Association of Acute Anti-inflammatory Treatment With Medium-term Outcomes for Coronary Artery Aneurysms in Kawasaki Disease.

Background: The impact of adjunctive anti-inflammatory treatment on outcomes for patients with Kawasaki disease (KD) and coronary artery aneurysms (CAAs) is unknown. Methods: Using data from the International KD Registry in patients with ≥ medium CAA we evaluate associations of treatment with outcomes and major adverse cardiac events (MACE). Results: Medium or large CAA was present in 527 (32%) patients. All were treated with intravenous immunoglobulin (IVIG), 70% were male, and the median age was 1.3 years (interquartile range: 0.4-4.0 years). The most common acute therapies included single IVIG alone in 243 (46%), multiple IVIG in 100 (19%), multiple IVIG + corticosteroids in 75 (14%), and multiple IVIG + infliximab + corticosteroids in 44 (8%) patients. Patients who received therapy beyond single IVIG had a larger CA z-score at baseline (P < 0.001) and a higher rate of bilateral CAA (P < 0.001). Compared with IVIG alone, early adjunctive treatments (within 3 days of initial IVIG) were not associated with time to CAA regression or MACE, whereas later adjunctive therapy was associated with MACE and longer time to CAA regression. Patients receiving IVIG plus steroids vs IVIG alone had a trend towards shorter time to CAA regression and lower risk of MACE (P = 0.07). A larger CAA z-score at baseline was the strongest predictor of an increase in the CAA z-score over follow-up, lower likelihood of CAA regression, and higher risk of MACE. Conclusions: Persistence of CAA and MACE are more strongly associated with baseline severity CAA than with acute adjuvant anti-inflammatory therapy. Patients who received late adjunctive therapy are at higher risk for worse outcomes.

Contexte: L'incidence d'un traitement anti-inflammatoire d'appoint chez les patients atteints de la maladie de Kawasaki (MK) compliquée d'anévrismes coronariens est inconnue. Méthodologie: À partir de données provenant du registre international de la maladie de Kawasaki portant sur les patients ayant subi des anévrismes coronariens modérés ou importants, nous avons évalué l'incidence des différents traitements sur les résultats cliniques et les événements cardiovasculaires indésirables majeurs (ECIM). Résultats: Des anévrismes coronariens modérés ou importants ont été relevés chez 527 patients (32 %). Tous les patients recevaient des immunoglobulines administrées par voie intraveineuse (IgIV); 70 % d'entre eux étaient de sexe masculin, et leur âge médian était de 1,3 an (écart interquartile : de 0,4 an à 4,0 ans). Les traitements d'urgence les plus fréquents comprenaient un seul traitement par IgIV chez 243 patients (46 %), plusieurs traitements par IgIV chez 100 patients (19 %), une association de plusieurs traitements IgIV et de corticostéroïdes chez 75 patients (14 %) et une association de plusieurs traitements IgIV, de corticostéroïdes et d'infliximab chez 44 patients (8 %). Les patients ayant reçu un traitement autre qu'un seul traitement IgIV présentaient des scores z initiaux plus élevés pour le diamètre des artères coronaires (P < 0,001) et un taux plus élevé d'anévrismes coronariens bilatéraux (P < 0,001). En comparaison d'un traitement par IgIV seulement, les traitements d'appoint précoces (administrés dans les trois jours suivant le début du traitement par IgIV) n'ont pas eu d'incidence sur la durée avant la régression des anévrismes coronariens ni sur la survenue d'ECIM, alors que les traitements d'appoint plus tardifs ont été associés à un risque plus élevé d'ECIM et à une régression plus tardive des anévrismes coronariens. Les patients ayant reçu une association d'IgIV et de corticostéroïdes avaient tendance à présenter une régression plus rapide des anévrismes coronariens et un plus faible risque d'ECIM que ceux recevant uniquement un traitement par IgIV (P = 0,07). Un score z initial plus élevé pour un anévrisme coronarien était le facteur prédictif le plus puissant d'une augmentation du score z pendant la période de suivi, d'une probabilité plus faible de régression de l'anévrisme et d'un risque plus élevé d'ECIM. Conclusions: La gravité initiale de l'anévrisme coronarien est plus fortement associée à la persistance de l'anévrisme et à la survenue d'ECIM que le recours à un traitement anti-inflammatoire d'urgence en appoint. Les patients recevant un traitement d'appoint tardif étaient par ailleurs plus susceptibles de présenter des résultats défavorables.

