVIG and CLI and SII after IVIG were significantly and positively associated with IVIG resistance and that there was a larger decline in the B/A ratio and smaller decline in CLI and SII pre- and post-treatment in the IVIG-resistant group than in the IVIG-responsive group. However, no statistical differences in the fluctuations of the B/A ratio, CLI, and SII as well as all parameters before and after therapy were observed in patients with and without CAA. ROC curve analyses found a greater AUC value of post-treatment parameters (0.751 and 0.706 for CLI and SII, respectively) compared with pre-treatment parameters (0.654 for B/A ratio) in predicting IVIG resistance; however, the predictive ability of the fluctuations in risk factors before and after therapy was not superior to that of baseline values.ConclusionsThe B/A ratio before IVIG and CLI and SII after IVIG were risk factors for IVIG resistance in patients with KD, independent of CAA development.Key Points• A high total bilirubin-to-albumin ratio before IVIG and high capillary leakage and systemic immune-inflammation indices after IVIG may indicate an increased risk of intravenous immunoglobulin resistance in patients with Kawasaki disease.• Post-treatment parameters were superior to pre-treatment parameters in terms of prediction; therefore, rapid and repeated assessment of risk factors before and after treatment must be considered in children in whom the vital signs and symptoms do not improve after treatment.

Circulating Immune Cell Profile and Changes in Intravenous Immunoglobulin Responsiveness Over the Disease Course in Children With Kawasaki Disease.

Kawasaki disease (KD) is an acute, self-limited febrile illness of young children. The etiology of KD remains to be poorly understood. There has been limited research on longitudinal examination of peripheral blood leukocytes for immune profiling particularly in relation to treatment response with intravenous immunoglobulin (IVIG). This study profiles immune cells at the time of diagnosis and over the disease course. In addition, we identified the characteristics of the immune cells in IVIG-responsive patients with KD. We enrolled patients diagnosed with KD between May 1, 2017, and January 1, 2020. Blood was taken at least three times from all enrolled patients: at diagnosis (before IVIG infusion) and immediately and 2 weeks after IVIG infusion. We evaluated the laboratory findings and results of flow cytometry analysis of immune cells at all stages, focusing on CD4+ T lymphocytes, CD8+ T lymphocytes, CD19+ B lymphocytes, granulocytes, classical monocytes, and natural killer (NK) cells. Non-febrile healthy controls (NFCs) and other febrile controls (OFCs) were also enrolled. A total of 68 patients were enrolled and divided into two groups according to IVIG resistance status: IVIG-responsive (n = 55) and IVIG-resistant (n = 13). The total fever duration was significantly longer in the IVIG-resistant group (9.7 ± 5.3 days) than in the IVIG-responsive group (6.7 ± 3.0 days; P = 0.02). There was a significant difference in intermediate CD14+CD16+ monocytes between KD patients and both NFC and OFCs; they were significantly higher and lower in KD patients than NFC and OFCs, respectively (P < 0.001). The levels of all three subtypes of NK cells were significantly lower in KD patients than in both NFC and OFCs (P < 0.001). Regarding IVIG responsiveness, CD14+CD16+ intermediate monocyte levels were significantly lower in the IVIG-resistant group (P < 0.001). In addition, CD56−CD16+ NK cell expression was significantly lower in the IVIG-resistant group than in the IVIG-responsive group (P = 0.002). In conclusion, our results suggest CD56−CD16+N NK cells and CD14+CD16+ intermediate monocytes might play an essential role in immunopathogenesis of KD. Further studies are warranted to explore the role of these subpopulations particularly for the observed association with coronary artery lesions (CAL) and treatment response.

Correlation between the Level of Inflammatory Cytokines and Prognosis in Children with IVIG-sensitive Kawasaki Disease and IVIG-resistant Kawasaki Disease.

