BC Children's Hospital Research Articles

Separating myths from reality for vaccines causing adverse events following immunization: an interview with Manish Sadarangani.

Dr Manish Sadarangani is Director of the Vaccine Evaluation Center at the BC Children's Hospital Research Institute and an Assistant Professor in the Division of Infectious Diseases, UBC Department of Pediatrics. He completed his undergraduate medical and pediatric training in Cambridge, Oxford and London in the UK. He then completed his DPhil with the Oxford Vaccine Group in the UK, developing novel vaccine candidates for protection against capsular group B meningococcal disease, and completed a fellowship in pediatric infectious diseases in Vancouver in 2013 before returning to Oxford to work as a pediatric infectious diseases physician. His research links clinical trials with basic microbiology, immunology and epidemiology to address clinically relevant problems related to immunization and vaccine-preventable diseases.

Co-existence of Rolandic and 3 Hz Spike-Wave Discharges on EEG in Children with Epilepsy.

Benign epilepsy of childhood with central temporal spikes (BECTS) and absence epilepsy are common epilepsy syndromes in children with similar age of onset and favorable prognosis. However, the co-existence of the electrocardiogram (EEG) findings of rolandic spike and 3 Hz generalized spike-wave (GSW) discharges is extremely rare, with few cases reported in the literature. Our objective was to characterize the EEG findings of these syndromes in children in our center and review the electro-clinical features. All EEGs at BC Children's Hospital are entered in a database, which include EEG findings and clinical data. Patients with both centro-temporal spikes and 3 Hz GSW discharges were identified from the database and clinical data were reviewed. Among the 43,061 patients in the database from 1992 to 2017, 1426 with isolated rolandic discharges and 528 patients with isolated 3 Hz GSW discharges were identified, and 20 (0.05%) patients had both findings: 3/20 had BECTS, and subsequently developed childhood absence epilepsy and 17/20 had no seizures characteristic for BECTS. At follow-up, 17 (85%) were seizure-free, 1 (5%) had rare, and 2 (10%) had frequent seizures. This is the largest reported group of patients to our knowledge with the co-existence of rolandic and 3 Hz GSW discharges on EEGs in one institution, not drug-induced. As the presence of both findings is extremely rare, distinct pathophysiological mechanisms are likely. The majority had excellent seizure control at follow-up, similar to what would be expected for each type of epilepsy alone.

Predicting Future Glucose Fluctuations Using Machine Learning and Wearable Sensor Data

Predicting blood glucose values (BG) using machine learning (ML) algorithms and data fusion techniques. There has been a recent explosion of interest in BG prediction due to its application in the development of insulin regulating algorithms for the Artificial Pancreas Project. During this study, we measured the predictive accuracy of a software system designed to predict glucose behaviour using step-count and heart-rate data in addition to BG-insulin dynamics. The software was tested in a blinded pilot study at BC Children's Hospital for 9 type 1 diabetic children. Using continuous glucose monitors (CGM) and fitness wearables (Fitbit), the software aggregated 60-days of continuous data from each participant. The data from the first 30-days of the study was used to train the algorithem. The trained algorithm was then used to make predictions every 5mins for the next 30days. On average, the software was able to predict user's future glucose values with 93% accuracy rate for 60-mins ahead of time. Although encouraging, the algorithm required further testing. We have since released the app under the commercial name "DiaBits" for more testing and further data collection. Disclosure A. Hayeri: Other Relationship; Self; Dexcom, Inc., Fitbit, Inc.. Research Support; Self; BC Children's Hospital - Vancouver Canada. Other Relationship; Self; University Of British Columbia.

Time Trends and Determinants of Fistula in Cleft Patients at BC Children's Hospital, Canada: A Retrospective 18-Year Medical Chart Audit.

