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Objective To test the hypothesis that children and adults with a history of Kawasaki disease (KD) are more likely to have abnormal lipoprotein particle profiles that could place them at increased risk for developing atherosclerosis later in life. Study design Fasting serum samples were obtained from 192 children and 63 adults with history of KD and 90 age-similar healthy controls. Lipoprotein particle concentrations and sizes were measured by nuclear magnetic resonance spectroscopy (LipoScience Inc, Raleigh, North Carolina), and serum was assayed for total cholesterol (TC), triglycerides, and high-density lipoprotein (HDL) cholesterol (HDL-C). Low-density lipoprotein (LDL) cholesterol was estimated using the Friedewald formula. Data were analyzed in a least-square means model, with adjustment for age and sex and with the use of Holm correction for multiple comparisons. Results Compared with respective control groups, both adult and pediatric subjects with KD had significantly lower mean very low-density lipoprotein-chylomicron particles, intermediate-density lipoproteins, triglycerides, and TC concentrations. Pediatric subjects with KD had significantly lower LDL particle and LDL cholesterol concentrations and lower mean TC/HDL-C ratio (P < .001). In contrast, the adult subjects with KD had significantly lower HDL particle, small HDL particle, and HDL-C concentrations (P < .001), but HDL-C was within normal range. Conclusions Nuclear magnetic resonance lipoprotein particle analysis suggests that pediatric and adult subjects with KD, regardless of their aneurysm status, are no more likely than age-similar, healthy controls to have lipid patterns associated with increased risk of atherosclerosis. [ABSTRACT FROM AUTHOR]

Objectives: To determine the safety, pharmacokinetics, and immunomodulatory effects of 2-6 weeks of anakinra therapy in patients with acute Kawasaki disease with a coronary artery aneurysm (CAA).Study Design: We performed a Phase I/IIa dose-escalation study of anakinra (2-11 mg/kg/day) in 22 patients with acute Kawasaki disease with CAA. We measured interleukin (IL)-1RA concentrations after the first dose and trough levels up to study week 6. Markers of inflammation and coronary artery z-scores were assessed pretreatment and at 48 hours, 2 weeks, and 6 weeks after initiation of therapy.Results: Up to 6 weeks of anakinra (up to 11 mg/kg/day) was safe and well tolerated by the 22 participants (median age, 1.1 years), with no serious adverse events attributable to the study drug. All participants were treated with intravenous immunoglobulin (IVIG), and 20 also received infliximab (10 mg/kg) before initiation of anakinra. Serum levels of IL-6, IL-8, and tumor necrosis factor α decreased similarly in patients with Kawasaki disease treated with IVIG, infliximab, and anakinra compared with age- and sex-matched patients with Kawasaki disease treated only with IVIG and infliximab. Anakinra clearance increased with illness day at diagnosis. Simulations demonstrated that more frequent intravenous (IV) dosing may result in more sustained concentrations without significantly increasing the peak concentration compared with subcutaneous (SC) dosing.Conclusions: Both IV and SC anakinra are safe in infants and children with acute Kawasaki disease and CAA. IV dosing every 8-12 hours during the acute hospitalization of patients with Kawasaki disease may result in a sustained concentration while avoiding frequent SC injections. The efficacy of a short course of IV therapy during hospitalization should be studied. TRIAL REGISTRATION CLINICALTRIALS.GOV: NCT02179853. [ABSTRACT FROM AUTHOR]

Objective To identify characteristics differentiating the node-first presentation of Kawasaki disease (NFKD) from bacterial cervical lymphadenitis (BCL) and typical Kawasaki disease (KD). Study design From our prospectively collected database, we compared clinical, laboratory, and imaging characteristics of NFKD and BCL cohorts and performed multivariable logistic regression to identify variables that distinguish NFKD from BCL. We then compared outcomes of patients with NFKD and patients with typical KD treated during the same period. Results Over 7 years, 57 patients were hospitalized for NFKD, 78 for BCL, and 287 for typical KD. Patients with NFKD were older and had more medical encounters and longer duration of illness before the correct diagnosis was made than did patients with BCL. Of patients with NFKD, 33% had an admission diagnosis of bacterial adenitis or abscess. Compared with patients with BCL, patients with NFKD had lower leukocyte (white blood cell), hemoglobin, and platelet counts and higher absolute band counts (ABCs), C-reactive protein (CRP), alanine transaminase and γ-glutamyl transpeptidase levels, and erythrocyte sedimentation rates. In the multivariable analysis, smaller nodes, lower white blood cell count, and higher ABC and CRP were independently associated with NFKD. Patients with NFKD had multiple enlarged solid nodes and comparable rates of retropharyngeal edema. Compared with patients with typical KD, patients with NFKD were older, had more severe inflammation, and had similar rates of coronary artery abnormalities and resistance to intravenous immune globulin. Conclusions High ABC and CRP values and multiple enlarged solid nodes in febrile patients with cervical adenopathy should prompt consideration of NFKD to prevent delayed diagnosis of KD. Retropharyngeal edema on radiography should not dissuade from the diagnosis of NFKD. [ABSTRACT FROM AUTHOR]