A direct comparison of next generation sequencing enrichment methods using an aortopathy gene panel- clinical diagnostics perspective.

BACKGROUND: Aortopathies are a group of disorders characterized by aneurysms, dilation, and tortuosity of the aorta. Because of the phenotypic overlap and genetic heterogeneity of diseases featuring aortopathy, molecular testing is often required for timely and correct diagnosis of affected individuals. In this setting next generation sequencing (NGS) offers several advantages over traditional molecular techniques. METHODS: The purpose of our study was to compare NGS enrichment methods for a clinical assay targeting the nine genes known to be associated with aortopathy. RainDance emulsion PCR and SureSelect RNA-bait hybridization capture enrichment methods were directly compared by enriching DNA from eight samples. Enriched samples were barcoded, pooled, and sequenced on the Illumina HiSeq2000 platform. Depth of coverage, consistency of coverage across samples, and the overlap of variants identified were assessed. This data was also compared to whole-exome sequencing data from ten individuals. RESULTS: Read depth was greater and less variable among samples that had been enriched using the RNA-bait hybridization capture enrichment method. In addition, samples enriched by hybridization capture had fewer exons with mean coverage less than 10, reducing the need for followup Sanger sequencing. Variants sets produced were 77% concordant, with both techniques yielding similar numbers of discordant variants. CONCLUSIONS: When comparing the design flexibility, performance, and cost of the targeted enrichment methods to whole-exome sequencing, the RNA-bait hybridization capture enrichment gene panel offers the better solution for interrogating the aortopathy genes in a clinical laboratory setting.

Characterization of large genomic deletions in the FBN1 gene using multiplex ligation-dependent probe amplification.

BACKGROUND: Connective tissue diseases characterized by aortic aneurysm, such as Marfan syndrome, Loeys-Dietz syndrome and Ehlers Danlos syndrome type IV are heterogeneous and despite overlapping phenotypes, the natural history, clinical manifestations and interventional course for each diagnosis can be quite unique. The majority of mutations involved in the etiology of these disorders are missense and nonsense mutations. However, large deletions and duplications undetected by sequencing may be implicated in their pathogenesis, and may explain the apparent lack of genotype-phenotype correlation in a subset of patients. The objective of this study was to search for large pathogenic deletions and/or duplications in the FBN1, TGFßR1, and TGFßR2 genes using multiplex-ligation dependent probe amplification (MLPA) in patients with aortopathy, in whom no mutations in the FBN1, TGFßR1, and TGFßR2 genes were identified by sequencing. METHODS: The study included 14 patients from 11 unrelated families with aortic aneurysm. Of those, six patients (including 3 first-degree relatives), fulfilled the revised Ghent criteria for Marfan syndrome, and eight had predominantly aortic aneurysm/dilatation with variable skeletal and craniofacial involvement. MLPA for FBN1, TGFßR1, and TGFßR2 was carried out in all patients. A 385 K chromosome 15 specific array was used in two patients with a deletion of the entire FBN1 in order to define its size and boundaries. RESULTS: We identified two novel large deletions in the FBN1 gene in four patients of two unrelated families who met clinical diagnostic criteria for Marfan syndrome. One patient was found to have a FBN1 deletion encompassing exons 1-5. The other three patients had a 542 Kb deletion spanning the whole FBN1 gene and five additional genes (SLC24A5, MYEF2, CTXN2, SLC12A1, DUT) in the chromosome 15. CONCLUSIONS: Our findings expand the number of large FBN1 deletions, and emphasize the importance of screening for large genomic deletions in connective tissue disorders featuring aortopathies, especially for those with classic Marfan phenotype.