To examine the time trends and determinants of palatal fistula in children with different types of cleft at British Columbia's Children's Hospital between 1995 and 2012. A total of 558 medical charts of nonsyndromic patients with cleft lip and palate were eligible for the chart review. The occurrence of primary palatal fistula was assessed at any time throughout the patient's total observation period. Three types of clefts were recorded: unilateral cleft lip and palate (ULCLP), bilateral cleft lip and palate (BLCLP), and isolated cleft palate (ICP). Cleft severity, time period of treatment, type of surgery and surgeon's experience were tested as determinants. Of all 558 patients, 228 had ULCLP, 226 had ICP, and 104 had BLCLP. The combined postoperative palatal fistula rate was 28%. The significant differences in fistula rates related to type of cleft (patients with BLCLP had the highest fistula rates), time period (rates were higher in earlier years than in later years), type of surgery (highest rates were for two-flap palatoplasty), and surgeons with less experience. Almost one quarter of the patients, developed fistula, and fistula incidence declined after 2009. The higher fistula rates were determined by cleft severity, time period of treatment, type of surgery, and surgeon's experience.

Editorial introductions

Editorial introductions

Traumatic Neonatal Lumbar Punctures: Experience at a Large Pediatric Tertiary Care Center in Canada.

Contamination of cerebrospinal fluid (CSF) by blood during neonatal lumbar puncture (LP) is common and poses diagnostic difficulties. Our objectives were to determine the number of traumatic LPs performed at the BC Children's Hospital over 9 years and whether there was an association between traumatic LPs and demographic variables, hospital location, or time of the procedure. This study was a retrospective review of neonatal CSF samples from May 2006 to March 2015. The data were analyzed to establish the rate of traumatic samples and whether there was an association between traumatic LPs and demographic variables (age, gender), location of procedure, positive CSF culture, and/or timing of the procedure. A total of 1,263 LPs were reviewed, 47.7% (n = 602) were contaminated with >400 red blood cells/high-power field. The median age of neonates whose samples were uncontaminated was 10.580 days compared with 6.535 days in the group with contaminated samples (z = - 2.884, p = 0.004). None of the other factors studied was associated with traumatic taps. Detected organisms included Escherichia coli (n = 12), coagulase-negative Staphylococcus (n = 7), Enterococcus faecalis (n = 3), and group B Streptococcus (n = 2). Nearly half of all CSF samples in the study period were contaminated. Traumatic samples were more common in younger neonates.

Secondary Abnormal CSF Neurotransmitter Metabolite Profiles in a Pediatric Tertiary Care Centre.

Secondary neurotransmitter deficiencies have been reported in several reviews. Our primary aim was to assess the relationship among epilepsy, antiseizure medications, and specific neurotransmitter abnormalities. We also evaluated movement disorders and brain abnormalities via magnetic resonance imaging scans in patients with secondary neurotransmitter defects. This is a retrospective case series of 376 patients who underwent neurotransmitter analysis at BC Children's Hospital between 2009 and 2013, for a variety of neurological presentations. The biochemical genetics laboratory database was interrogated for results of cerebrospinal fluid neurotransmitter analyses. Clinical data for patients with abnormal results were collected from the hospital charts. Statistical analysis included one-way analysis of variance, chi-square, and a two-way contingency table. Abnormal neurotransmitter values were identified in 67 (17.8%) patients, two (0.53%) of which were attributable to a congenital neurotransmitter disorder and 11 (16.9%) secondary to other genetic diagnoses. Of 64 patients with secondary abnormal neurotransmitter values, 38 (59%) presented with epilepsy and 20 (31%) with movement disorders. A combination of epilepsy and movement disorder was less frequent. Acknowledging the limitations of this retrospective chart review, we conclude that, in our cohort, in addition to patients with movement disorders, a considerable number of patients with epilepsy and epileptic encephalopathy also showed secondary neurotransmitter mono-amine abnormalities. There is no clear relation, however, between clinical phenotype and type of neurotransmitter affected. In addition, no association was identified between the type of antiseizure medications and affected neurotransmitter type. We outline the need for prospective studies to further enrich our understanding of the relation between epilepsy and neurotransmitters with a focus on improving treatments and patient outcomes.

Lymphatic Malformation Architecture: Implications for Treatment With OK-432.