Objectives:To investigate whether the levels of interleukin 1β (IL-1β), interferon γ (IFN-γ), tumor necrosis factor α (TNF-α) in children with Kawasaki disease (KD) are correlated with coronary artery lesion (CAL) and resistance to intravenous immunoglobulin (IVIG) treatment.Methods:A total of 216 children in line with KD diagnostic criteria were continuously included as subjects, and 50 healthy children at the same period were selected as the control group, and their levels of IL-1β, IFN-γ, and TNF-α were detected.Results:Subjects were subdivided according to the presence or absence of CAL: 42 cases (19.4%) of 216 children with KD developed CAL and were subdivided into the CAL group, while 174 (80.6%) of those who did not develop CAL were subdivided into the NCAL group. The levels of IL-1β, IFN-γ, and TNF-α in the CAL group and the NCAL group were higher than those in the control group (P<0.05), and the levels of those in the CAL group were higher than those in the NCAL group (P<0.05). Subjects were subdivided according to the effect of IVIG treatment: 194 cases (89.8%) of 216 children with KD had a good control of inflammation after the initial IVIG treatment, and were considered to have IVIG-sensitive KD and divided into the IVIG-sensitive group; 22 cases (10.2%) could not get good control of inflammation after the initial IVIG treatment, and were considered to have IVIG-resistant KD and divided into the IVIG-resistant group. The levels of IL-1β, IFN-γ, and TNF-α in the IVIG-sensitive group and the IVIG-resistant group were higher than those in the control group; The levels of IL-1β, IFN-γ, and TNF-α in the IVIG-resistant group were higher than those in the IVIG-sensitive group (P<0.05), while the fever time of the IVIG-sensitive group was lower than that of the IVIG-resistant group (P<0.05).Conclusion:Children with KD may experience changes in IL-1β, IFN-γ, and TNF-α levels in the acute phase. Such a significant increase in levels may be a risk factor for CAL and resistance to IVIG treatment in children with KD, while the prolonged fever time is a risk factor for resistance to IVIG treatment in children with KD.

Predictive value of serum ferritin and a new predictive model for intravenous immunoglobulin resistance in Kawasaki disease

Objective: To evaluate the predictive value of serum ferritin (SF) and construct a novel predictive model for intravenous immunoglobulin (IVIG)-resistant Kawasaki disease (KD) (IVIGRKD). Methods: The clinical data of 422 children with KD from January 2017 to December 2019 in Quanzhou Women's and Children's Hospital were retrospectively analyzed. According to the response to IVIG, they were divided into IVIG-resistant group and IVIG-sensitive group. Forty-one clinical indicators including general characteristics and laboratory results were compared between the two groups. Comparisons between groups were performed with unpaired Student t test or Mann-Whitney U test or chi-square test. Receiver operating characteristic (ROC) curve was applied to evaluate the predictive value of SF for IVIGRKD. Binary Logistic regression analysis was used to test whether SF was an independent risk factor for IVIGRKD. Meanwhile, a novel predictive scoring system was established. The comparisons between the new predictive scoring system with four commonly used prediction scoring systems were conducted. Results: A total of 422 KD cases (285 males and 137 females, 17.0 (9.0,29.0) years of age) were enrolled and divided into IVIG-resistant group (n=57) and IVIG-sensitive group (n=365). Seventeen clinical indicators differed significantly between the two groups. SF level of the IVIG-resistant group was significantly higher than that of the sensitive group (245.0 (131.0, 519.0) vs. 145.0 (92.5, 232.5) μg/L, Z=-5.109, P<0.05). ROC curve showed that the Youden index of SF for predicting IVIGRKD was 0.326 (cutoff value 403.5 μg/L). Binary logistic regression analysis showed that SF, days of illness at initial IVIG treatment, cervical lymphadenopathy, pleomorphic rash, white blood cell, C-reactive protein (CRP), activated partial thromboplastin time (APTT), alanine transaminase (ALT) and creatinine were independent risk factors for IVIGRKD. A novel prediction model was constructed, and the cutoff points and score points were as follows: pleomorphic rash, 2 points; cervical lymphadenopathy, 1 point; SF≥ 403.5 μg/L, 1 point; white blood cell ≥ 18.3×109/L, 1 point; CRP≥83.1 mg/L, 1 point; APTT≥25.3 s, 1 point; ALT≥37.5 U/L, 1 point. And patients with scores of 4 or more were at high-risk for IVIGRKD. The Youden index of the four commonly used scoring systems ranged from 0.315 to 0.512. However, the Youden index of the new scoring system was 0.695 (sensitivity 0.772, specificity 0.923) and was the highest among the five scoring systems. Conclusions: SF shows well predictive efficiency for IVIGRKD and is an independent risk factor for IVIGRKD. SF can be used as a new predictor of IVIGRKD.

