Risk Model Development and Validation for Prediction of Coronary Artery Aneurysms in Kawasaki Disease in a North American Population.

Background Accurate prediction of coronary artery aneurysms ( CAAs ) in patients with Kawasaki disease remains challenging in North American cohorts. We sought to develop and validate a risk model for CAA prediction. Methods and Results A binary outcome of CAA was defined as left anterior descending or right coronary artery Z score ≥2.5 at 2 to 8 weeks after fever onset in a development cohort (n=903) and a validation cohort (n=185) of patients with Kawasaki disease. Associations of baseline clinical, laboratory, and echocardiographic variables with later CAA were assessed in the development cohort using logistic regression. Discrimination (c statistic) and calibration (Hosmer-Lemeshow) of the final model were evaluated. A practical risk score assigning points to each variable in the final model was created based on model coefficients from the development cohort. Predictors of CAAs at 2 to 8 weeks were baseline Z score of left anterior descending or right coronary artery ≥2.0, age <6 months, Asian race, and C-reactive protein ≥13 mg/ dL (c=0.82 in the development cohort, c=0.93 in the validation cohort). The CAA risk score assigned 2 points for baseline Z score of left anterior descending or right coronary artery ≥2.0 and 1 point for each of the other variables, with creation of low- (0-1), moderate- (2), and high- (3-5) risk groups. The odds of CAA s were 16-fold greater in the high- versus the low-risk groups in the development cohort (odds ratio, 16.4; 95% CI , 9.71-27.7 [ P<0.001]), and >40-fold greater in the validation cohort (odds ratio, 44.0; 95% CI, 10.8-180 [ P<0.001]). Conclusions Our risk model for CAA in Kawasaki disease consisting of baseline demographic, laboratory, and echocardiographic variables had excellent predictive utility and should undergo prospective testing

Treatment Intensification in Patients With Kawasaki Disease and Coronary Aneurysm at Diagnosis.

BackgroundCoronary artery aneurysms (CAA) are a serious complication of Kawasaki disease. Treatment with intravenous immunoglobulin (IVIg) within 10 days of fever onset reduces the risk of CAA from 25% to <5%. Corticosteroids and infliximab are often used in high-risk patients or those with CAA at diagnosis, but there are no data on their longer-term impact on CAA.MethodsRetrospective multicenter study including children who had CAA with a z score ≥2.5 and <10 at time of diagnosis and who received primary therapy with IVIg alone or in combination with either corticosteroids or infliximab within 10 days of onset of fever.ResultsOf 121 children, with a median age of 2.8 (range 0.1-15.5) years, 30 (25%) received primary therapy with corticosteroids and IVIg, 58 (48%) received primary therapy with infliximab and IVIg, and 33 (27%) received primary therapy with IVIg only. Median coronary z scores at the time of diagnosis did not differ among treatment groups (P = .39). Primary treatment intensification with either corticosteroids or infliximab were independent protective factors against progression of coronary size on follow-up (coefficient: -1.31 [95% confidence interval: -2.33 to -0.29]; coefficient: -1.07 [95% confidence interval: -1.95 to -0.19], respectively).ConclusionsAmong a high-risk group of patients with Kawasaki disease with CAA on baseline echocardiography, those treated with corticosteroids or infliximab in addition to IVIg had less progression in CAA size compared with those treated with IVIg alone. Prospective randomized trials are needed to determine the best adjunctive treatment of patients who present with CAA

Temporal Trends in Pulse Pressure and Mean Arterial Pressure During the Rise of Pediatric Obesity in US Children

Background: Somatic growth in childhood is accompanied by substantial remodeling of the aorta. Obesity is associated with increased aortic stiffness and flow and may interfere with aortic remodeling during growth. Wide pulse pressure (PP) indicates mismatch between aortic impedance and pulsatile flow and increases risk for future systolic hypertension and cardiovascular disease (CVD). We hypothesized that the rise of pediatric obesity would be associated with a temporal trend to higher PP. Methods and Results: We analyzed demographic, anthropometric, and blood pressure (BP) data for 8‐ to 17‐year‐old children (N=16 457) from the cross‐sectional National Health and Nutrition Examination Surveys (NHANES) for 1976 through 2008. Multivariable adjusted survey regression was used to examine temporal trends in PP and mean arterial pressure (MAP) and the relation to obesity. Across this period, unadjusted PP was higher (0.29 mm Hg/y, 95% CI 0.26 to 0.33 mm Hg/y; P<0.0001), while MAP was lower (−0.24 mm Hg/y, 95% CI −0.27 to −0.20 mm Hg/y; P<0.0001) across examinations. Adjusting for body mass index partially attenuated the temporal trend for PP by 32% (P<0.0001). Obesity amplified the relation between taller height and higher PP (from 0.23 [95% CI 0.19 to 0.28] to 0.27 [95% CI 0.21 to 0.34] mm Hg/cm height in boys and from 0.08 [95% CI 0.04 to 0.13] to 0.22 [95% CI 0.13 to 0.31] mm Hg/cm height in girls; P<0.01 for both). Conclusions: PP has increased during the rise of pediatric obesity. Higher PP may indicate mismatch between aortic diameter, wall stiffness, and flow in obese children during a period of rapid somatic growth when the aorta is already under considerable remodeling stress

