Andrew E. Warren

Safety and Immunogenicity of 26-Valent Group A Streptococcus Vaccine in Healthy Adult Volunteers

BACKGROUND Group A streptococcus (GAS) causes illness ranging from uncomplicated pharyngitis to life-threatening necrotizing fasciitis, toxic shock, and rheumatic fever. Attempts to develop an M protein-based vaccine have been hindered by the fact that some M proteins elicit both protective antibodies and antibodies that cross-react with human tissues. New molecular techniques have allowed the previous obstacles to be largely overcome. METHODS The vaccine is comprised of 4 recombinant proteins adsorbed to aluminum hydroxide that contain N-terminal peptides from streptococcal protective antigen and M proteins of 26 common pharyngitis, invasive, and/or rheumatogenic serotypes. Thirty healthy adult subjects received intramuscular 26-valent GAS vaccine (400 microg) at 0, 1, and 4 months, with clinical and laboratory follow-up for safety and immunogenicity using assays for tissue cross-reactive antibodies, type-specific M antibodies to 27 vaccine antigens, and functional (opsonization) activity of M protein antibodies. RESULTS The incidence of local reactogenicity was similar to that for other aluminum hydroxide-adsorbed vaccines in adults. No subject developed evidence of rheumatogenicity or nephritogenicity, and no induction of human tissue-reactive antibodies was detected. Overall, 26 of 27 antigenic peptides evoked a >4-fold increase in the geometric mean antibody titer over baseline. The mean log2 fold-increase in serum antibody titer (+/- standard error of the mean) for all 27 antigens was 3.67 +/- 0.21. A significant mean log2 reduction in streptococcal bacterial counts in serum samples obtained after immunization was seen in opsonization assays for all M serotypes. CONCLUSIONS On the basis of epidemiological data demonstrating that the majority of cases of pharyngitis, necrotizing fasciitis, and other invasive streptococcal infections are caused by a limited number of serotypes, this 26-valent vaccine could have significant impact on the overall burden of streptococcal disease.

Dilatation of the ascending aorta in paediatric patients with bicuspid aortic valve: frequency, rate of progression and risk factors

Objectives: To describe the incidence and rate of dilatation of the ascending aorta in children with bicuspid aortic valve (BAV) and to determine factors that predict rapid aortic dilatation. Design: Retrospective cohort study. Setting: Regional tertiary care children’s hospital. Patients: All children aged 0–18 years seen at the authors’ institution between 1990 and 2003 with an “isolated” BAV. All patients had had more than one technically adequate echocardiogram, at least six months apart, with concomitant height and weight data. Interventions: Offline echocardiographic measurements of multiple levels of the aortic root were completed for each participant at each serial echocardiogram. These measurements were then compared with expected measurements derived from a normal local control population. Main outcome measures: Rate of change of the ascending aorta size over time, where aortic size is expressed as the number of standard deviations above or below the mean size expected for a given body surface area (z score). Results: 279 echocardiograms spanning a period of from 9 months to 13.3 years were analysed for 88 patients with BAV. The ascending aorta in the BAV group was larger than expected for body surface area at diagnosis and continued to increase in relative size at each of the four subsequent follow-up echocardiograms. Ascending aortic z score increased at an average rate of 0.4/year. A faster rate of increase in z score was predicted by both larger initial aortic valve gradient and non-use of β blockers. Conclusions: Children with BAV are at risk of having a dilated ascending aorta. This risk increases with longer follow up.

Human leukocyte antigen-DR and ABO mismatch are associated with accelerated homograft valve failure in children: implications for therapeutic interventions