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

BackgroundRepeated 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.MethodsA 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.ResultsThe 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.ConclusionsOur 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.

The \u201cIntermediate\u201d CD14\u2009+\u2009CD16\u2009+\u2009monocyte subpopulation plays a role in IVIG responsiveness of children with Kawasaki disease

BackgroundKawasaki disease (KD) is an acute, self-limited febrile illness of unknown cause. Intravenous immunoglobulin (IVIG)-resistance are related to greater risk for permanent cardiac complications. We aimed to determine the correlation between monocytes and the phenotype of KD in relation to IVIG responsiveness in children.Materials and methods The study cohort included 62 patients who were diagnosed with KD, 20 non febrile healthy controls (NFC), and 15 other febrile controls (OFC). In all enrolled patients, blood was taken at least 4 times and laboratory tests were performed. In addition, subtypes of monocytes were characterized via flow cytometry.ResultsThe numbers of intermediate monocytes were significantly lower in IVIG-resistant group compared to IVIG-responsive group before IVIG infusion (p < 0.0001). After infusion, intermediate monocytes decreased in the responsive group, while a trend of increase was observed in the resistant group. Only intermediate monocytes were significant in logistic regression with adjusted OR of 0.001 and p value of 0.03.ConclusionsCD14 + CD16 + intermediate monocyte may play an important role in IVIG responsiveness among KD children. Low starting levels of intermediate monocytes, followed by a dramatic increase post-IVIG infusion during acute phase of KD are associated with IVIG-resistance. Functional studies on intermediate monocyte may help to reveal the pathophysiology.

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.

Predictive value of coagulation profiles for both initial and repeated immunoglobulin resistance in Kawasaki disease: A prospective cohort study.

BackgroundIntravenous immunoglobulin (IVIG) resistance prediction remains substantial in Kawasaki disease (KD), with limited data on the predictive value of coagulation profile for IVIG resistance, particularly for repeated IVIG resistance. Therefore, the aim of our study was to testify the predictive validity of coagulation profile for both initial IVIG resistance and repeated IVIG resistance in KD.MethodsA total of 385 KD patients were prospectively recruited between April 2015 and May 2019. Coagulation and other profiles were evaluated between the IVIG‐responsive and IVIG‐resistant groups. Multivariate logistic regression analysis was applied to determine the association between coagulation profiles and IVIG resistance. ROC curves analysis was further performed to assess the validity of coagulation profiles in predicting both initial IVIG resistance and repeated IVIG resistance.ResultsProthrombin time (PT), activated partial thromboplastin time (APTT), international normalized ratio (INR), fibrinogen degradation products (FDPs), and D‐dimer were significantly increased in the initial IVIG‐resistant group with antithrombin III (ATIII) and thrombin time (TT) significantly reduced. Meanwhile, ATIII was declined markedly in repeated IVIG‐resistant patients. Multivariate logistic regression analysis showed that PT, APTT, D‐dimer, and ATIII were independent risk factors for predicting initial IVIG resistance and ATIII for predicting repeated IVIG‐resistant patients with KD. PT, APTT, D‐dimer, and ATIII cutoff values of 13.95 s, 41.15 s, 1.48 mg/L, and 89.5% yielded sensitivities of 73%, 32%, 71%, and 81%, and specificities of 55%, 88%, 62%, and 51% for predicting initial IVIG resistance, respectively. The cutoff value of ATIII for predicting repeated IVIG resistance was 68.5%, with sensitivity of 71% and specificity of 55%.ConclusionsKD patients who have hypercoagulation during the acute phase might be at higher risk of developing IVIG resistance.

The combination of the neutrophil-to-lymphocyte and platelet-to-lymphocyte ratios as a novel predictor of intravenous immunoglobulin resistance in patients with Kawasaki disease: a multicenter study.

The neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) have been reported to be a predictor for intravenous immunoglobulin (IVIG) resistance in patients with Kawasaki disease (KD) recently. The objective of the present study was to elucidate the predictive validity of this new marker in a multicenter study. We retrospectively reviewed the clinical records of 520 consecutive KD patients (development data set) and 332 subsequent patients (validation data set) at 7 hospitals in Japan. Both NLR and PLR were significantly higher in the IVIG-resistant group than in the IVIG-responsive group. When we set the cut-off point as NLR ≥ 4.11 and PLR ≥ 119, multiple logistic regression analyses showed that a high NLR and PLR before initial IVIG were independent predictors of IVIG resistance, and their combination was a stronger predictor than either alone. The sensitivity and specificity of the combination of NLR ≥ 4.11 and PLR ≥ 119 were 0.58 and 0.73 in the development data set. Validated using an independent data set, they were 0.54 and 0.72 in the validation data set. On comparing the AUC of this predictor with those of the Gunma and Kurume scores, the AUC was highest for this predictor, followed by the Gunma score and Kurume score (0.70, 0.68, and 0.64, respectively). The predictive validity of the combination of a high NLR and PLR, which is a simple and convenient indicator, was equal to or better than that of the existing scoring systems. The new predictive marker may be a suitable indicator for predicting IVIG resistance in KD patients.

Prediction of intravenous immunoglobulin resistance in Kawasaki disease in children.

We aimed to explore predictive measures for intravenous immunoglobulin (IVIG) resistance in children with Kawasaki disease (KD). Patients diagnosed with KD were enrolled in this study. Univariate analysis and multiple logistic regression were utilized to analyze the clinical features and laboratory results prior to IVIG-treatment of the two groups. Independent predictors of IVIG resistance were analyzed, and a predictive model for KD children with IVIG resistance was constructed. A total of 277 children with KD, 180 boys and 97 girls, aged 2-128 (median 23) months, were enrolled in the study. Compared with the IVIG-responsive group, the IVIG-resistant group had higher levels of the peripheral neutrophil count, mean platelet volume, mean platelet volume-to-lymphocyte ratio and C-reactive protein, and total serum bilirubin, but lower levels of peripheral lymphocyte count, serum albumin and serum prealbumin. Age (in months), peripheral neutrophil count, lymphocyte count and mean platelet volume and serum albumin were independent indicators for IVIG resistance by multivariate logistic regression analysis. A logistic regression model and a scoring system were set up, where cut-off values of -0.46 and 6.5 points yielded sensitivities of 83.9% and 77.4%, and specificities of 74.8% and 61.0%, respectively. The areas under the curve (AUC) were 0.808 in the logistic regression model, and 0.750 in the scoring system. Our model for predicting IVIG-resistant children with KD, involving age (months), peripheral neutrophil count, lymphocyte count and mean platelet volume and serum albumin prior to IVIG-treatment, is helpful for clinical prediction of children with IVIG-resistant KD.

A New Scoring System for Prediction of Intravenous Immunoglobulin Resistance of Kawasaki Disease in Infants Under 1-Year Old.

Background: Children with Kawasaki disease (KD) under 1-year old are at high risk for intravenous immunoglobulin (IVIG) resistance. The study was designed to explore the predictive measure of IVIG resistance in infants under 1-year old with KD.Methods: This study enrolled children under 1-year old suffering from KD in Peking University First Hospital and Wuhan Children's Hospital. All infants were divided into IVIG-responsive and IVIG-resistant groups. The differences in demographic characteristics, clinical features, and laboratory examinations were compared and the risk factors of IVIG resistant KD were analyzed. Furthermore, a scoring system was developed for predicting IVIG resistance in KD infants and an external validation was performed.Result: A total of 282 infants (194 boys, median age of 7.0 months) were enrolled in this study, of whom 23 children were IVIG-resistant. Compared with IVIG-responsive infants, those in the IVIG-resistant group had a high neutrophil-to-lymphocyte ratio (NLR), high platelet-to-lymphocyte ratio (PLR), high mean platelet volume-to-lymphocyte ratio (MPVLR) in peripheral blood, and low serum albumin, and low serum sodium before IVIG therapy (all P < 0.01). Multiple regression analysis indicated that high levels of peripheral NLR and MPVLR, and low levels of serum albumin and serum sodium were independent risk factors for IVIG resistant KD infants. A scoring system, which included peripheral NLR ≥ 2.69 (1 point), MPVLR ≥ 2.78 (1 point), serum albumin ≤ 30.7 g/L (1 point), and serum sodium ≤ 135.2 mmol/L (1 point), was established. A cut-off value of a total score of 2 points or higher yielded a sensitivity of 87.0% and a specificity of 78.4%, with an area under the curve of 0.891. External validation with clinical diagnostic standard showed that a cut-off value of total score of 2 points or higher for predicting the IVIG-resistance yielded a sensitivity of 70.0% and a specificity of 75.1%.Conclusion: For the first time, we proposed a predictive model of IVIG resistance in KD infants under 1-year old. The scoring system, which accounts for baseline peripheral NLR, MPVLR, and serum albumin and sodium, predicts with relatively high sensitivity and specificity for IVIG-resistant infants with KD under 1-year old.