Objective: To evaluate practice variation in pharmacologic management in the International Kawasaki Disease Registry (IKDR).Study Design: Practice variation in intravenous immunoglobulin (IVIG) therapy, anti-inflammatory agents, statins, beta-blockers, antiplatelet therapy, and anticoagulation was described.Results: We included 1627 patients from 30 IKDR centers with maximum coronary artery aneurysm (CAA) z scores 2.5-4.99 in 848, 5.0-9.99 in 349, and ≥10.0 (large/giant) in 430 patients. All centers reported IVIG and acetylsalicylic acid (ASA) as primary therapy and use of additional IVIG or steroids as needed. In 23 out of 30 centers, (77%) infliximab was also used; 11 of these 23 centers reported using it in <10% of their patients, and 3 centers used it in >20% of patients. Nonsteroidal anti-inflammatory agents were used in >10% of patients in only nine centers. Beta-blocker (8.8%, all patients) and abciximab (3.6%, all patients) were mainly prescribed in patients with large/giant CAAs. Statins (2.7%, all patients) were mostly used in one center and only in patients with large/giant CAAs. ASA was the primary antiplatelet modality for 99% of patients, used in all centers. Clopidogrel (18%, all patients) was used in 24 centers, 11 of which used it in >50% of their patients with large/giant CAAs.Conclusions: In the IKDR, IVIG and ASA therapy as primary therapy is universal with common use of a second dose of IVIG for persistent fever. There is practice variation among centers for adjunctive therapies and anticoagulation strategies, likely reflecting ongoing knowledge gaps. Randomized controlled trials nested in a high-quality collaborative registry may be an efficient strategy to reduce practice variation. [ABSTRACT FROM AUTHOR]

Objectives: To explore the increased incidence of intravenous immunoglobulin- (IVIG) resistance among San Diego County patients with Kawasaki disease (KD) in 2006 and to evaluate a scoring system to predict IVIG-resistant patients with KD. Study design: We performed a retrospective review of patients with KD treated within 10 days of fever onset. With multivariate analysis, independent predictors of IVIG-resistance were combined into a scoring system. Results: In 2006, 38.3% of patients with KD in San Diego County were IVIG-resistant, a significant increase over previous years. IVIG-resistance was not associated with a particular brand or lot of IVIG. Resistant patients were diagnosed earlier, had higher percent bands, and higher concentrations of C-reactive protein, alanine aminotransferase, and γ-glutamyl transferase. They also had lower platelet counts and age-adjusted hemoglobin concentrations and were more likely to have aneurysms (P = .0008). A scoring system developed to predict IVIG-resistant patients using illness day, percent bands, γ-glutamyl transferase, and age-adjusted hemoglobin had a sensitivity of 73.3% and specificity of 61.9%. Conclusions: An unexplained increase in IVIG-resistance was noted among patients with KD in San Diego County in 2006. Scoring systems based on demographic and laboratory data were insufficiently accurate to be clinically useful in our ethnically diverse population. [Copyright &y& Elsevier]

Objective: To test the hypothesis that cases of Kawasaki disease within a temporal cluster have a similar pattern of host response that is distinct from cases of Kawasaki disease in different observed clusters and randomly constructed clusters.Study Design: We designed a case-control study to analyze 47 clusters derived from 1332 patients with Kawasaki disease over a 17-year period (2002-2019) from a single clinical site and compared the cluster characteristics with those of 2 control groups of synthetic Kawasaki disease clusters. We defined a "true" Kawasaki disease cluster as at least 5 patients within a 7-day moving window. The observed and synthetic Kawasaki disease clusters were compared with respect to demographic and clinical characteristics and median values for standard laboratory data using univariate analysis and a multivariate, rotated empirical orthogonal function analysis.Results: In a univariate analysis, the median values for age, coronary artery z-score, white blood cell count, erythrocyte sedimentation rate, C-reactive protein, and age-adjusted hemoglobin for several of the true Kawasaki disease clusters exceeded the 95th percentile for the 2 synthetic clusters. REOF analyses revealed distinct patterns of demographic and clinical measures within clusters.Conclusions: Cases of Kawasaki disease within a cluster were more similar with respect to demographic and clinical features and levels of inflammation than would be expected by chance. These observations suggest that different triggers and/or different intensities of exposures result in clusters of cases of Kawasaki disease that share a similar response pattern. Analyzing cases within clusters or cases who share demographic and clinical features may lead to new insights into the etiology of Kawasaki disease. [ABSTRACT FROM AUTHOR]