Herein, the authors aim to describe their findings of novel architectural types of lymphatic malformations (LM) and explain the relationship between these architectures and OK-432 treatment outcomes. A retrospective review was conducted of all patients diagnosed with a LM treated with OK-432 at the Vascular Anomalies Clinic at BC Children's Hospital from December 2002 to January 2012. Twenty-seven patients were included in the study. Sixty percent of lesions were present by 2 years of age with the majority located in the head and neck (59%). The average number of sclerotherapy procedures was 1.4 per patient. Treatment under fluoroscopic guidance revealed 3 new LM architectures: open-cell microcystic, closed-cell microcystic, and lymphatic channel. Response to treatment was complete or good for 14/19 macrocystic and for 1/2 mixed lesions. Open-cell microcystic LMs gave a complete or good response for 3/3, which was attributed to OK-432 freely communicating between cysts. Closed-cell microcystic LM had localized cysts that did not allow OK-432 to freely communicate and were associated with partial responses, 2/2. The lymphatic channel had a partial response. There were 2 minor complications and 1 instance of recurrence. The identification of 3 new LM architectures expands the current accepted classification to include: open-cell microcystic, closed-cell microcystic, and lymphatic channels. The majority of complete responses to OK-432 were found with macrocystic lesions. Open-cell microcystic lesions respond better to OK-432 than closed-cell microcystic lesions, and lymphatic channels may respond to OK-432. These key architecture-response relationships have direct clinical implications for treatment with OK-432 sclerotherapy.

Clinical Experience With Perampanel for Refractory Pediatric Epilepsy in One Canadian Center.

Perampanel (PER) is a new antiseizure medication that inhibits the α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) class of glutamate receptors. It is important for physicians to be aware of the efficacy and tolerability of new drugs in the postmarketing phase. We performed a retrospective review of our experience with perampanel at BC Children's Hospital. Twenty-four pediatric patients prescribed perampanel from 2014 to 2016 were identified. Fifteen (63%) discontinued perampanel, and 10 (42%) had greater than 50% reduction in seizures. Twelve (50%) had behavioral and 8 (33%) had nonbehavioral adverse events. One-third experienced serious adverse events. One patient experienced oculogyric crisis, which is not previously reported with perampanel. Adverse events were not dose related and were reversible. Possible risk factors for behavioral adverse events include a history of behavioral problems with other antiseizure medications and preexisting behavioral comorbidities. It is important to counsel patients about the potential for serious adverse events, particularly behavioral, when prescribing perampanel.

Physician and parent barriers to the use of oral corticosteroids for the prevention of paediatric URTI-induced acute asthma exacerbations at home.

Administration of oral corticosteroids at the onset of an upper respiratory tract infection (URTI) can be effective in the management of acute asthma exacerbations in children. This study was designed to identify barriers to parent-initiated implementation of clinical practice guideline-recommended use of oral corticosteroids for prophylaxis against severe asthma exacerbations in children. Twenty-seven children who presented to BC Children's Hospital with URTI-induced asthma exacerbations were recruited. Parents received a filled prescription for a course of oral corticosteroids to be used at the earliest onset of their child's next URTI. Each family was contacted monthly over a 1-year period to inquire about URTI events, asthma symptoms, medication use and health care utilization. Focus groups were held with family physicians, paediatricians and parents; transcripts were analyzed qualitatively to identify key themes. Incidence of URTI events among participants was high (85%). Uptake of study medication was low; 44% used the medication as directed at their first URTI event. Eleven per cent of the patients who used the study medication also visited the emergency department for an exacerbation. Focus groups identified four main barriers to the effective use of parent-initiated oral corticosteroids: physician resistance and conflicting messages from providers; parent uncertainty about oral corticosteroids; multiple caregivers and relative ease of access to an emergency department. We have identified key barriers to the effective use of parent-administered oral corticosteroids as an asthma management strategy and gained important insights regarding the research that is required to enhance the applicability of the strategy.

Opsoclonus-Myoclonus Syndrome: A New Era of Improved Prognosis?

