Initial Intravenous Immunoglobulin Research Articles

Predictive indicators and risk model construction for coronary artery lesions in Kawasaki disease children over 5 years old

To study predictive indicators for coronary artery lesions (CAL) and construct a risk prediction model for CAL in Kawasaki disease (KD) children over 5 years old. A retrospective analysis of KD children over 5 years old at Wuhan Children's Hospital of Tongji Medical College of Huazhong University of Science and Technology from January 2018 to January 2023 was conducted. Among them, 47 cases were complicated with CAL, and 178 cases were not. Multivariate logistic regression analysis was used to explore predictive indicators for CAL in KD children over 5 years old and construct a risk prediction model. The receiver operating characteristic curve was used to evaluate the effectiveness of the prediction model. Finally, the Framingham risk scoring method was used to quantify the predictive indicators, calculate the contribution of each indicator to the prediction of CAL in KD children over 5 years old, and construct a risk prediction scoring model. The multivariate logistic regression analysis showed that the duration of fever before the initial intravenous immunoglobulin (IVIG) treatment (OR=1.374, 95%CI: 1.117-1.689), levels of hypersensitive C-reactive protein (hs-CRP; OR=1.008, 95%CI: 1.001-1.015), and serum ferritin levels (OR=1.002, 95%CI: 1.001-1.003) were predictive indicators for CAL in KD children over 5 years old. The optimal cutoff values for predicting CAL were: duration of fever before initial IVIG treatment of 6.5 days (AUC=0.654, 95%CI: 0.565-0.744), hs-CRP of 110.50 mg/L (AUC=0.686, 95%CI: 0.597-0.774), and ferritin of 313.62 mg/L (AUC=0.724, 95%CI: 0.642-0.805). According to the Framingham risk scoring method, the low, medium, and high-risk states of CAL occurrence were defined as probabilities of <10%, 10%-20%, and >20%, respectively, with corresponding scores of 0-4 points, 5-6 points, and ≥7 points. In KD children over 5 years old, those with a longer duration of fever before initial IVIG treatment, higher levels of hs-CRP, or elevated serum ferritin levels are more likely to develop CAL.

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.

Hemolytic anemia associated with intravenous immunoglobulin in Kawasaki disease

BackgroundThe administration of high-dose intravenous immunoglobulin (IVIG) is a standard treatment for the management of Kawasaki disease (KD). IVIG is known to be a highly effective and safe treatment.Case presentationWe report the development of hemolytic anemia in seven children receiving repeated doses of IVIG. The children were aged 3–44 months and included 4 girls and 3 boys. All children received 10% IVIG and a second course of immunoglobulin because they did not respond to the first course of immunoglobulin. Two received high-dose aspirin (50 mg/kg), and five received low-dose aspirin (5 mg/kg). Two patients required additional methylprednisolone pulse therapy (30 mg/kg) after the second dose of immunoglobulin, and three patients received oral prednisolone therapy for defervescence. Three patients showed coronary artery dilation during hospitalization and normalized within two months. Pretreatment hemoglobin averaged 11.3–14.2 g/dL, and post-hemolytic anemia hemoglobin ranged from 7.4 to 9.6 g/dL, with a difference of 1.7–6.8 g/dL. Reticulocytes were increased to 3.3–13.2%. Peripheral blood smears showed normochromic normocytic anemia, and anisopoikilocytosis. All children were positive for warm-type antibodies with IgG+, C3d- in direct antiglobulin test, and the blood group was A + in five and B + in two. None of the patients received immunomodulatory therapy or red blood cell transfusions. They were followed for a year and all recovered.ConclusionEspecially, in non-O blood group KD patients who are refractory to initial IVIG and require a second dose of IVIG or 10% formulation the possibility of immune hemolytic anemia should be carefully considered, and close follow-up should be maintained after therapy.

Initial intravenous immunoglobulin therapy without aspirin for acute Kawasaki disease: a retrospective cohort study with a Bayesian inference

ObjectiveTo clarify the necessity of acetylsalicylic acid (ASA) administration combined with intravenous immunoglobulin (IVIG) therapy in the treatment of acute Kawasaki disease.DesignRetrospective cohort study.SettingMulticentre.ParticipantsThis study included 735 patients with Kawasaki...

