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BackgroundGlycosylation patterns of serum proteins, such as α1-acid glycoprotein, are modified during an acute phase reaction. The response of acute Kawasaki disease (KD) patients to IVIG treatment has been linked to sialic acid levels on native IgG, suggesting that protein glycosylation patterns vary during the immune response in acute KD. Additionally, the distribution and function of lipoprotein particles are altered during inflammation. Therefore, the aim of this study was to explore the potential for GlycA, a marker of protein glycosylation, and the lipoprotein particle profile to distinguish pediatric patients with acute KD from those with other febrile illnesses.MethodsNuclear magnetic resonance was used to quantify GlycA and lipoprotein particle classes and subclasses in pediatric subjects with acute KD (n = 75), post-treatment subacute (n = 36) and convalescent (n = 63) KD, as well as febrile controls (n = 48), and age-similar healthy controls (n = 48).ResultsGlycA was elevated in acute KD subjects compared to febrile controls with bacterial or viral infections, IVIG-treated subacute and convalescent KD subjects, and healthy children (P

In the changing landscape of libraries and the roles of librarians, the area of Research Data Management (RDM) is emerging with new opportunities and challenges. This literature review identifies the current levels of publication that deal with the relationship of the librarian and their role in the research data management process and provides an examination of institutional research policies supporting collaboration of librarians as part of the research team.

Despite the extensive use of intermittent catheters (ICs) in healthcare, various issues persist for long-term IC users, such as pain, discomfort, infection, and tissue damage, including strictures, scarring and micro-abrasions. A lubricous IC surface is considered necessary to reduce patient pain and trauma, and therefore is a primary focus of IC development to improve patient comfort. While an important consideration, other factors should be routinely investigated to inform future IC development. An array of in vitro tests should be employed to assess IC's lubricity, biocompatibility and the risk of urinary tract infection development associated with their use. Herein, we highlight the importance of current in vitro characterisation techniques, the demand for optimisation and an unmet need to develop a universal 'toolkit' to assess IC properties. [ABSTRACT FROM AUTHOR]

BackgroundThe natural history of coronary artery aneurysms (CAA) after intravenous immunoglobulin (IVIG) treatment in the United States is not well described. We describe the natural history of CAA in US Kawasaki disease (KD) patients and identify factors associated with major adverse cardiac events (MACE) and CAA regression.Methods and ResultsWe evaluated all KD patients with CAA at 2 centers from 1979 to 2014. Factors associated with CAA regression, maximum CA z‐score over time (zMax), and MACE were analyzed. We performed a matched analysis of treatment effect on likelihood of CAA regression. Of 2860 KD patients, 500 (17%) had CAA, including 90 with CAA z‐score >10. Most (91%) received IVIG within 10 days of illness, 32% received >1 IVIG, and 27% received adjunctive anti‐inflammatory medications. CAA regression occurred in 75%. Lack of CAA regression and higher CAA zMax were associated with earlier era, larger CAA z‐score at diagnosis, and bilateral CAA in univariate and multivariable analyses. MACE occurred in 24 (5%) patients and was associated with higher CAA z‐score at diagnosis and lack of IVIG treatment. In a subset of patients (n=132) matched by age at KD and baseline CAA z‐score, those receiving IVIG plus adjunctive medication had a CAA regression rate of 91% compared with 68% for the 3 other groups (IVIG alone, IVIG ≥2 doses, or IVIG ≥2 doses plus adjunctive medication).ConclusionsCAA regression occurred in 75% of patients. CAA z‐score at diagnosis was highly predictive of outcomes, which may be improved by early IVIG treatment and adjunctive therapies.

ObjectiveTo 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 designUsing 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.ResultsThe 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.ConclusionThe 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.