Objectives: To determine the safety, tolerability, pharmacokinetics, and immunomodulatory effects of a 6-week course of atorvastatin in patients with acute Kawasaki disease with coronary artery (CA) aneurysm (CAA).Study Design: This was a Phase I/IIa 2-center dose-escalation study of atorvastatin (0.125-0.75 mg/kg/day) in 34 patients with Kawasaki disease (aged 2-17 years) with echocardiographic evidence of CAA. We measured levels of the brain metabolite 24(S)-hydroxycholesterol (24-OHC), serum lipids, acute-phase reactants, liver enzymes, and creatine phosphokinase; peripheral blood mononuclear cell populations; and CA internal diameter normalized for body surface area before atorvastatin treatment and at 2 and 6 weeks after initiation of atorvastatin treatment.Results: A 6-week course of up to 0.75 mg/kg/day of atorvastatin was well tolerated by the 34 subjects (median age, 5.3 years; IQR, 2.6-6.4 years), with no serious adverse events attributable to the study drug. The areas under the curve for atorvastatin and its metabolite were larger in the study subjects compared with those reported in adults, suggesting a slower rate of metabolism in children. The 24-OHC levels were similar between the atorvastatin-treated subjects and matched controls.Conclusions: Atorvastatin was safe and well tolerated in our cohort of children with acute Kawasaki disease and CAA. A Phase III efficacy trial is warranted in this patient population, which may benefit from the known anti-inflammatory and immunomodulatory effects of this drug. [ABSTRACT FROM AUTHOR]

Objectives: To describe the epidemiology, response to therapy, and outcomes of Kawasaki disease in a multiethnic community with a large Hispanic and Asian population.Study Design: We analyzed prospectively collected data from 788 unselected patients with Kawasaki disease diagnosed and treated at a single medical center over a 10-year period.Results: The average incidence of Kawasaki disease in children <5 years in San Diego County over the 10 years from 2006 to 2015 was 25 per 100 000 children, with the greatest incidence (50 per 100 000) for Asian/Pacific Islanders. Compared with other race/ethnicities, Asian/Pacific Islander patients with Kawasaki disease were younger, were diagnosed earlier in the course of their fever, had higher levels of inflammatory markers, and were more likely to develop aneurysms. There was no difference across race/ethnicity groups in response to intravenous immunoglobulin therapy. Filipino children had the highest recurrence rates (9.1%; 95% CI, 3.0%-22.6%) and 12 of 788 patients (1.5%) had a first- or second-degree relative with a history of Kawasaki disease. After correcting for age of onset, sex, and illness day at diagnosis, Asian/Pacific Islander children had an increased risk of developing aneurysms (aOR, 2.37; 95% CI, 1.37-4.11; P  = .002). Overall, 180 of 788 patients (22.8%) had a maximal Z score of 2.5-10.0 and 14 of the 788 patients (1.8%) had a maximal Z score ≥10.0 despite 84% of these patients being treated within 10 days of fever onset.Conclusions: Our data provide new insights into the natural history of treated Kawasaki disease in a multiethnic population. Patient race/ethnicity influenced susceptibility to Kawasaki disease, timing of diagnosis, coronary artery outcome, and recurrence rates. [ABSTRACT FROM AUTHOR]