BackgroundOpsoclonus-myoclonus syndrome is an autoimmune neurological disorder characterized by opsoclonus, myoclonus, ataxia, and behavioral changes. Although long-term outcomes have historically been poor, including motor and cognitive disabilities, the advent of new and more aggressive immunotherapy regimens may be improving prognosis in opsoclonus-myoclonus syndrome. MethodsWe retrospectively reviewed the records of all children diagnosed with opsoclonus-myoclonus syndrome at BC Children's Hospital from 2000 to 2010. Neurological outcomes were compared with those previously reported in the literature. ResultsTwelve children with opsoclonus-myoclonus syndrome were identified, four of whom had an associated neuroblastoma. Two thirds of patients received initial treatment with a combination of corticosteroids, intravenous immunoglobulin (IVIG), and an additional immunosuppressant agent. After a median follow-up of three years from diagnosis, ten patients had no or minimal neurological abnormalities. Two patients had poor outcome with significant cognitive impairment. ConclusionsMost patients in this series were treated with early multimodal immunotherapy, and neurological outcomes were better than those in most historical reports. This finding is consistent with recent studies that suggest multimodal immunotherapy regimens may be improving the prognosis in this challenging disease. However, some individuals did well with less aggressive treatment, and further studies are required to determine optimal treatment approach.

Respiratory Syncytial Virus Infection Rates with Limited Use of Palivizumab for Infants Born at 29 to 31+6/7 Weeks Gestational Age.

Immunoprophylaxis with palivizumab can reduce respiratory syncytial virus (RSV) infections and hospitalizations. Criteria in British Columbia limit the use of palivizumab to infants born at 29 to 31+6/7 weeks gestational age, which differ from guidelines of the American Academy of Pediatrics (AAP) and the Canadian Paediatric Society (CPS). To determine whether the limited use of palivizumab affected the frequency of hospital visits by RSV-positive infants (termed "RSV-positive hospital visits") who received approval for palivizumab and those who met the AAP/CPS criteria but did not receive approval for palivizumab. Data sets were generated for the period May 1, 2008, to April 30, 2011, to identify infants with gestational age of 29 to 31+6/7 weeks who were born in or transferred to the Fraser Health authority, RSV-positive results for infants less than 12 months of age who had visited Fraser Health sites and BC Children's Hospital, and palivizumab approvals. Infants were matched across these 3 data sets through their personal health numbers. The study included 359 infants born at 29 to 31+6/7 weeks, of whom 297 met the AAP/CPS criteria. However, only 46 of these 297 received approval for palivizumab according to the BC criteria. Sixteen (4.5%) of the 359 infants had RSV-positive hospital visits during the RSV season (November through March). Of the 46 infants who received approval for palivizumab, 2 (4.3%) had RSV-positive hospital visits, and of the 251 who met the AAP/CPS criteria but did not receive palivizumab approval, 14 (5.6%) had RSV-positive hospital visits. Of the 359 infants, 6 (1.7%) had RSV-positive results while admitted to the neonatal intensive care unit, and 10 (2.8%) tested positive for RSV during a subsequent hospital visit. The frequency of RSV-positive hospital visits did not differ between infants who received and those who did not receive approval for palivizumab in the Fraser Health authority. Limited use of palivizumab for RSV prophylaxis led to reasonable rates of RSV-positive hospital visits in the study population.

Business Planning for a Campus-Wide Biobank.

Biobanks are resources that facilitate research. Many biobanks exist around the world, but most tend to focus on a specific disease or research area. BC Children's Hospital and BC Women's Hospital are located on the same campus (Oak Street Campus) in Vancouver, BC, Canada. A campus-wide biobank has been established on the site of these two hospitals to collect specimens and annotated data from children or women seeking medical care at either of the hospitals. Such an initiative requires careful planning and consideration of many factors such as buy in and support of key stakeholders, governance, financial planning, and optimizing specimen collection. We developed a business plan to account for the many aspects associated with integrating the "BC Children's Hospital BioBank." This document describes the approach our business plan took for the implementation of our biobank and the progress, including deviations from the business plan. We also provide a perspective on the current status with a focus on sustainability.

Editorial introductions

Editorial introductions

Inter-observer and intra-observer reliability in the radiographic diagnosis of avascular necrosis of the femoral head following reconstructive hip surgery in children with cerebral palsy.