ImportanceBecause clinical features do not reliably distinguish bacterial from viral infection, many children worldwide receive unnecessary antibiotic treatment, while bacterial infection is missed in others.ObjectiveTo identify a blood RNA expression signature that distinguishes bacterial from viral infection in febrile children.Design, setting, and participantsFebrile children presenting to participating hospitals in the United Kingdom, Spain, the Netherlands, and the United States between 2009-2013 were prospectively recruited, comprising a discovery group and validation group. Each group was classified after microbiological investigation as having definite bacterial infection, definite viral infection, or indeterminate infection. RNA expression signatures distinguishing definite bacterial from viral infection were identified in the discovery group and diagnostic performance assessed in the validation group. Additional validation was undertaken in separate studies of children with meningococcal disease (n = 24) and inflammatory diseases (n = 48) and on published gene expression datasets.ExposuresA 2-transcript RNA expression signature distinguishing bacterial infection from viral infection was evaluated against clinical and microbiological diagnosis.Main outcomes and measuresDefinite bacterial and viral infection was confirmed by culture or molecular detection of the pathogens. Performance of the RNA signature was evaluated in the definite bacterial and viral group and in the indeterminate infection group.ResultsThe discovery group of 240 children (median age, 19 months; 62% male) included 52 with definite bacterial infection, of whom 36 (69%) required intensive care, and 92 with definite viral infection, of whom 32 (35%) required intensive care. Ninety-six children had indeterminate infection. Analysis of RNA expression data identified a 38-transcript signature distinguishing bacterial from viral infection. A smaller (2-transcript) signature (FAM89A and IFI44L) was identified by removing highly correlated transcripts. When this 2-transcript signature was implemented as a disease risk score in the validation group (130 children, with 23 definite bacterial, 28 definite viral, and 79 indeterminate infections; median age, 17 months; 57% male), all 23 patients with microbiologically confirmed definite bacterial infection were classified as bacterial (sensitivity, 100% [95% CI, 100%-100%]) and 27 of 28 patients with definite viral infection were classified as viral (specificity, 96.4% [95% CI, 89.3%-100%]). When applied to additional validation datasets from patients with meningococcal and inflammatory diseases, bacterial infection was identified with a sensitivity of 91.7% (95% CI, 79.2%-100%) and 90.0% (95% CI, 70.0%-100%), respectively, and with specificity of 96.0% (95% CI, 88.0%-100%) and 95.8% (95% CI, 89.6%-100%). Of the children in the indeterminate groups, 46.3% (63/136) were classified as having bacterial infection, although 94.9% (129/136) received antibiotic treatment.Conclusions and relevanceThis study provides preliminary data regarding test accuracy of a 2-transcript host RNA signature discriminating bacterial from viral infection in febrile children. Further studies are needed in diverse groups of patients to assess accuracy and clinical utility of this test in different clinical settings.

BackgroundA psoriasis-like eruption develops in a subset of patients with Kawasaki disease (KD).ObjectiveWe sought to systematically compare KD-associated psoriasiform eruptions with classic psoriasis and the outcomes of KD in children with and without this rash.MethodsThis was a retrospective study of 11 KD cases with a psoriasiform eruption matched 1:2 by age, gender, and ethnicity with psoriasis-only and KD-only controls. Genotyping was performed in 10 cases for a deletion of 2 late cornified envelope (LCE) genes, LCE3C_LCE3B-del, associated with increased risk for pediatric-onset psoriasis.ResultsSimilar to classic psoriasis, KD-associated eruptions were characterized clinically by well-demarcated, scaly pink plaques and histopathologically by intraepidermal neutrophils, suprabasilar keratin 16 expression, and increased Ki-67 expression. They showed less frequent diaper area involvement, more crust and serous exudate, and an enduring remission (91% vs 23% with confirmed resolution; P

Kawasaki disease (KD) is the most common cause of acquired heart disease in children in developed countries.(1,2) The primary goal of treatment is to prevent coronary artery aneurysms (CAA). Between 10 and 20% of KD patients are resistant to treatment with intravenous immunoglobulin (IVIG) and have an almost nine-fold increased risk of developing CAA.(3) In addition, approximately 80-90% of patients who go on to develop CAA have abnormal coronary artery dimensions on their first echocardiogram and can therefore be identified as high-risk patients. These two subsets of KD patients are candidates for adjunctive therapy, in addition to IVIG. Understanding the mechanism of action of IVIG may provide insight into IVIG resistance and guidance for choosing adjunctive therapies in KD. Therapeutic options in the treatment of refractory KD and patients with early CAA include additional IVIG, glucocorticoids, tumor necrosis factor inhibitors, calcineurin inhibitors and interleukin-1 (IL-1) blockers.(3-10) Animal studies suggest that the anti-inflammatory properties of statins may also be beneficial in blocking CAA progression.(6) It is unlikely that these therapies will be studied in large, randomized controlled trials in the future due to required sample size and funding constraints. Thus, data from the research laboratory may be helpful in guiding selection of the most promising adjunctive therapies.

ObjectiveDelayed diagnosis of Kawasaki disease (KD) may lead to serious cardiac complications. We sought to create and test the performance of a natural language processing (NLP) tool, the KD-NLP, in the identification of emergency department (ED) patients for whom the diagnosis of KD should be considered.MethodsWe developed an NLP tool that recognizes the KD diagnostic criteria based on standard clinical terms and medical word usage using 22 pediatric ED notes augmented by Unified Medical Language System vocabulary. With high suspicion for KD defined as fever and three or more KD clinical signs, KD-NLP was applied to 253 ED notes from children ultimately diagnosed with either KD or another febrile illness. We evaluated KD-NLP performance against ED notes manually reviewed by clinicians and compared the results to a simple keyword search.ResultsKD-NLP identified high-suspicion patients with a sensitivity of 93.6% and specificity of 77.5% compared to notes manually reviewed by clinicians. The tool outperformed a simple keyword search (sensitivity = 41.0%; specificity = 76.3%).ConclusionsKD-NLP showed comparable performance to clinician manual chart review for identification of pediatric ED patients with a high suspicion for KD. This tool could be incorporated into the ED electronic health record system to alert providers to consider the diagnosis of KD. KD-NLP could serve as a model for decision support for other conditions in the ED.