Objectives: To characterize the clinical presentation and outcome in infants <6 months of age with Kawasaki disease (KD) and to describe the use of newer anti-inflammatory therapies in this young population.Study Design: We evaluated 88 infants?<6 months old and 632??6 months old treated for KD. We compared differences in laboratory data, response to treatment, and coronary artery outcomes between the 2 cohorts. Fisher exact test was used to analyze categorical variables, whereas the Wilcoxon rank sum test was used for continuous variables.Results: The majority of children in both cohorts were diagnosed and treated within the first 10 days of illness (median illness day 6 in both cohorts). For patients treated within the first 10 days after fever onset, a larger proportion of infants <6 months old had a dilated or aneurysmal coronary artery on the initial echocardiogram compared with those ?6 months old (43.4% vs 19.5%). Furthermore, 18.6% of infants?<6 months old who had a normal echocardiogram at diagnosis, developed a dilated or aneurysmal coronary artery on a subsequent echocardiogram within 8 weeks of diagnosis. Twenty-eight infants?<6 months old received a single dose of infliximab without any untoward effects.Conclusions: Despite treatment in the first 10 days, infants?<6 months old with acute KD are more likely to develop coronary artery abnormalities. Thus, the development of adjunctive therapies to reduce coronary artery damage should target this population. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the relationship between ampicillin dosing, exposure, and seizures.Study Design: This was a retrospective observational cohort study of electronic health record (EHR) data combined with pharmacokinetic model derived drug exposure predictions. We used the EHR from 348 Pediatrix Medical Group neonatal intensive care units from 1997 to 2012. We included all infants 24-41 weeks gestational age, 500-5400 g birth weight, first exposed to ampicillin prior to 25 days postnatal age. Using a 1-compartment pharmacokinetic model and EHR data, we simulated maximum ampicillin concentration at steady state (Cmaxss, µg/mL) and area under the concentration time curve from 0 to 24 hours (AUC24, µg*h/dL). Using multivariable logistic regression, we evaluated association between ampicillin dosing, exposure, and seizures as documented in the EHR.Results: We identified 131 723 infants receiving 134 041 courses of ampicillin for 653 506 infant-days of exposure. The median daily dose was 200 mg/kg/d (25th, 75th percentile; 100, 200). Median Cmaxss and AUC24 were 256.6 µg/mL (164.3, 291.5) and 2593 µg*h/dL (1917, 3334). On multivariable analysis, dosing was not associated with seizures. However increasing Cmaxss (OR = 1.10, 95% CI 1.03, 1.17) and AUC24 (OR 1.11, 95% CI 1.05, 1.18) were associated with increased odds of seizures.Conclusions: In this cohort of hospitalized infants, higher ampicillin exposure was associated with seizures as documented in the EHR. [ABSTRACT FROM AUTHOR]

Objective: To develop and validate a novel decision tree-based clinical algorithm to differentiate Kawasaki disease (KD) from other pediatric febrile illnesses that share common clinical characteristics.Study Design: Using clinical and laboratory data from 801 subjects with acute KD (533 for development, and 268 for validation) and 479 febrile control subjects (318 for development, and 161 for validation), we developed a stepwise KD diagnostic algorithm combining our previously developed linear discriminant analysis (LDA)-based model with a newly developed tree-based algorithm.Results: The primary model (LDA) stratified the 1280 subjects into febrile controls (n = 276), indeterminate (n = 247), and KD (n = 757) subgroups. The subsequent model (decision trees) further classified the indeterminate group into febrile controls (n = 103) and KD (n = 58) subgroups, leaving only 29 of 801 KD (3.6%) and 57 of 479 febrile control (11.9%) subjects indeterminate. The 2-step algorithm had a sensitivity of 96.0% and a specificity of 78.5%, and correctly classified all subjects with KD who later developed coronary artery aneurysms.Conclusion: The addition of a decision tree step increased sensitivity and specificity in the classification of subject with KD and febrile controls over our previously described LDA model. A multicenter trial is needed to prospectively determine its utility as a point of care diagnostic test for KD. [ABSTRACT FROM AUTHOR]

Objective: To describe the clinical course and outcome of 10 patients with Kawasaki disease (KD) treated with a calcineurin inhibitor after failing to respond to multiple therapies.Study Design: Demographic and clinical data were prospectively collected using standardized case report forms. T-cell phenotypes were determined by flow cytometry, and KD risk alleles in ITPKC (rs28493229), CASP3 (rs72689236), and FCGR2A (rs1801274) were genotyped.Results: Intravenous followed by oral therapy with cyclosporine (CSA) or oral tacrolimus was well tolerated and resulted in defervescence and resolution of inflammation in all 10 patients. There were no serious adverse events, and a standardized treatment protocol was developed based on our experiences with this patient population. Analysis of T-cell phenotype by flow cytometry in 2 subjects showed a decrease in circulating activated CD8(+) and CD4(+) T effector memory cells after treatment with CSA. However, suppression of regulatory T-cells was not seen, suggesting targeting of specific, proinflammatory T-cell compartments by CSA.Conclusion: Treatment of refractory KD with a calcineurin inhibitor appears to be a safe and effective approach that achieves rapid control of inflammation associated with clinical improvement. [ABSTRACT FROM AUTHOR]