PurposeThe incidence of avascular necrosis (AVN) following reconstructive hip surgery in cerebral palsy (CP) ranges from 0 to 69 % in the current literature. The purpose of this study was to determine the inter- and intra-observer reliability of radiographically diagnosing AVN in children with CP after hip surgery.MethodsA retrospective review of 65 children with CP who had reconstructive hip surgery between 2009 and 2012 at BC Children’s Hospital was completed. Anterior–posterior and lateral radiographs were presented to four pediatric orthopaedic surgeons over two rounds. Surgeons were asked to review the set of unidentified radiographs and comment ‘yes’ or ‘no’ for the presence of AVN. Two weeks later the same set of radiographs was sent in a different order and the surgeons were again asked to comment on AVN. Inter- and intra-observer reliability was determined using kappa statistics.ResultsThe intra-observer reliability ranged from 0.65 to 0.88 with an average score of 0.76. Inter-observer reliability showed greater variability, ranging from 0.41 to 0.77 with an average score of 0.56 across all surgeons.ConclusionsAlthough the intra-rater reliability produced a strength of “good” and the inter-rater reliability a strength of “moderate” agreement, the variability within these scores is clinically important as it demonstrates the difficulty in identifying AVN. This may explain the variability in AVN that is reported in the literature. The need for further education and research in the diagnosis of AVN in children with CP who have undergone reconstructive hip surgery is clinically necessary.

Paediatric infectious keratitis at tertiary referral centres in Vancouver, Canada

ObjectiveTo report the clinical and microbiological profiles of paediatric patients with infectious keratitis in Vancouver, Canada.DesignIn this observational case series, the microbiology results and medical records of 17 eyes with...

Chloral hydrate sedation for auditory brainstem response (ABR) testing in children: Safety and effectiveness

IntroductionThe auditory brainstem response (ABR) test is used to identify hearing loss and measure hearing thresholds of infants and children who cannot be tested using standard behavioral hearing testing methods. In order for the ABR to yield useful data, a child must be asleep throughout the duration of the test. In many centers, this is achieved through the use of a general anesthetic, with its inherent risks and costs. Since 2004, ABRs have been routinely conducted at BC Children's Hospital in an ambulatory care setting under oral chloral hydrate sedation, with monitoring by a specialist nurse. The aim of this retrospective study was to assess the effectiveness and safety of nurse-led sedation with chloral hydrate for ABR testing at our tertiary pediatric center. MethodsMedical and audiology records were reviewed for children aged 6 months to 17 years who underwent ABR testing from 2004 to 2012. We reviewed the dosage of drug used, condition of the child after chloral hydrate administration, adverse effects, audiological results, patients’ vital signs, and the effectiveness of the sedative in keeping the child asleep throughout the duration of the test. Frequency distributions were derived for adverse outcomes. Results725 ABR records encompassing 635 children (multiple ABR tests in some children) were reviewed. The average dose of chloral hydrate used was 52mg/kg. The majority of sedated ABR's (80.8%) were completed without any incident. Significant events [apnea and/or bradycardia], minor complications [vomiting, hypoxemia, prolonged sedation, and/or tachypnea] and restlessness were noted in 3.4%, 6.2%, and 5.0% of the cases, respectively. The majority of these issues resolved without medical intervention, such as the need to provide supplementary oxygen. In 95.9% of ABRs, chloral hydrate was successful in sedating the child adequately to answer the audiological question. ConclusionsThis forms the largest study to date on oral sedation for ABR testing. Based on our results, the use of chloral hydrate in the presence of a sedation nurse was a safe and reliable method of performing ABR in infants and children. This may be of significant value to centres worldwide exploring alternatives to general anesthesia for ABR testing.

Minor surgery procedures: A retrospective review and prospective survey in a pediatric population