BackgroundAlthough Kawasaki disease (KD) is the most common cause of acquired heart disease in children and may result in coronary artery aneurysms (CAA) with an attendant risk of myocardial infarction, there is no recommended therapy to halt progression of arterial wall damage and prevent aneurysm formation in the acute phase of the vasculitis. While intravenous immunoglobulin (IVIG) reduces the risk of CAA, up to 20% of KD patients are IVIG resistant and have a higher risk for developing CAA. The IL-1 pro-inflammatory pathway is upregulated in children with acute KD and plays a critical role in the experimental animal model of KD. Thus, IL-1 is a logical therapeutic target.ObjectivesThe goal of this study is to determine the safety, tolerability, pharmacokinetics, and immunomodulatory effects of anakinra, a recombinant human IL-1 receptor antagonist, in acute KD patients with coronary artery abnormalities on the baseline echocardiogram.DesignThis is a two-center dose-escalation Phase I/IIa trial in 30 acute KD patients ≥8months old with a coronary artery Z score≥3.0 in the right coronary artery and/or left anterior descending artery or an aneurysm. Subjects will receive a 2- to 6-week course of anakinra by daily subcutaneous injection and will be assessed for resolution of inflammation and dose limiting toxicities (leukopenia, anaphylactoid reaction, or severe infection).ConclusionThe safety and tolerability of blocking both IL-1α and Il-1β by anakinra will be evaluated as a strategy to prevent or attenuate coronary artery damage in infants and children with acute KD.Trial registrationClinical Trials.gov # NCT02179853, registered June 28, 2014.

Kawasaki disease is an acute, self-limited vasculitis of unknown etiology that occurs predominantly in infants and children. If not treated early with high-dose intravenous immunoglobulin, 1 in 5 children develop coronary artery aneurysms; this risk is reduced 5-fold if intravenous immunoglobulin is administered within 10 days of fever onset. Coronary artery aneurysms evolve dynamically over time, usually reaching a peak dimension by 6 weeks after illness onset. Almost all the morbidity and mortality occur in patients with giant aneurysms. Risk of myocardial infarction from coronary artery thrombosis is greatest in the first 2 years after illness onset. However, stenosis and occlusion progress over years. Indeed, Kawasaki disease is no longer a rare cause of acute coronary syndrome presenting in young adults. Both coronary artery bypass surgery and percutaneous intervention have been used to treat Kawasaki disease patients who develop myocardial ischemia as a consequence of coronary artery aneurysms and stenosis.

ObjectivesThe aim of this study was to characterize the range of management issues raised by adults with cardiovascular sequelae from Kawasaki disease (KD) in childhood.BackgroundAneurysms resulting from vascular inflammation associated with KD in childhood may remain clinically silent until adulthood. Adults with large aneurysms, unstable angina, or myocardial infarction following KD in childhood present unique challenges to interventional cardiologists and cardiothoracic surgeons.MethodsIn an observational study of adults with histories of KD in childhood, data were collected regarding the medical histories and outcomes of 154 adult KD patients, of whom 21 underwent either percutaneous interventions or surgery.ResultsOf the 21 subjects with interventions, 11 had been diagnosed with KD in childhood, and 10 had histories of KD-compatible illnesses. Seventeen subjects were asymptomatic until experiencing acute cardiovascular symptoms: acute myocardial infarction (n = 12), angina (n = 2), end-stage congestive heart failure requiring cardiac transplantation (n = 1), and claudication (n = 2).ConclusionsCardiovascular complications in these subjects illustrate the following points: 1) even small to moderate-sized aneurysms that "normalize" on echocardiography in childhood can lead to stenosis and thrombosis decades after the acute illness; 2) coronary interventions without intravascular ultrasound may result in clinically significant underestimation of vessel luminal diameter; 3) failure to assess the extent of calcification may lead to suboptimal procedural outcomes; and 4) patients with symptomatic peripheral aneurysms may benefit from endarterectomy or resection. Interventional cardiologists should be aware of the potential challenges in treating this growing population of adults.