Diagnosis of incomplete Kawasaki disease

Several authors suggested that the clinical characteristics of incomplete presentation of Kawasaki disease are similar to those of complete presentation and that the 2 forms of presentation are not separate entities. Based on this suggestion, a diagnosis of incomplete Kawasaki disease in analogy to the findings of complete presentation is reasonable. Currently, the diagnosis of incomplete Kawasaki disease might be made in cases with fewer classical diagnostic criteria and with several compatible clinical, laboratory or echocardiographic findings on the exclusion of other febrile illness. Definition of incomplete presentation in which coronary artery abnormalities are included as a necessary condition, is restrictive and specific. The validity of the diagnostic criteria of incomplete presentation by the American Heart Association should be thoroughly tested in the immediate future

Kawasaki syndrome: an intriguing disease with numerous unsolved dilemmas

More than 40 years have passed since Kawasaki syndrome (KS) was first described. Yet KS still remains an enigmatic illness which damages the coronary arteries in a quarter of untreated patients and is the most common cause of childhood-acquired heart disease in developed countries. Many gaps exist in our knowledge of the etiology and pathogenesis of KS, making improvements in therapy difficult. In addition, many KS features and issues still demand further efforts to achieve a much better understanding of the disease. Some of these problem areas include coronary artery injuries in children not fulfilling the classic diagnostic criteria, genetic predisposition to KS, unpredictable ineffectiveness of current therapy in some cases, vascular dysfunction in patients not showing echocardiographic evidence of coronary artery abnormalities in the acute phase of KS, and risk of potential premature atherosclerosis. Also, the lack of specific laboratory tests for early identification of the atypical and incomplete cases, especially in infants, is one of the main obstacles to beginning treatment early and thereby decreasing the incidence of cardiovascular involvement. Transthoracic echocardiography remains the gold-standard for evaluation of coronary arteries in the acute phase and follow-up. In KS patients with severe vascular complications, more costly and potentially invasive investigations such as coronary CT angiography and MRI may be necessary. As children with KS with or without heart involvement become adolescents and adults, the recognition and treatment of the potential long term sequelae become crucial, requiring that rheumatologists, infectious disease specialists, and cardiologists cooperate to develop specific guidelines for a proper evaluation and management of these patients. More education is needed for physicians and other professionals about how to recognize the long-term impact of systemic problems related to KS

Clinical characteristics of Kawasaki disease with sterile pyuria

PurposeKawasaki disease (KD) is a systemic vasculitis and affects many organ systems. It often presents sterile pyuria, microscopic hematuria, and proteinuria due to renal involvement. The aims of this study were to define clinical characteristics of acute KD patients with pyuria and to analyze meaning of pyuria in KD.MethodsThe medical records and laboratory findings including serum and urine test of 133 patients with KD admitted to Yeungnam University Hospital from March 2006 to December 2010 were reviewed retrospectively.ResultsForty patients had sterile pyuria and their clinical characteristics including age, gender and body weight were not significantly different with those who did not have pyuria. Fever duration after treatment was significantly longer in KD patients with pyuria. Erythrocyte sedimentation rate, C-reactive protein and serum concentration of alanine aminotransferase were significantly higher in patients with pyuria. Hyponatremia and coronary artery lesion were seen more often in patients with pyuria but there was no significant difference. Also serum blood urea nitrogen was significantly higher in KD patients with pyuria. Urine β2-microglobulin was elevated in both patients groups and showed no difference between two groups.ConclusionWe found more severe inflammatory reaction in KD patients with pyuria. We also found elevation of some useful parameters like β2-microglobulin that indicate renal involvement of KD through the urine test. Careful management and follow up will need for KD patients with pyuria and it is necessary in the future to study the specific parameters for renal involvement of KD

High Resolution Models of Transcription Factor-DNA Affinities Improve In Vitro and In Vivo Binding Predictions

Accurately modeling the DNA sequence preferences of transcription factors (TFs), and using these models to predict in vivo genomic binding sites for TFs, are key pieces in deciphering the regulatory code. These efforts have been frustrated by the limited availability and accuracy of TF binding site motifs, usually represented as position-specific scoring matrices (PSSMs), which may match large numbers of sites and produce an unreliable list of target genes. Recently, protein binding microarray (PBM) experiments have emerged as a new source of high resolution data on in vitro TF binding specificities. PBM data has been analyzed either by estimating PSSMs or via rank statistics on probe intensities, so that individual sequence patterns are assigned enrichment scores (E-scores). This representation is informative but unwieldy because every TF is assigned a list of thousands of scored sequence patterns. Meanwhile, high-resolution in vivo TF occupancy data from ChIP-seq experiments is also increasingly available. We have developed a flexible discriminative framework for learning TF binding preferences from high resolution in vitro and in vivo data. We first trained support vector regression (SVR) models on PBM data to learn the mapping from probe sequences to binding intensities. We used a novel -mer based string kernel called the di-mismatch kernel to represent probe sequence similarities. The SVR models are more compact than E-scores, more expressive than PSSMs, and can be readily used to scan genomics regions to predict in vivo occupancy. Using a large data set of yeast and mouse TFs, we found that our SVR models can better predict probe intensity than the E-score method or PBM-derived PSSMs. Moreover, by using SVRs to score yeast, mouse, and human genomic regions, we were better able to predict genomic occupancy as measured by ChIP-chip and ChIP-seq experiments. Finally, we found that by training kernel-based models directly on ChIP-seq data, we greatly improved in vivo occupancy prediction, and by comparing a TF's in vitro and in vivo models, we could identify cofactors and disambiguate direct and indirect binding