OBJECTIVE This study examines the incidence and factors associated with the failure of homograft valves and identifies those factors that are modifiable. METHODS From 1990 to 2001, 96 homograft valves were implanted in the right ventricular outflow tract of 83 children (mean age 5.1 +/- 5.6 years). Clinical and blinded serial echocardiographic follow-up was performed on all 90 valves in the 77 survivors. RESULTS Eighteen homograft valves were replaced as the result of pulmonary insufficiency (3), stenosis (9), or both (6). Freedom from reoperation was 71% at 9 years (95% confidence interval, 58%-84%). Forty-eight valves developed progressive pulmonary insufficiency of at least 2 grades, 26 valves developed transvalvular gradients of 50 mm Hg or greater, and 14 of these valves were also insufficient. The freedom from echocardiographic failure (progressive pulmonary insufficiency >or=2 grades or >or=50 mm Hg gradient) was only 27% at 5 years (95% confidence interval, 17%-37%). In a multivariate analysis (Cox regression), use of an aortic homograft (P =.001) and short antibiotic preservation time (P =.04) were associated with reoperation. Younger age (P =.01), ABO mismatch (P =.04), and diagnosis (P =.005) were associated with echocardiographic failure. In the subanalysis of patients with human leukocyte antigen typing, age (P =.002), aortic homograft (P =.04), and human leukocyte antigen-DR mismatch (P =.03) were associated with echocardiographic valve failure. CONCLUSION Many homografts rapidly become insufficient and require replacement. In our analysis of both reoperation and echocardiographic failure, several immunologic factors are consistently associated with homograft failure. Matching for human leukocyte antigen-DR, blood group, and avoiding short preservation times (thus minimizing antigenicity) offers the potential to extend the life of these valves.

Assessing Children’s Heart Sounds at a Distance With Digital Recordings

OBJECTIVE. The objective of this study was to assess whether computer-stored digital sound recordings can be used to distinguish innocent from pathologic systolic murmurs. METHODS. Recordings of 55 children aged 1 month to 19 years were made remotely with the use of a digital stethoscope and were e-mailed to a computer in our center for later assessment. Eight-second recordings were made by a physician in 2 to 4 locations on the chest. Three cardiologists who were blinded to the diagnosis reviewed the recordings independently using stethophones to assess the splitting of the second heart sound and whether murmurs were innocent or pathologic. Diagnoses were confirmed with echocardiography. RESULTS. Seventeen children had innocent murmurs and 38 had pathologic murmurs. For the 3 cardiologists, sensitivity was 0.87 to 1.0, specificity was 0.82 to 0.88, negative predictive value was 0.75 to 1.0, and positive predictive value was 0.93 to 0.95. Assessment of splitting of second heart sound was highly accurate. CONCLUSIONS. Digital recordings of children’s heart sounds allow reliable differentiation between innocent and pathologic murmurs. Use of this technology may allow remote diagnosis of childhood murmurs and avoid the expense and stress of travel to pediatric cardiology centers for some children. Cardiologists who use recordings should assess their diagnostic accuracy before clinical application.

Cardiac risk assessment before the use of stimulant medications in children and youth: A joint position statement by the Canadian Paediatric Society, the Canadian Cardiovascular Society, and the Canadian Academy of Child and Adolescent Psychiatry

Regulatory decisions and scientific statements regarding the management of attention-deficit hyperactivity disorder (ADHD) raise questions about the safety of medications and the appropriate pretreatment evaluation to determine suitability for treatment with medication. This is particularly true in the setting of known structural or functional heart disease. The present paper reviews the available data, including peer-reviewed literature, data from the United States Food and Drug Administration Web site on reported adverse reactions in children using stimulant medication, and Health Canada data on the same problem. A consensus-based guideline on appropriate assessment is provided, based on input from members of the Canadian Paediatric Society, the Canadian Cardiovascular Society and the Canadian Academy of Child and Adolescent Psychiatry, with specific expertise and knowledge in the areas of both ADHD and pediatric cardiology. The present statement advocates a thorough history and physical examination before starting stimulant medications, with an emphasis on the identification of risk factors for sudden death, but does not routinely recommend electrocardiographic screening or cardiac subspecialist consultation unless indicated by history or physical examination findings. A checklist for identifying children who are potentially at risk of sudden death (independent of ADHD or medications used to treat it) is provided. Although recommendations are based on the best evidence currently available, the committee further agrees that more research on this subject is necessary to optimize the approach to this common clinical scenario.