BackgroundImportant therapeutic decisions are made based on the presence or absence of fever in patients with Kawasaki disease (KD), yet no standard method or threshold exists for temperature measurement during the diagnosis and treatment of these patients. We sought to compare surface and internal (rectal or oral) routes of temperature measurement for the detection of fever as a marker of treatment resistance.MethodsFrom a randomized, placebo-controlled trial of infliximab as an adjunct to primary intravenous immunoglobulin treatment for acute KD, we collected concurrent (within 5 minutes) axillary and internal temperature measurements and performed receiver-operating characteristic and Bland-Altman analyses. We also determined the ability of surface temperatures to detect treatment resistance defined by internal temperature measurements.ResultsAmong 452 oral-axillary and 439 rectal-axillary pairs from 159 patients, mean axillary temperatures were 0.25 and 0.43 °C lower than oral and rectal temperatures and had high receiver-operating characteristic areas under curves. However, axillary temperatures ≥ 38.0 °C had limited sensitivity to detect fever defined by internal temperatures. Axillary thresholds of 37.5 and 37.2 °C provided maximal sensitivity and specificity to detect oral and rectal temperatures ≥ 38.0 °C, respectively.ConclusionsAxillary temperatures are an insensitive metric for fevers defining treatment resistance. Clinical trials should adopt temperature measurement by the oral or rectal routes for adjudication of treatment resistance in KD.

BackgroundKawasaki disease (KD) is an acute vasculitis in children that can cause coronary artery abnormalities. Its diagnosis is challenging, and many cytokines, chemokines, acute phase reactants, and growth factors have failed evaluation as specific biomarkers to distinguish KD from other febrile illnesses. We performed protein profiling, comparing plasma from children with KD with febrile control (FC) subjects to determine if there were specific proteins or peptides that could distinguish the two clinical states.Materials and methodsPlasma from three independent cohorts from the blood of 68 KD and 61 FC subjects was fractionated by anion exchange chromatography, followed by surface-enhanced laser desorption ionization (SELDI) mass spectrometry of the fractions. The mass spectra of KD and FC plasma samples were analyzed for peaks that were statistically significantly different.ResultsA mass spectrometry peak with a mass of 7,860 Da had high intensity in acute KD subjects compared to subacute KD (p = 0.0003) and FC (p = 7.9 x 10-10) subjects. We identified this peak as a novel truncated form of serum amyloid A with N-terminal at Lys-34 of the circulating form and validated its identity using a hybrid mass spectrum immunoassay technique. The truncated form of serum amyloid A was present in plasma of KD subjects when blood was collected in tubes containing protease inhibitors. This peak disappeared when the patients were examined after their symptoms resolved. Intensities of this peptide did not correlate with KD-associated laboratory values or with other mass spectrum peaks from the plasma of these KD subjects.ConclusionsUsing SELDI mass spectrometry, we have discovered a novel truncated form of serum amyloid A that is elevated in the plasma of KD when compared with FC subjects. Future studies will evaluate its relevance as a diagnostic biomarker and its potential role in the pathophysiology of KD.

ObjectivesKawasaki disease (KD) is an acute pediatric vasculitis of infants and young children with unknown etiology and no specific laboratory-based test to identify. A specific molecular diagnostic test is urgently needed to support the clinical decision of proper medical intervention, preventing subsequent complications of coronary artery aneurysms. We used a simple and low-cost colorimetric sensor array to address the lack of a specific diagnostic test to differentiate KD from febrile control (FC) patients with similar rash/fever illnesses.Study designDemographic and clinical data were prospectively collected for subjects with KD and FCs under standard protocol. After screening using a genetic algorithm, eleven compounds including metalloporphyrins, pH indicators, redox indicators and solvatochromic dye categories, were selected from our chromatic compound library (n = 190) to construct a colorimetric sensor array for diagnosing KD. Quantitative color difference analysis led to a decision-tree-based KD diagnostic algorithm.ResultsThis KD sensing array allowed the identification of 94% of KD subjects (receiver operating characteristic [ROC] area under the curve [AUC] 0.981) in the training set (33 KD, 33 FC) and 94% of KD subjects (ROC AUC: 0.873) in the testing set (16 KD, 17 FC). Color difference maps reconstructed from the digital images of the sensing compounds demonstrated distinctive patterns differentiating KD from FC patients.ConclusionsThe colorimetric sensor array, composed of common used chemical compounds, is an easily accessible, low-cost method to realize the discrimination of subjects with KD from other febrile illness.