Pediatric emergency department use by adults with chronic pediatric disorders.

OBJECTIVE: To describe pediatric emergency department use by adults with chronic pediatric disorders, known as transition patients. DESIGN: Retrospective descriptive study. SETTING: The pediatric emergency department of a tertiary care pediatric hospital during calendar year 2005. PARTICIPANTS: All patients presenting to the pediatric emergency department during the study period. MAIN OUTCOME MEASURES: Association of presenting complaint with the patient's chronic pediatric disorder, emergency department interventions and dispositions, and duration of inpatient admissions. RESULTS: Patient encounters totaled 43 621, with 445 (1%) involving adult patients. Transition patients accounted for 197 (44%) of the adult encounters. Eighty-nine transition patient encounters (45%) were for complaints unrelated to the patients' chronic pediatric disorders. Only 14 (7%) transition patient visits did not involve diagnostic studies or procedures. Transition patients were 2.1 times (95% confidence interval, 1.8-2.5; P < .001) more likely to require admission than pediatric patients and were 4.5 times (95% confidence interval, 3.3-6.1; P < .001) more likely to require intensive care. Median length of stay for admitted transition patients was 4 days (range, 1-35 days) compared with 2 days (range, 1-80 days) for pediatric patients (P < .001). CONCLUSIONS: A substantial number of adult patients with chronic pediatric disorders use the pediatric emergency department and often present with complaints unrelated to their pediatric conditions. They have high rates of hospital and intensive care unit admissions. Pediatric hospitals should be prepared with adequate resources and training to deal with these complex adult patients.

Stentless porcine valves in the right ventricular outflow tract: improved durability?

OBJECTIVE: Stentless porcine valves are commonly used for aortic valve replacement in adults, yet their long-term performance in the right ventricular (RV) outflow tract is unknown. We evaluated intermediate-term performance of stentless porcine valves in the RV outflow tract in 150 children and adults over a 10-year period. METHODS: We retrospectively reviewed data on all patients undergoing placement of a pulmonary valve or RV-PA conduit with a stentless porcine prosthesis (>/=19 mm) from 1998 to 2008. Valvar function was assessed with echocardiography. Freedom from reintervention (explantation or catheter-based intervention) was determined by actuarial methods. RESULTS: A stentless porcine prosthesis was placed in the pulmonary position in 150 patients with a median weight and age of 50.1 kg (range 9.8-127) and 15.8 years (range 1.4-55), respectively. There were three early deaths (2%) and no late deaths. Actuarial freedom from reintervention was 100% at 1 year and 95.5% at 5 years. Peak transvalvar gradient at 1 and 5 years was 13+/-12 mmHg and 25+/-11 mmHg, respectively. At last follow-up no patient had severe insufficiency (PI), five patients had moderate PI and the remainder mild or no PI. CONCLUSIONS: Stentless porcine valves function well in the pulmonary position over the intermediate-term and are associated with low rates of reintervention in patients requiring a >19 mm valve or valved conduit. Longer-term follow-up and comparison with other alternatives will be necessary to determine if these valves are superior to commonly used allograft or bovine jugular venous valved conduits.

Clinical stress testing in the pediatric age group: a statement from the American Heart Association Council on Cardiovascular Disease in the Young, Committee on Atherosclerosis, Hypertension, and Obesity in Youth.

This statement is an updated report of the American Heart Association's previous publications on exercise in children. In this statement, exercise laboratory requirements for environment, equipment, staffing, and procedures are presented. Indications and contraindications to stress testing are discussed, as are types of testing protocols and the use of pharmacological stress protocols. Current stress laboratory practices are reviewed on the basis of a survey of pediatric cardiology training programs.