Objective: To test the hypothesis that first re-treatment with infliximab, compared with intravenous immunoglobulin (IVIG), might improve outcomes in IVIG-resistant Kawasaki disease. Study design: In a two-center retrospective review from January 2000 to March 2008, we compared duration of fever and coronary artery dimensions in patients with IVIG-resistance whose first re-treatment was with IVIG compared with infliximab given for fever ≥38.0°C beyond 36 hours after first IVIG completion. Results: Patients in the IVIG group (n = 86, 2 g/kg) and infliximab group (n = 20, 5 mg/kg) were similar in demographics, days of fever at diagnosis, and baseline coronary artery dimensions. Patients had similar coronary dimensions 6 weeks after diagnosis, both in univariate and multivariate analysis. The infliximab group had fewer days of fever (median 8 days versus10 days, P = .028), and in a multivariate analysis, the infliximab group had 1.2 fewer days of fever (P = .033). Patients who received infliximab had shorter lengths of hospitalization (median 5.5 days versus 6 days, P = .040). Treatment groups did not differ significantly in adverse events (0% versus 2.3%, P = 1.0). Conclusions: In our retrospective study, patients with IVIG-resistant Kawasaki disease whose first re-treatment was with infliximab, compared with IVIG, had faster resolution of fever and fewer days of hospitalization. Coronary artery outcomes and adverse events were similar; the power of the study was limited. [ABSTRACT FROM AUTHOR]

Objectives: To describe the clinical presentation, management, and outcomes of Kawasaki disease (KD) in Latin America and to evaluate early prognostic indicators of coronary artery aneurysm (CAA)., Study Design: An observational KD registry-based study was conducted in 64 participating pediatric centers across 19 Latin American countries retrospectively between January 1, 2009, and December 31, 2013, and prospectively from June 1, 2014, to May 31, 2017. Demographic and initial clinical and laboratory data were collected. Logistic regression incorporating clinical factors and maximum coronary artery z-score at initial presentation (between 10 days before and 5 days after intravenous immunoglobulin [IVIG]) was used to develop a prognostic model for CAA during follow-up (>5 days after IVIG)., Results: Of 1853 patients with KD, delayed admission (>10 days after fever onset) occurred in 16%, 25% had incomplete KD, and 11% were resistant to IVIG. Among 671 subjects with reported coronary artery z-score during follow-up (median: 79 days; IQR: 36, 186), 21% had CAA, including 4% with giant aneurysms. A simple prognostic model utilizing only a maximum coronary artery z-score ≥2.5 at initial presentation was optimal to predict CAA during follow-up (area under the curve: 0.84; 95% CI: 0.80, 0.88)., Conclusion: From our Latin American population, coronary artery z-score ≥2.5 at initial presentation was the most important prognostic factor preceding CAA during follow-up. These results highlight the importance of early echocardiography during the initial presentation of KD., Competing Interests: Declaration of Competing Interest The authors declare no conflicts of interest., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Objective: To describe the similarities and differences in the evaluation and treatment of multisystem inflammatory syndrome in children (MIS-C) at hospitals in the US., Study Design: We conducted a cross-sectional survey from June 16 to July 16, 2020, of US children's hospitals regarding protocols for management of patients with MIS-C. Elements included characteristics of the hospital, clinical definition of MIS-C, evaluation, treatment, and follow-up. We summarized key findings and compared results from centers in which >5 patients had been treated vs those in which ≤5 patients had been treated., Results: In all, 40 centers of varying size and experience with MIS-C participated in this protocol survey. Overall, 21 of 40 centers required only 1 day of fever for MIS-C to be considered. In the evaluation of patients, there was often a tiered approach. Intravenous immunoglobulin was the most widely recommended medication to treat MIS-C (98% of centers). Corticosteroids were listed in 93% of protocols primarily for moderate or severe cases. Aspirin was commonly recommended for mild cases, whereas heparin or low molecular weight heparin were to be used primarily in severe cases. In severe cases, anakinra and vasopressors frequently were recommended; 39 of 40 centers recommended follow-up with cardiology. There were similar findings between centers in which >5 patients vs ≤5 patients had been managed. Supplemental materials containing hospital protocols are provided., Conclusions: There are many similarities yet key differences between hospital protocols for MIS-C. These findings can help healthcare providers learn from others regarding options for managing MIS-C., (Copyright © 2020 Elsevier Inc. All rights reserved.)