Predictive value of serum procalcitonin for both initial and repeated immunoglobulin resistance in Kawasaki disease: a prospective cohort study

BackgroundIntravenous immunoglobulin (IVIG) resistance prediction is one pivotal topic of interests in Kawasaki disease (KD) since those patients with KD resistant to IVIG might improve of an early-intensified therapy. Data regarding predictive value of procalcitonin (PCT) for IVIG resistance, particularly for repeated IVIG resistance in KD was limited. This study aimed to testify the predictive validity of PCT for both initial and repeated IVIG resistance in KD.MethodsA total of 530 KD patients were prospectively recruited between January 2015 and March 2019. The clinical and laboratory data were compared between IVIG-responsive and IVIG-resistant groups. Multivariate logistic regression analysis was applied to determine the association between PCT and IVIG resistance. Receiver operating characteristic (ROC) curves analysis was further performed to assess the validity of PCT in predicting both initial and repeated IVIG resistance.ResultsThe serum PCT level was significantly higher in initial IVIG-resistance group compared with IVIG-response group (p = 0.009), as well as between repeated IVIG responders and nonresponders (p = 0.017). The best PCT cutoff value for initial and repeated IVIG resistance prediction was 1.48 ng/ml and 2.88 ng/ml, respectively. The corresponding sensitivity was 53.9 and 51.4%, while the specificity were 71.8 and 73.2%, respectively. Multivariate logistic regression analysis failed to identify serum PCT level as an independent predictive factor for both initial and repeated IVIG resistance in KD.ConclusionsSerum PCT levels were significantly higher in IVIG nonresponders, but PCT may not be suitable as a single marker to accurately predict both initial and repeated IVIG resistance in KD.

Dynamics of immunocyte activation during intravenous immunoglobulin treatment in Kawasaki disease

Objectives: Kawasaki disease (KD) is a systemic vasculitis of early childhood. Intravenous immunoglobulin (IVIG) is the standard treatment for KD. However, IVIG is not effective in approximately 15% of children with KD, and the mechanisms for this are unclear. We investigated changes in monocyte and T-cell activation from pre- to post-IVIG in IVIG-effective and IVIG-resistant KD.Method: We analysed peripheral CD14+CD16+ cells and human leucocyte antigen-DR (HLA-DR) expression on CD4+ and CD8+ cells in 46 children with KD who were admitted to Yamaguchi University Hospital between January 2011 and May 2016. We compared the kinetics in the absolute numbers of CD14+CD16+ cells, CD4+HLA-DR+ cells, and CD8+HLA-DR+ cells before and after IVIG treatment between IVIG-effective and IVIG-resistant groups.Results: Among the 46 subjects, 30 had IVIG-effective KD and 16 had IVIG-resistant KD. The absolute number of CD14+CD16+ cells in the IVIG-effective group decreased significantly after IVIG, while that in the IVIG-resistant group showed no change after IVIG. The absolute number of CD4+HLA-DR+ cells increased significantly after IVIG in both groups. The absolute number of CD8+HLA-DR+ cells before IVIG was low and significantly increased after IVIG in the IVIG-resistant group, while that in the IVIG-effective group showed no change after IVIG.Conclusions: Our results suggest that insufficient control of monocyte suppression and T-cell activation, especially in terms of the CD8-related immune system, are associated with IVIG resistance. The restoration of T-cell suppression may be important for KD recovery. These findings provide insight into the mechanism of IVIG resistance.