Objective The present study evaluated minor surgery procedures undertaken by a single plastic surgeon at BC Children's Hospital (Vancouver, British Columbia) for patient and physician satisfaction, parent impressions, psychological concerns and complications. Methods Data were collected from a retrospective chart review and a prospective patient survey. Eligible subjects for the retrospective study included all pediatric patients undergoing minor surgery between May 2011 and April 2013. Parameters of interest included patient demographics, minor surgery specifics, complications and outcomes. Eligible subjects for the prospective patient survey included consecutive patients undergoing minor surgery between June 2013 and August 2013, as well as their parents. Results A total of 219 procedures were included in the retrospective review. The mean age of subjects was 13.1 years (range two weeks to 18 years). The median length of follow-up was 46 days (range four to 606 days). There were no major complications; however, 45 minor complications in 36 patients were found. Complications included crusting (4.6%), delayed wound healing (3.2%), hypersensitivity (2.3%), scar hypertrophy (1.8%), infection (0.9%) and other (7.8%). Outcomes were categorized as one of four outcomes: both satisfied (89.9%); patient satisfied but physician unsatisfied (0.8%); patient unsatisfied and physician satisfied (3.1%); and both unsatisfied (6.2%). In the prospective study, 32 subjects consented to participate in the survey. Of these subjects, 10 children and 12 parents responded to the questionnaires. Eighty-three percent of respondents indicated that their goals were accomplished by their procedure and that they would be willing to undergo minor surgery again. Conclusion Minor surgery is possible and practical in pediatric plastic surgery clinics, with few complications and high patient and surgeon satisfaction.

Functional hyposplenism after hematopoietic stem cell transplantation.

Functional hyposplenism is associated with chronic GvHD (cGvHD) following hematopoietic stem cell transplantation (HSCT). We hypothesized that hyposplenism measured by pitted red cell counts in cGvHD was transient and related to the severity of disease. We performed a serial, retrospective review of 36 pediatric post-HSCT patients' pit counts at BC Children's Hospital from 2005 to 2013 and compared those counts with the clinical course of patients with late acute GvHD (aGvHD)/cGvHD. Of the 36 patients, 22 had late aGvHD/cGvHD based on National Institutes of Health consensus criteria. Fourteen of 22 GvHD patients had an abnormal pitted red cell count. Ten of 14 abnormal patients had late acute or overlap GvHD syndrome, primarily gastrointestinal disease. A second cohort was prospectively evaluated in a multicenter adult HSCT biomarker trial. We identified 3 out of 10 control patients who had an abnormal pitted red cell count, 3 out of 10 with classic cGvHD and 5 out of 9 patients with overlap syndrome were abnormal. In both the retrospective and prospective studies, hyposplenism was present in patients without late aGvHD/cGvHD suggesting current guidelines regarding antibiotic prophylaxis against encapsulated bacteria after HSCT need to be re-addressed and abnormal pit counts could be used to guide prophylaxis in all HSCT patients.

Resective Epilepsy Surgery for Tuberous Sclerosis in Children: Determining Predictors of Seizure Outcomes in a Multicenter Retrospective Cohort Study.

There are no established variables that predict the success of curative resective epilepsy surgery in children with tuberous sclerosis complex (TSC). We performed a multicenter observational study to identify preoperative factors associated with seizure outcome in children with TSC undergoing resective epilepsy surgery. A retrospective chart review was performed in eligible children at New York Medical Center, Miami Children's Hospital, Cleveland Clinic Foundation, BC Children's Hospital, Hospital for Sick Children, and Sainte-Justine Hospital between January 2005 and December 2013. A time-to-event analysis was performed. The "event" was defined as seizures after resective epilepsy surgery. Seventy-four patients (41 male) were included. The median age of the patients at the time of surgery was 120 months (range, 3-216 months). The median time to seizure recurrence was 24.0 ± 12.7 months. Engel Class I outcome was achieved in 48 (65%) and 37 (50%) patients at 1- and 2-year follow-up, respectively. On univariate analyses, younger age at seizure onset (hazard ratio [HR]: 2.03, 95% confidence interval [CI]: 1.03-4.00, P = .04), larger size of predominant tuber (HR: 1.03, 95% CI: 0.99-1.06, P = .12), and resection larger than a tuberectomy (HR: 1.86, 95% CI: 0.92-3.74, P = .084) were associated with a longer duration of seizure freedom. In multivariate analyses, resection larger than a tuberectomy (HR: 2.90, 95% CI: 1.17-7.18, P = .022) was independently associated with a longer duration of seizure freedom. In this large consecutive cohort of children with TSC and medically intractable epilepsy, a greater extent of resection (more than just the tuber) is associated with a greater probability of seizure freedom. This suggests that the epileptogenic zone may include the cortex surrounding the presumed offending tuber.