The efficacy and safety of intravenous immunoglobulin infusion in 12 h for the initial treatment of Kawasaki disease

BackgroundApproximately 10–20 % of individuals develop a recrudescent or persistent fever after intravenous immunoglobulin (IVIG) infusion for the initial treatment of Kawasaki disease. The aim of this study was to evaluate the efficacy and safety of the initial IVIG treatment of Kawasaki disease based on duration of infusion. MethodsThis retrospective, single-center study included 53 patients with Kawasaki disease who were initially treated with 2 g/kg of IVIG by means of a single infusion from June 2018 to August 2019. We classified patients into two groups based on the duration of the infusion: the 12-h group and the 24-h group. We compared the treatment response of the primary IVIG and its adverse events using the Mann-Whitney U test and Fisher's exact or Chi-square tests. ResultsThere were no significant differences in the response to initial IVIG treatment between the two groups. The duration from treatment onset to defervescence was shorter in the 12-h group than the 24-h group (7 h vs. 12 h, respectively, p = 0.07); however, this was not significant. There were no significant between-group differences regarding adverse events. ConclusionWe concluded that the initial 12-h IVIG treatment was comparable to the 24-h treatment in terms of efficacy and safety. This will enable physicians to feel confident about pursuing a shorter course of treatment with similar results as conventional treatment and decide on administering additional therapy to their patients.

Thyroid hormone may predict treatment failure in Kawasaki disease.

In systemic inflammatory conditions, inflammatory cytokines can cause low thyroid hormone levels. There are no reports discussing the relation between thyroid hormone levels and response to treatment for Kawasaki disease. We investigated 67 patients who underwent treatment in the acute phase of Kawasaki disease. We divided patients into two groups based on their response to initial intravenous immunoglobulin (IVIG) treatment: the responder group (n = 40), and the non-responder group (n = 27). The serum levels of the thyroid hormones free triiodothyronine (FT3), free thyroxine (FT4), and thyroid-stimulating hormone (TSH) were compared before and after treatment in all patients, and between responder and non-responder groups. The FT3, FT4, and TSH levels were low before the initial treatment and increased significantly after treatment (p < 0.05). The FT3, FT4, and TSH levels before treatment were significantly lower in the non-responder group than in the responder group (p < 0.05). Logistic regression analysis suggested that the addition of pre-treatment FT4 values to Gunma score was useful in predicting treatment failure. Thyroid hormone and TSH levels were lower in the non-responder group than in the responder group in the initial IVIG treatment for Kawasaki disease. This study suggests that Kawasaki disease in the acute phase is associated with low thyroid hormone levels and TSH. It is possible that these hormone levels predict response to the initial IVIG.

Risk factors for coronary artery abnormalities and resistance to immunoglobulin plus ciclosporin A therapy in severe Kawasaki disease: subanalysis of the KAICA trial, randomized trial for cicrosporin A as the first-line treatment.

To investigate risk factors for coronary arterial abnormalities (CAAs) and resistance to treatment in patients with Kawasaki disease (KD) receiving intravenous immunoglobulin (IVIG) plus ciclosporin A (CsA) as the first-line treatment, we performed a subanalysis of baseline data of participants in the KAICA trial, a phase 3, randomized study (JMA-ILA00174). All data of the patients enrolled in the KAICA trial, who had a Gunma score ≥5 at diagnosis and had been randomly assigned to either IVIG (2 g/kg/24 h) plus CsA (5 mg/kg/day for 5 days) (n = 86) or IVIG alone (n = 87), were subjected to this study. CAA was defined by a Z score ≥2.5 observed within 4 weeks after treatment initiation. Baseline data including genotypes of KD susceptibility genes were compared between subgroups of patients for CAA or treatment response for each treatment group. Backword-forward stepwise logistic regression analyses were performed. Pre-Z-max, defined as the maximum among Z scores on four coronary artery branches before treatment, was higher in patients with CAA in both treatment groups and was associated with CAA in IVIG plus CsA treatment group [odds ratio (OR) = 17.0]. High serum total bilirubin level was relevant to treatment resistance only in the IVIG plus CsA group (OR = 2.34). Coronary artery enlargement before treatment is a major determinant of CAA even in KD patients treated with initial IVIG treatment intensified by addition of CsA. Baseline serum total bilirubin level was a risk factor associated with resistance to IVIG plus CsA.