BackgroundResistance to intravenous immunoglobulin (IVIG) occurs in 10-20% of patients with Kawasaki disease (KD). The risk of resistance is about two-fold higher in patients with elevated gamma glutamyl transferase (GGT) levels. We sought to understand the biological mechanisms underlying IVIG resistance in patients with elevated GGT levels.MethodWe explored the association between elevated GGT levels and IVIG-resistance with a cohort of 686 KD patients (Cohort I). Gene expression data from 130 children with acute KD (Cohort II) were analyzed using the R square statistic and false discovery analysis to identify genes that were differentially represented in patients with elevated GGT levels with regard to IVIG responsiveness. Two additional KD cohorts (Cohort III and IV) were used to test the hypothesis that sialylation and GGT may be involved in IVIG resistance through neutrophil apoptosis.ResultsThirty-six genes were identified that significantly explained the variations of both GGT levels and IVIG responsiveness in KD patients. After Bonferroni correction, significant associations with IVIG resistance persisted for 12 out of 36 genes among patients with elevated GGT levels and none among patients with normal GGT levels. With the discovery of ST6GALNAC3, a sialyltransferase, as the most differentially expressed gene, we hypothesized that sialylation and GGT are involved in IVIG resistance through neutrophil apoptosis. We then confirmed that in Cohort III and IV there was significantly less reduction in neutrophil count in IVIG non-responders.ConclusionsGene expression analyses combining molecular and clinical datasets support the hypotheses that: (1) neutrophil apoptosis induced by IVIG may be a mechanism of action of IVIG in KD; (2) changes in sialylation and GGT level in KD patients may contribute synergistically to IVIG resistance through blocking IVIG-induced neutrophil apoptosis. These findings have implications for understanding the mechanism of action in IVIG resistance, and possibly for development of novel therapeutics.

BackgroundWe sought to determine if fever in the early postintravenous immunoglobulin (IVIG) time period (first 36 hours after IVIG completion) for Kawasaki disease, with or without additional infliximab, can predict IVIG resistance and coronary artery abnormalities (CAA).MethodsAcute Kawasaki disease subjects enrolled in a clinical trial of infliximab plus IVIG (n = 96) versus placebo/IVIG (n = 94) had temperatures recorded every 6 hours after completion of IVIG infusion. Fever was defined as temperature >38.0°C; patients with persistent or recrudescent fever >36 hours after completion of IVIG were classified as IVIG resistant. Multivariable logistic regression by fever pattern was performed to predict outcomes (IVIG resistance and CAA).ResultsThere was no difference in the time to defervescence between the infliximab/IVIG group (n = 96) versus placebo/IVIG group (n = 94). There was no fever after completion of IVIG in the majority of subjects [66% of those with no CAA (n = 139) and 76.5% of those with CAA, (n = 51)]. Although subjects with at least 1 fever 24-36 hours post-IVIG had a higher probability of IVIG resistance [odds ratio = 30.6 (95% confidence interval: 6.7-139.8); P < 0.0001], fever at 24-36 hours was not associated with higher likelihood of CAA. There were also 11% (n = 19) of IVIG responders who had fever at 24-36 hours post-IVIG. The majority of subjects with CAA (43 of 51, 84.3%) were identified by the initial echocardiogram, so the effect of fever on development of CAA could not be assessed.ConclusionsFever in the first 36 hours after IVIG completion is not predictive of CAA. Our data support refraining from retreatment until 36 hours after completion of IVIG.

Galectin-3 (Gal-3) is a multifunctional matricellular protein associated with heart failure and cardiovascular events. Gal-3 is required for transforming growth factor-β pathway-mediated myofibroblast activation that is a key process in coronary artery aneurysm formation in Kawasaki Disease (KD). Autopsies from young adults late after KD onset (AKD) have demonstrated bridging fibrosis throughout the myocardium and arteries. In this study, we postulated that Gal-3 may participate in the pathogenesis of myocardial and vascular fibrosis and the remodeling of coronary artery aneurysms following acute KD.We measured plasma Gal-3 levels in 63 pediatric KD (PKD) and 81 AKD subjects. AKD subjects with giant aneurysms had significantly higher Gal-3 levels compared to the other adult groups (all p

BackgroundAs Kawasaki disease (KD) shares many clinical features with other more common febrile illnesses and misdiagnosis, leading to a delay in treatment, increases the risk of coronary artery damage, a diagnostic test for KD is urgently needed. We sought to develop a panel of biomarkers that could distinguish between acute KD patients and febrile controls (FC) with sufficient accuracy to be clinically useful.MethodsPlasma samples were collected from three independent cohorts of FC and acute KD patients who met the American Heart Association definition for KD and presented within the first 10 d of fever. The levels of 88 biomarkers associated with inflammation were assessed by Luminex bead technology. Unsupervised clustering followed by supervised clustering using a Random Forest model was used to find a panel of candidate biomarkers.ResultsA panel of biomarkers commonly available in the hospital laboratory (absolute neutrophil count, erythrocyte sedimentation rate, alanine aminotransferase, γ-glutamyl transferase, concentrations of α-1-antitrypsin, C-reactive protein, and fibrinogen, and platelet count) accurately diagnosed 81-96% of KD patients in a series of three independent cohorts.ConclusionAfter prospective validation, this eight-biomarker panel may improve the recognition of KD.

