Royal Children's Hospital Melbourne Research Articles

Mycobacteria-Specific Mono- and Polyfunctional CD4+ T Cell Profiles in Children With Latent and Active Tuberculosis: A Prospective Proof-of-Concept Study.

Background: Current immune-based TB tests, including the tuberculin skin test (TST) and interferon-gamma release assays (IGRA), have significant limitations, including the inability to distinguish between latent TB infection (LTBI) and active TB. Few biomarkers with the potential to discriminate between these two infection states have been identified.Objective: To determine whether functional profiling of mycobacteria-specific T cells can distinguish between TB-infected and -uninfected children, and simultaneously discriminate between LTBI and active TB.Methods: One hundred and forty-nine children with suspected active TB or risk factors for LTBI were recruited at the Royal Children's Hospital Melbourne. Whole-blood stimulation assays, using ESAT-6, CFP-10, PPD, and heat-killed M. tuberculosis as stimulants, were done, followed by intracellular cytokine staining and flow cytometric analysis.Results: Eighty-two participants in the well-defined diagnostic categories ‘uninfected individuals’ (asymptomatic, TST 0 mm / IGRA-; n = 61), LTBI (asymptomatic, TST ≥10 mm / IGRA+, normal chest radiograph; n = 15), or active TB [microbiologically-confirmed (n = 3) or fulfilling stringent criteria (n = 3)] were included in the final analysis. The proportions of mycobacteria-specific single-positive TNF-α+ and double-positive IFN-γ+/TNF-α+ CD4+ T cells were significantly higher in participants with active TB than in those with LTBI and uninfected individuals. Additionally, the frequency of IL-17-expressing CD4+ T cells, predominately with single-positive IL-17+ and double-positive IL-2+/IL-17+ phenotypes, was higher in participants with active TB than in the other two groups.Conclusions: The frequencies and functional profiles of mycobacteria-specific CD4+ T cells differ significantly both between TB-infected and TB-uninfected children, and between LTBI and active TB. Although confirmation in further studies will be required, these findings indicate that functional profiling of mycobacteria-specific CD4+ T cells could potentially be exploited for novel immune-based TB assays that enable the distinction between infection states based on a blood sample alone.

Vaccine Allergy? Skin Testing and Challenge at a Tertiary Pediatric Hospital in Melbourne, Australia

The rate of true vaccine allergy is unknown. Children with potential IgE-mediated adverse events following immunization (AEFI) should undergo allergy investigation that may include skin testing or challenge. Previous protocols tend to be highly conservative and often suggest invasive testing for all, a practice not evidence based, technically difficult, and unpleasant in children. It has more recently been suggested that skin testing may be restricted to those with allergic-like events within the first hour and those with a history of anaphylaxis. We aimed to describe the outcome of vaccine skin testing and challenge in children referred to a tertiary pediatric hospital with a potential IgE-mediated AEFI. The secondary aim was to identify any significant risk factors for vaccine allergy. A retrospective review of all children (<18 years) who underwent vaccine skin testing (skin prick testing or intradermal testing [IDT]) or challenge over a 5-year period (May 1, 2011, to April 30, 2016) at the Royal Children's Hospital Melbourne is presented. There were 95 admissions in 73 children. Eight percent (6 of 73) of children had confirmed vaccine allergy (positive skin testing or challenge to the index vaccination). Two had positive IDT to a suspect vaccine but challenge negative to an alternative brand vaccine. Two had negative IDT but subsequent positive challenge and two had immediate urticaria on challenge without prior skin testing. All children in the positive group either had index reaction within 15 minutes of vaccination or had history consistent with anaphylaxis. The vast majority of children (92%) presenting with a potential IgE-mediated AEFI are able to tolerate challenge to a suspect vaccine without reaction. We present our investigation protocol recommending skin testing in all children with anaphylaxis and challenge with a suspect vaccine if negative testing or previous nonanaphylactic potential IgE-mediated AEFI.

Itraconazole Dosing and Drug Monitoring at a Tertiary Children's Hospital.