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.

Epidemiology and Clinical Outcomes of Refractory Kawasaki Disease in South Korea

Refractory Kawasaki disease (KD) is defined as KD resistant to initial intravenous immunoglobulin (IVIG) therapy. The proportion of refractory KD is reported to be 10%−20%, and the risk of coronary arterial aneurysm (CAA) is increased in refractory KD. We analyzed data of Korean nationwide surveys on KD to know the epidemiology, treatment modalities, and clinical outcomes of refractory KD in South Korea. We analyzed the data of three triennial Korean nationwide surveys on KD from 2009 to 2017, and selected patients with refractory KD who had persistent or recrudescent fever at least 36 hours after completion of initial IVIG therapy. Among a total of 42,705 KD patients from 2009 through 2017, 5,581 (13.1%) had refractory KD. The annual proportions of refractory KD were between 10.1% and 18.7%, which showed significant changes with the nadir in 2013 and increased proportions in 2015−2017 (P &lt; 0.05). Treatment modalities for refractory KD were second IVIG in 86.2%, third or more IVIG in 3.8%, corticosteroids in 34.4%, infliximab in 3.7%, methotrexate in 1.0%, plasmapheresis in 0.1%, and cyclosporine in 0.02%. The use of third or more IVIG showed a decreasing trend, and the use of corticosteroids and infliximab showed an increasing trend. The incidence of CAA was significantly higher in refractory KD patients than in total KD patients (5.5% vs 1.8%; P &lt; 0.05). The overall proportion of refractory KD was 13.1% from 2009 through 2017 in South Korea. The annual proportions of refractory KD showed significant changes with increased proportions in recent years. Treatment modalities for refractory KD showed a decreasing trend in the use of third or more IVIG and an increasing trend in the use of corticosteroids and infliximab. The incidence of CAA was significantly higher in refractory KD patients than in total KD patients.

Intravenous Immunoglobulin Initiation in Patients with Chronic Inflammatory Demyelinating Polyradiculoneuropathy: A US Claims-based Cohort Study.

Intravenous immunoglobulin (IVIG) is recommended as first-line therapy for chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), an immune-mediated neuropathy. The clinical profile of patients with CIDP newly initiating IVIG is poorly characterized. This claims-based cohort study describes characteristics of US patients with CIDP initiating IVIG treatment. Adult immunoglobulin (IG)-naïve patients with CIDP diagnosed between 2008 and 2018 and a subgroup of patients subsequently initiating IVIG were identified in the Merative MarketScan Research Databases. Demographics, clinical characteristics, and diagnostic procedures were described for patients initiating IVIG. Of 32,090 patients with CIDP identified, 3975 (mean age 57years) subsequently initiated IVIG. In the 6months prior to IVIG initiation, diagnoses of comorbidities including neuropathy (75%), hypertension (62%), and diabetes (33%) were frequent, as were CIDP features/symptoms/markers of functional status including chronic pain (80%), difficulty walking (30%), and weakness (30%). CIDP-related laboratory/diagnostic procedures were performed in approximately 20- > 40% of patients in the 3months prior to IVIG initiation (63.7% underwent electrodiagnostic/nerve conduction testing in the 6months prior to IVIG initiation). Patient characteristics by initial IVIG product differed only in IVIG initiation year, US geographic region, and insurance type. Comorbidities, CIDP severity or functional status markers, and other clinical variables were generally well balanced across initial IVIG product groups. A heavy burden of symptoms, comorbidities, and diagnostic testing exists in patients with CIDP initiating IVIG. Characteristics of patients with CIDP initiating different IVIG products are well balanced, suggesting an absence of clinical or demographic determinants underlying IVIG selection.

Intravenous Immunoglobulin Treatment Patterns and Outcomes in Patients with Chronic Inflammatory Demyelinating Polyradiculoneuropathy: A US Claims Database Analysis.

Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is a rare progressive or relapsing inflammatory disease. Intravenous immunoglobulin (IVIG) is recommended as a first-line therapy. The aim of this study was to describe real-world treatment patterns and outcomes of patients with CIDP in the Define initiating IVIG treatment. This cohort study used health insurance claims data from the Merative MarketScan Research Databases (2008-2018). Adult patients (≥ 18years old) with CIDP without prior immunoglobulin treatment were identified using International Statistical Classification of Diseases and Related Health Problems (ICD) codes, and patients subsequently initiating IVIG were included in the analysis. Real-world IVIG treatment patterns and treatment and safety outcomes (assessed via ICD codes) were described. In total, 3975 patients (median age 58years) with CIDP who initiated IVIG were identified. After the initial IVIG loading period, patients received IVIG at a median dosing interval of 21days (quartile [Q]1, Q3: 7, 28), and continued treatment for a median of 129days (Q1, Q3: 85, 271). After the 2-year follow-up period, 55% of patients had discontinued all IVIG treatment; more than one-half of these discontinuations occurred within 4months. Diagnoses of impaired functional status were evident in more than 30% of patients at baseline, but at lower rates during follow-up. Rates of new-onset safety outcomes after IVIG treatment were low. This real-world analysis of IVIG treatment patterns and treatment and safety outcomes of patients with CIDP who initiated IVIG highlights the unmet need for improved long-term management. Further research is needed to evaluate the use of functional status measures as endpoints for immunoglobulin treatment effectiveness.

Prediction Models for Intravenous Immunoglobulin Resistance in Kawasaki Disease: A Meta-analysis.

Approximately 10% to 20% of patients with Kawasaki disease (KD) are refractory to initial intravenous immunoglobulin (IVIG) therapy. KD is mainly associated with coronary artery abnormalities. To identify and evaluate all developed prediction models for IVIG resistance in patients with KD and synthesize evidence from external validation studies that evaluated their predictive performances. PubMed Medline, Dialog Embase, the Cochrane Central Register of Controlled Trials, the World Health Organization International Clinical Trials Registry Platform, and ClinicalTrials.gov were searched from inception until October 5, 2021. All cohort studies that reported patients diagnosed with KD who underwent an initial IVIG of 2 g/kg were selected. Study and patient characteristics and model performance measures. Two authors independently extracted data from the studies. The Kobayashi, Egami, Sano, Formosa, and Harada scores were the only prediction models with 3 or more external validation of the161 model analyses in 48 studies. The summary C-statistics were 0.65 (95% confidence interval [CI]: 0.57-0.73), 0.63 (95% CI: 0.55-0.71), 0.58 (95% CI: 0.55-0.60), 0.50 (95% CI: 0.36-0.63), and 0.63 (95% CI: 0.44-0.78) for the Kobayashi, Egami, Sano, Formosa, and Harada models, respectively. All 5 models showed low positive predictive values (0.14-0.39) and high negative predictive values (0.85-0.92). Potential differences in the characteristics of the target population among studies and lack of assessment of calibrations. None of the 5 prediction models with external validation accurately distinguished between patients with and without IVIG resistance.

The therapeutic window of intravenous immunoglobulin (IVIG) and its correlation with clinical outcomes in Kawasaki disease: a systematic review and meta-analysis

BackgroundThe optimal therapeutic window to start intravenous immunoglobulin (IVIG) for Kawasaki disease (KD) is highly debatable. We aimed to summarize the existing literature to evaluate the therapeutic window of IVIG treatment and its correlation with clinical outcomes in KD patients.MethodsWe searched the databases from inception to August 26, 2022, without language restrictions. The primary outcomes were initial IVIG resistance and coronary artery lesions (CALs) in acute phase. Secondary outcome was CALs during 1–2 months of follow-up.Results27 studies involving 41,139 patients were included in this study. Very low-quality evidence showed that the earlier IVIG treatment within 4 days had a higher IVIG-resistance rate (RR, 1.80; 95% CI, 1.50–2.15; P < .00001; I2 = 75%) than the late treatment. Very low-quality evidence showed that IVIG treatment for more than 7 days was associated with a higher risk of CALs in acute phase(RR, 0.57; 95% CI, 0.40–0.80; P = .001; I2 = 76%). There was a lower risk of CALs during 1–2 months follow-up for those who started IVIG administration within 10 days from the onset.ConclusionsOverall, IVIG treatment within 7 days of illness seems to be the optimal therapeutic window of IVIG. IVIG treatment within 7 days is found to be effective for reducing the risk of coronary artery lesions and cardiac sequelae in KD patients. The early IVIG treatment within 4 days should be vigilant for the IVIG resistance although large multi-center randomized trials with well design are needed.