IntroductionSince the 1980s, the primary treatment of acute Kawasaki disease (KD) has been intravenous immunoglobulin and aspirin. However, 5-10% of children with acute KD will develop coronary artery abnormalities despite treatment within the first ten days after fever onset. There is no approved adjunctive therapy to prevent progression of coronary artery damage in these patients.Areas coveredThe rationale and study design of a Phase I/IIa trial of atorvastatin in children with acute KD and coronary artery inflammation is presented. The studies of host genetics and KD pathogenesis leading up to this trial are reviewed.Expert opinionThe repurposing of well-studied drugs used in the adult population is a cost-effective and efficient strategy to identify new therapies for pediatric diseases. Exploiting the anti-inflammatory, non-lipid-lowering effects of statins may open up new applications for this class of drugs for the pediatric age group.

PurposeCoronary artery aneurysms (CAA) may remain silent after Kawasaki disease (KD) until adulthood when myocardial ischemia can lead to sudden death. We postulated that there would be young adults with sudden, unexpected death due to CAA from KD who would have a state-mandated autopsy performed by the San Diego County Medical Examiner's Office (SDCMEO).MethodsWe reviewed all autopsy cases

The introduction of intravenous immunoglobulin (IVIG) for modulation of inflammation in acute Kawasaki disease was a great therapeutic triumph. However, three decades later, the mechanisms underlying immune regulation by IVIG are only beginning to be revealed. Stimulation of an immature myeloid population of dendritic cells that secretes IL-10 and the elucidation of Fc-specific natural regulatory T cells provide insights into the mechanisms of IVIG. Other potential mechanisms include provision of agent-specific neutralizing antibody, anti-idiotype and anti-cytokine antibodies, blockade of activating Fcγ receptors and stimulation of the inhibitory FcγRIIb receptor. New initiatives must seek to understand the mechanisms of IVIG in order to replace it one day with more affordable and more targeted therapies.

Coronary artery aneurysms (CAA) remain an important complication of Kawasaki disease (KD), the most common form of pediatric acquired heart disease in developed countries. Potentially life-threatening CAA develop in 25% of untreated children and 5% of children treated with high-dose intravenous immunoglobulin during the acute phase of the self-limited vasculitis. Noncoronary artery aneurysms (NCAA) in extraparenchymal, muscular arteries occur in a minority of patients with KD who also have CAA, yet little is understood about their formation and remodeling. We postulated that activation of the transforming growth factor-β (TGF-β) pathway in KD may influence formation and remodeling of aneurysms in iliac, femoral, and axillary arteries, the most common sites for NCAA. We studied a resected axillary artery from one adult and endarterectomy tissue from the femoral artery from a second adult, both with a history of CAA and NCAA following KD in infancy. Histology of the axillary artery aneurysm revealed destruction of the internal elastic lamina and recanalization of organized thrombus, while the endarterectomy specimen showed dense calcification and luminal myofibroblastic proliferation. Immunohistochemistry for molecules in the TGF-β signaling pathway revealed increased expression of TGF-β2, TGF-β receptor 2, and phosphorylated SMAD3. These findings suggest ongoing tissue remodeling of the aneurysms decades after the acute injury and demonstrate the importance of the TGF-β signaling pathway in this process.

The activation of natural regulatory T cells (nTreg) recognizing the heavy constant region (Fc) of IgG is an important mechanism of action of intravenous immunoglobulin (IVIG) therapy in Kawasaki disease (KD). Lack of circulating Fc-specific nTreg in the sub-acute phase of KD is correlated with the development of coronary artery abnormalities (CAA). Here, we characterize the fine specificity of nTreg in sub-acute (2- to 8-week post-IVIG) and convalescent (1- to 10-year post-IVIG) KD subjects by testing the immunogenicity of 64 peptides, 15 amino acids in length with a 10 amino acid-overlap spanning the entire Fc protein. About 12 Fc peptides (6 pools of 2 consecutive peptides) were recognized by nTreg in the cohorts studied, including two patients with CAA. To test whether IVIG expands the same nTreg populations that maintain vascular homeostasis in healthy subjects, we compared these results with results obtained in healthy adult controls. Similar nTreg fine specificities were observed in KD patients after IVIG and in healthy donors. These results suggest that T cell fitness rather than T cell clonal deletion or anergy is responsible for the lack of Fc-specific nTreg in KD patients who develop CAA. Furthermore, we found that adolescents and adults who had KD during childhood without developing CAA did not respond to the Fc protein in vitro, suggesting that the nTreg response induced by IVIG in KD patients is short-lived. Our results support the concept that peptide epitopes may be a viable therapeutic approach to expand Fc-specific nTreg and more effectively prevent CAA in KD patients.