Rationale and Design of the Canadian Outcomes Registry Late After Tetralogy of Fallot Repair: The CORRELATE Study

BACKGROUND Chronic hemodynamically relevant pulmonary regurgitation (PR) resulting in important right ventricular dilation and ventricular dysfunction is commonly seen after tetralogy of Fallot (TOF) repair. Late adverse clinical outcomes, including exercise intolerance, arrhythmias, heart failure and/or death accelerate in the third decade of life and are cause for considerable concern. Timing of pulmonary valve replacement (PVR) to address chronic PR is controversial, particularly in asymptomatic individuals, and effect of PVR on clinical measures has not been determined. METHODS Canadian Outcomes Registry Late After Tetralogy of Fallot Repair (CORRELATE) is a prospective, multicentre, Canada-wide cohort study. Candidates will be included if they are ≥ 12 years of age, have had surgically repaired TOF resulting in moderate or severe PR, and are able to undergo cardiovascular magnetic resonance imaging. Enrollment of > 1000 individuals from 15 participating centres (Toronto, Montreal, Quebec City, Sherbrooke, Halifax, Calgary, Edmonton, and Vancouver) is anticipated. Clinical data, health-related quality of life metrics, and adverse outcomes will be entered into a web-based database. A central core lab will analyze all cardiovascular magnetic resonance studies (PR severity, right ventricular volumes, and ventricular function). Major adverse outcomes (sustained ventricular tachycardia and cardiovascular cause of death) will be centrally adjudicated. RESULTS To the best of our knowledge, CORRELATE will be the first prospective pan-Canadian cohort study of congenital heart disease in children and adults. CONCLUSIONS CORRELATE will uniquely link clinical, imaging, and functional data in those with repaired TOF and important PR, thereby enabling critical evaluation of clinically relevant outcomes in those managed conservatively compared with those referred for PVR.

Understanding, teaching and assessing the elements of the CanMEDS Professional Role: Canadian Program Directors’ views

Abstract Background: Physicians are required to maintain and sustain professional roles during their careers, making the Professional Role an important component of postgraduate education. Despite this, this role remains difficult to define, teach and assess. Objective: To (a) understand what program directors felt were key elements of the CanMEDS Professional Role and (b) identify the teaching and assessment methods they used. Methods: A two-step sequential mixed method design using a survey and semi-structured interviews with Canadian program directors. Results: Forty-six program directors (48% response rate) completed the questionnaire and 10 participated in interviews. Participants rated integrity and honesty as the most important elements of the Role (96%) but most difficult to teach. There was a lack of congruence between elements perceived to be most important and most frequently taught. Role modeling was the most common way of informally teaching professionalism (98%). Assessments were most often through direct feedback from faculty (98%) and feedback from other health professionals and residents (61%). Portfolios (24%) were the least used form of assessment, but they allowed residents to reflect and stimulated self-assessment. Conclusion: Program directors believe elements of the Role are difficult to teach and assess. Providing faculty with skills for teaching/assessing the Role and evaluating effectiveness in changing attitudes/behaviors should be a priority in postgraduate programs.

Left Ventricular Noncompaction and Coronary Artery Fistula in an Infant with Deletion 22q11.2

This report describes an infant presenting with deletion 22q11.2 in combination with left ventricular noncompaction and a coronary artery fistula. These two cardiac findings have rarely been reported in association with each other and have never been reported together in combination with deletion 22q11.2. The reported case demonstrates the expanding cardiac phenotype of individuals with deletion 22q11.2, suggesting that it may be appropriate to offer studies for the detection of deletion 22q11.2 to individuals with a wide range of structural cardiac defects.

Late-Appearing Brachiocephalic Aneurysm: An Atypical Vascular Sequella of Kawasaki Disease

Kawasaki disease (KD) is an acute vasculitis that can result in cardiovascular sequelae. One of the most serious consequences of KD is the development of arterial aneurysms that can lead to thrombosis and ischemia. Commonly, these lesions, occurring early in the course of KD, are found in the coronary arteries. However, this location is not exclusive. This report presents a case of KD with atypical findings of a late-appearing brachiocephalic artery aneurysm. The authors suggest that for patients with complicated KD, surveillance should include a careful vascular survey to discover aneurysms distant from the heart.

Fetal diagnosis of an "extra cardiac chamber".

Congenital right ventricular aneurysms and diverticula are rare congenital anomalies and prenatal detection is uncommon. Distinguishing between these two anomalies by imaging alone is difficult. Recently, we were asked to review a 21-week ultrasound that detected an “extra cardiac chamber.” This represents the first report of an isolated out-pouching of the right ventricular free wall to be detected by prenatal screening ultrasound. Based on preoperative imaging, this out-pouching was diagnosed as a ventricular aneurysm, but intraoperative findings suggested it was a diverticulum. This case will review the differences between ventricular aneurysms and diverticula and illustrate the use and limitations of various imaging modalities used in their evaluation, both prenatally and postnatally. A plan of management is suggested.