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

IntroductionIn Kawasaki disease (KD), accurate prediction of intravenous immunoglobulin (IVIG) resistance is crucial to reduce a risk for developing coronary artery lesions.ObjectiveTo establish a simple scoring model predicting IVIG resistance in KD patients based on the machine learning model.MethodsA 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.ResultsLight 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.ConclusionA simple scoring system based on the findings in machine learning seems to be a useful tool to accurately predict IVIG resistance in KD patients.Key Points• In Kawasaki disease (KD), accurate prediction of intravenous immunoglobulin (IVIG) resistance is crucial to reduce a risk for developing coronary artery lesions.• Machine learning model predicted IVIG resistance in KD patients, and Shapley additive explanation (SHAP) was a useful approach for explaining the outcome of the machine learning model.• A simple scoring system using three clinical features (days of illness at initial therapy, serum levels of CRP, and total cholesterol at diagnosis) based on SHAP efficiently predicted IVIG resistance.

Prednisolone versus cyclosporine as initial treatment for Kawasaki disease.

Several studies have demonstrated the efficacy of prednisolone and cyclosporine as initial combination treatments for the prevention of coronary artery abnormalities (CAA) in patients with Kawasaki disease. However, whether prednisolone or cyclosporine results in superior clinical outcomes is unknown. Thus, this study aimed to compare the outcomes of these two treatments. Using the Japanese Diagnosis Procedure Combination database, we identified patients with Kawasaki disease who had received prednisolone or cyclosporine in addition to initial intravenous immunoglobulin treatment between April 2014 and March 2021. The primary outcome was the proportion of CAA; secondary outcomes included intravenous immunoglobulin resistance, medical costs, and length of hospital stay. Propensity score matching was conducted to compare outcomes between the two groups. We identified 6288 patients with Kawasaki disease who had received prednisolone (n = 6147) or cyclosporine (n = 141) as an initial treatment in combination with intravenous immunoglobulin. Four-to-one propensity score-matched analysis demonstrated no significant difference in the proportion of CAA (0.7% vs. 2.8%; p = 0.098), intravenous immunoglobulin resistance, or medical costs between the treatment groups. The length of hospital stay was significantly longer in the prednisolone group (14 vs. 11 days, p < 0.001). Prednisolone and cyclosporine used in the initial combination treatment for Kawasaki disease showed similar clinical outcomes regarding the risk of CAA, intravenous immunoglobulin resistance, and medical costs, whereas the length of hospital stay was longer in the prednisolone group than in the cyclosporine group.

Clinical characteristics of patients with recurrent Kawasaki disease: a nationwide cohort study of 19 456 patients with minimum 3-year follow up

ObjectiveTo identify the clinical characteristics of patients with recurrent Kawasaki disease (KD).DesignA nationwide, population-based, cohort study using the Korean National Health Insurance claims database between 2013 and 2016.PatientsA total of...

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.

Therapeutic Window of Intravenous Immunoglobulin (IVIG) and its correlation with IVIG-resistant in Kawasaki Disease: a retrospective study

ObjectiveTo investigate the optimal timing of initial intravenous immunoglobulin (IVIG) treatment in Kawasaki disease (KD) patients. MethodsKD patients were classified as the early group (day 1-4), conventional group (day 5-7), conventional group (day 8-10), and late group (after day 10). Differences among the groups were analyzed by ANOVA and Chi-square analysis. Predictors of IVIG resistance and the optimal cut-off value were determined by multiple logistic regression analyses and receiver operating characteristic (ROC) curve analysis. ResultsThere were no significant differences in IVIG resistance among the 4 groups (p = 0.335). The sensitivity analysis also confirmed no difference in the IVIG resistance between those who started the initial IVIG ≤ day 7 of illness and those who received IVIG >day 7 of illness (p = 0.761). In addition, patients who received IVIG administration more than 7 days from the onset had a higher proportion of coronary artery abnormalities (p = 0.034) and longer length of hospitalization (p = 0.033) than those who started IVIG administration less than 7 days. The optimal cut-off value of initial IVIG administration time for predicting IVIG resistance was >7 days, with a sensitivity of 75.25% and specificity of 82.41%. ConclusionsIVIG therapy within 7 days of illness is found to be more effective for reducing the risk of coronary artery abnormalities than those who received IVIG >day 7 of illness. IVIG treatment within the 7 days of illness seems to be the optimal therapeutic window of IVIG. However, further prospective studies with long-term follow-up are required.