Coronary artery aneurysms that occur in 25% of untreated Kawasaki disease (KD) patients may remain clinically silent for decades and then thrombose resulting in myocardial infarction. Although KD is now the most common cause of acquired heart disease in children in Asia, the United States, and Western Europe, the incidence of KD in Egypt is unknown. We tested the hypothesis that young adults in Egypt presenting with acute myocardial ischemia may have coronary artery lesions because of KD in childhood. We reviewed a total of 580 angiograms of patients ≤40 years presenting with symptoms of myocardial ischemia. Coronary artery aneurysms were noted in 46 patients (7.9%), of whom 9 presented with myocardial infarction. The likelihood of antecedent KD as the cause of the aneurysms was classified as definite (n = 10), probable (n = 29), or equivocal (n = 7). Compared with the definite and probable groups, the equivocal group had more traditional cardiovascular risk factors, smaller sized aneurysms, and fewer coronary arteries affected. In conclusion, in a major metropolitan center in Egypt, 6.7% of adults aged ≤40 years who underwent angiography for evaluation of possible myocardial ischemia had lesions consistent with antecedent KD. Because of the unique therapeutic challenges associated with these lesions, adult cardiologists should be aware that coronary artery aneurysms in young adults may be because of missed KD in childhood.

Kawasaki disease (KD) is the leading cause of acquired heart disease in children and can result in life-threatening coronary artery aneurysms in up to 25 % of patients. These aneurysms put patients at risk of thrombus formation, myocardial infarction, and sudden death. Clinicians must therefore decide which patients should be treated with anticoagulant medication, and/or surgical or percutaneous intervention. Current recommendations regarding initiation of anticoagulant therapy are based on anatomy alone with historical data suggesting that patients with aneurysms [Formula: see text]8 mm are at greatest risk of thrombosis. Given the multitude of variables that influence thrombus formation, we postulated that hemodynamic data derived from patient-specific simulations would more accurately predict risk of thrombosis than maximum diameter alone. Patient-specific blood flow simulations were performed on five KD patients with aneurysms and one KD patient with normal coronary arteries. Key hemodynamic and geometric parameters, including wall shear stress, particle residence time, and shape indices, were extracted from the models and simulations and compared with clinical outcomes. Preliminary fluid structure interaction simulations with radial expansion were performed, revealing modest differences in wall shear stress compared to the rigid wall case. Simulations provide compelling evidence that hemodynamic parameters may be a more accurate predictor of thrombotic risk than aneurysm diameter alone and motivate the need for follow-up studies with a larger cohort. These results suggest that a clinical index incorporating hemodynamic information be used in the future to select patients for anticoagulant therapy.

BackgroundGlobal gene expression profiling can provide insight into the underlying pathophysiology of disease processes. Kawasaki disease (KD) is an acute, self-limited vasculitis whose etiology remains unknown. Although the clinical illness shares certain features with other pediatric infectious diseases, the occurrence of coronary artery aneurysms in 25% of untreated patients is unique to KD.MethodsTo gain further insight into the molecular mechanisms underlying KD, we investigated the acute and convalescent whole blood transcriptional profiles of 146 KD subjects and compared them with the transcriptional profiles of pediatric patients with confirmed bacterial or viral infection, and with healthy control children. We also investigated the transcript abundance in patients with different intravenous immunoglobulin treatment responses and different coronary artery outcomes.ResultsThe overwhelming signature for acute KD involved signaling pathways of the innate immune system. Comparison with other acute pediatric infections highlighted the importance of pathways involved in cell motility including paxillin, relaxin, actin, integrins, and matrix metalloproteinases. Most importantly, the IL1β pathway was identified as a potential therapeutic target.ConclusionOur study revealed the importance of the IL-1 signaling pathway and a prominent signature of innate immunity and cell migration in the acute phase of the illness.

ObjectiveTo 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 designFasting 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.ResultsCompared 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

This article describes the patient-centered Scalable National Network for Effectiveness Research (pSCANNER), which is part of the recently formed PCORnet, a national network composed of learning healthcare systems and patient-powered research networks funded by the Patient Centered Outcomes Research Institute (PCORI). It is designed to be a stakeholder-governed federated network that uses a distributed architecture to integrate data from three existing networks covering over 21 million patients in all 50 states: (1) VA Informatics and Computing Infrastructure (VINCI), with data from Veteran Health Administration's 151 inpatient and 909 ambulatory care and community-based outpatient clinics; (2) the University of California Research exchange (UC-ReX) network, with data from UC Davis, Irvine, Los Angeles, San Francisco, and San Diego; and (3) SCANNER, a consortium of UCSD, Tennessee VA, and three federally qualified health systems in the Los Angeles area supplemented with claims and health information exchange data, led by the University of Southern California. Initial use cases will focus on three conditions: (1) congestive heart failure; (2) Kawasaki disease; (3) obesity. Stakeholders, such as patients, clinicians, and health service researchers, will be engaged to prioritize research questions to be answered through the network. We will use a privacy-preserving distributed computation model with synchronous and asynchronous modes. The distributed system will be based on a common data model that allows the construction and evaluation of distributed multivariate models for a variety of statistical analyses.

Evidence indicates that the densely cultivated region of northeastern China acts as a source for the wind-borne agent of Kawasaki disease (KD). KD is an acute, coronary artery vasculitis of young children, and still a medical mystery after more than 40 y. We used residence times from simulations with the flexible particle dispersion model to pinpoint the source region for KD. Simulations were generated from locations spanning Japan from days with either high or low KD incidence. The postepidemic interval (1987-2010) and the extreme epidemics (1979, 1982, and 1986) pointed to the same source region. Results suggest a very short incubation period (

To perform experimental validation of computational fluid dynamics (CFD) applied to patient specific coronary aneurysm anatomy of Kawasaki disease. We quantified hemodynamics in a patient-specific coronary artery aneurysm physical phantom under physiologic rest and exercise flow conditions. Using phase contrast MRI (PCMRI), we acquired 3-component flow velocity at two slice locations in the aneurysms. We then performed numerical simulations with the same geometry and inflow conditions, and performed qualitative and quantitative comparisons of velocities between experimental measurements and simulation results. We observed excellent qualitative agreement in flow pattern features. The quantitative spatially and temporally varying differences in velocity between PCMRI and CFD were proportional to the flow velocity. As a result, the percent discrepancy between simulation and experiment was relatively constant regardless of flow velocity variations. Through 1D and 2D quantitative comparisons, we found a 5-17% difference between measured and simulated velocities. Additional analysis assessed wall shear stress differences between deformable and rigid wall simulations. This study demonstrated that CFD produced good qualitative and quantitative predictions of velocities in a realistic coronary aneurysm anatomy under physiological flow conditions. The results provide insights on factors that may influence the level of agreement, and a set of in vitro experimental data that can be used by others to compare against CFD simulation results. The findings of this study increase confidence in the use of CFD for investigating hemodynamics in the specialized anatomy of coronary aneurysms. This provides a basis for future hemodynamics studies in patient-specific models of Kawasaki disease.

BackgroundKawasaki disease, the most common cause of acquired heart disease in developed countries, is a self-limited vasculitis that is treated with high doses of intravenous immunoglobulin. Resistance to intravenous immunoglobulin in Kawasaki disease increases the risk of coronary artery aneurysms. We assessed whether the addition of infliximab to standard therapy (intravenous immunoglobulin and aspirin) in acute Kawasaki disease reduces the rate of treatment resistance.MethodsWe undertook a phase 3, randomised, double-blind, placebo-controlled trial in two children's hospitals in the USA to assess the addition of infliximab (5 mg per kg) to standard therapy. Eligible participants were children aged 4 weeks-17 years who had a fever (temperature ≥38·0°C) for 3-10 days and met American Heart Association criteria for Kawasaki disease. Participants were randomly allocated in 1:1 ratio to two treatment groups: infliximab 5 mg/kg at 1 mg/mL intravenously over 2 h or placebo (normal saline 5 mL/kg, administered intravenously). Randomisation was based on a randomly permuted block design (block sizes 2 and 4), stratified by age, sex, and centre. Patients, treating physicians and staff, study team members, and echocardiographers were all masked to treament assignment. The primary outcome was the difference between the groups in treatment resistance defined as a temperature of 38·0°C or higher at 36 h to 7 days after completion of the infusion of intravenous immunoglobulin. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, NCT00760435.Findings196 patients were enrolled and randomised: 98 to the infliximab group and 98 to placebo. One patient in the placebo group was withdrawn from the study because of hypotension before receiving treatment. Treatment resistance rate did not differ significantly (11 [11·2%] for infliximab and 11 [11·3%] for placebo; p=0·81). Compared with the placebo group, participants given infliximab had fewer days of fever (median 1 day for infliximab vs 2 days for placebo; p

Intravenous immunoglobulin therapy (IVIG) is the treatment of choice for many immune-mediated diseases, yet its mechanisms of action are incompletely elucidated. We investigated the possibility that IVIG played a direct role in the expansion of regulatory T cells (Treg) that recognize the heavy chain constant region of immunoglobulin G (Fc) as a mechanism for the recovery of Kawasaki disease (KD), a T cell mediated pediatric vasculitis of the coronary arteries. We successfully generated Fc-specific Treg clones from sub-acute KD subjects that did not develop arterial complications after IVIG and defined an unusual functional phenotype: Fc-specific Treg secrete IL-10 and small amounts of IL-4 but not TGF-β. Antigen presentation studies demonstrated that these Treg clones can be activated by autologous B cells that express IgG on their cell surface in the absence of exogenous Fc. The IgG molecule has to be canonically processed and presented by autologous MHC molecules to be recognized by Treg. In support of the importance of this novel Treg population in downsizing vascular inflammation, KD patients with dilated coronary arteries or aneurysms despite IVIG treatment failed to expand Fc-specific Treg. Our results point to a specificity of a previously un-described Treg population for the clinical benefit provided by IVIG therapy in children.