A retrospective comparative analysis of factors affecting the decision and outcome of initial intravenous immunoglobulin alone or intravenous immunoglobulin plus methylprednisolone use in children with the multisystem inflammatory syndrome

BackgroundFor children with the multisystem inflammatory syndrome(MIS-C), intravenous immunoglobulins (IVIG) with or without methylprednisolone are the most effective treatment. In this study, IVIG combined with methylprednisolone was compared to IVIG used alone in children with MIS-C.MethodsThis retrospective cohort study was carried out between April 1, 2020, and November 1, 2021. This study covered all children with MIS-C. According to whether they received IVIG alone or IVIG with methylprednisolone as an initial treatment for MIS-C, the patients were split into two groups. The IVIG dosage for the patients in group I was 2 gr/kg, whereas the IVIG dosage for the patients in group II was 2 gr/kg + 2 mg/kg/day of methylprednisolone. These two groups were contrasted in terms of the frequency of fever, length of hospital stay, and admission to the pediatric intensive care unit.ResultsThe study comprised 91 patients who were diagnosed with MIS-C and were under the age of 18. 42 (46.2%) of these patients were in the IVIG alone group (group I), and 49 (53.8%) were in the IVIG + methylprednisolone group (group II). Patients in group II had a severe MIS-C ratio of 36.7%, which was substantially greater than the rate of severe MIS-C patients in group I (9.5%) (p 0.01). When compared to group I (9.5%), the rate of hypotension was considerably higher in group II (30.6%) (p = 0.014). Additionally, patients in group II had considerably higher mean serum levels of C-reactive protein. The incidence of fever recurrence was 26.5% in group II and 33.3% in group I, however the difference was not statistically significant (p > 0.05).ConclusionsThe choice of treatment for patients with MIS-C should be based on an individual evaluation. In MIS-C children with hypotension and/or with an indication for a pediatric intensive care unit, a combination of IVIG and methylprednisolone may be administered. For the treatment modalities of children with MIS-C, however, randomized double-blind studies are necessary.

Development of a score for early identification of children with Kawasaki disease requiring second-line treatment in multi-ethnic populations in Europe: A multicentre retrospective cohort study.

SummaryBackgroundEarly identification of high-risk patients is essential to stratify treatment algorithms of Kawasaki disease (KD) and to appropriately select patients at risk for complicated disease who would benefit from intensified first-line treatment. Several scores have been developed and validated in Asian populations but have shown low sensitivity in predicting intravenous immunoglobulin (IVIG) resistance in non-Asian populations. We sought methods to predict the need for secondary treatment after initial IVIG in non-Asian populations.MethodsWe conducted a retrospective, multicenter study including consecutive patients with KD admitted to two tertiary pediatric hospitals in France and Italy from 2005 to 2019. We evaluated the performance of the Kawanet-score and compared it with the performances of initial echocardiography findings, and of a newly proposed score combining the Kawanet-score and initial echocardiography findings. For each score, we assessed the AUC, sensitivity and specificity for predicting the need for second-line treatment.FindingsWe included 363 children with KD, 186 from France and 177 from Italy, of whom 57 (16%) required second-line therapy after the first IVIG dose. The Kawanet score, coronary artery dilation or aneurysm with maximal Z-score ≥2.0 at baseline, and abnormal initial echocardiography had a sensitivity of 43%, 55% and 65% and a specificity of 73%, 78%, 73%, respectively, for predicting the need for second-line treatment. The Kawanet-score was significantly improved by combining it with initial echocardiography findings. The best predictive performance (Sensitivity 76%, Specificity 54%) was obtained by combining the Kawanet-score with abnormal initial echocardiography, defined by the presence of either coronary artery maximal Z-score ≥2.0, pericarditis, myocarditis and/or ventricular dysfunction. This score predicted the need for second-line treatment in European, African/Afro-Caribbean and Asian ethnicity with a sensitivity of 80%, 65% and 100%, respectively, and a specificity of 56%, 51% and 61%, respectively.InterpretationOur study proposes a score that we named the Kawanet-echo score, which allows early identification of children with KD who require a second-line treatment in multi-ethnic populations in Europe.FundingNone.