Itraconazole is a broad-spectrum antifungal agent used for prophylaxis and treatment of fungal infections in immunocompromised children. Achieving the recommended target serum itraconazole trough concentration of ≥0.5 mg/L is challenging in children because of variation in itraconazole pharmacokinetics with age. We studied itraconazole use and treatment outcomes in a tertiary children's hospital. We did a 10-year retrospective review of medical records of children at the Royal Children's Hospital Melbourne who received oral itraconazole and had therapeutic drug monitoring (TDM). Overall, 81 children received 92 courses of oral itraconazole and had TDM. Of 222 TDM samples, 183 (82.4%) were taken at the appropriate time (trough level at steady state). Patients ≤12 and >12 years of age required median doses of 6.2 and 3.9 mg/kg/d, respectively, to attain target trough levels (P < 0.001). Of children ≤12 years of age, 71.4% required doses above the recommended dose of 5 mg/kg/d to achieve therapeutic levels, compared with 17.4% of those >12 years of age. At least 1 subtherapeutic trough concentration was reported in 63 (76.8%) courses; in only 18 (28.6%) of these was the dose adjusted. Gastrointestinal symptoms [14/92 (15.2%) courses] and hepatotoxicity [6/92 (6.5%)] were the most frequent adverse events. Neither was associated with elevated trough levels. The poor attainment of target levels with current recommended dosing in children <12 years of age suggests that higher empiric doses are needed in this age group. The poor compliance with TDM guidelines highlights the need for better education about appropriate timing of sampling and dose adjustment.

Molecular characterization of hepatitis B virus (HBV) in African children living in Australia identifies genotypes and variants associated with poor clinical outcome.

Migration from sub-Saharan Africa is contributing to the rising incidence of chronic hepatitis B (CHB) infection and its complications in Australia. African CHB is associated with unique genotypes, such as E and A1, which are associated with reduced vaccine efficacy and early-onset hepatocellular carcinoma, respectively, although the prevalence of these genotypes outside Africa is poorly described. Treatment-naïve children of African origin with CHB were recruited at the Royal Children's Hospital Melbourne. Population-based sequencing of the complete HBV genome, or the clinically relevant basal core promoter (BCP)/precore (PC) region, was performed, and the HBV genotype/subgenotype assigned by phylogenetic analysis. HBV was characterized in serum from 67 children, median age 12.5 years. HBV genotype E was most frequent (70 %), with genotype D [25 %; subgenotypes D6 (formerly D7)/D3/D2)] and subgenotype A1 (5 %) also being identified. Despite their young age, over 50 % of the children were HBeAg-negative and had seroconverted to anti-HBe, with this being associated with canonical BCP/PC mutations in the majority of cases. The profile of HBV in African children living in Australia was characterized by early HBeAg seroconversion and infection with HBV variants associated with poor clinical outcome, as well as genotypes previously associated with reduced vaccine efficacy or rapid progression to liver cancer. These findings have important ramifications for patient monitoring and treatment guidelines in the Australian paediatric setting.

Fertility Preservation Toolkit: A Clinician Resource to Assist Clinical Discussion and Decision Making in Pediatric and Adolescent Oncology.

Fertility preservation (FP) discussions in children with cancer presents unique challenges due to ethical considerations, lack of models-of-care, and the triadic nature of discussions. This study evaluated a fertility toolkit for clinicians involved in FP discussions with pediatric, adolescent, and young adult patients and parents. A survey-based, longitudinal study of clinicians at The Royal Children's Hospital Melbourne involved in FP discussions undertaken at 3 time-points: 2014, alongside an education session for baseline assessment of oncofertility practices (survey 1); after each toolkit use to evaluate case-specific implementation (survey 2); 2016, to evaluate impact on clinical practice (survey 3). Fifty-nine clinicians completed survey 1. Over 66% reported baseline dissatisfaction with the existing FP system; 56.7% were not confident in providing up-to-date information. Only 34.5% "often" or "always" provided verbal information; 14.0% "often" or "always" provided written information. Survey 2 was completed after 11 consultations. All clinicians were satisfied with the discussions and outcomes using the toolkit. Thirty-nine clinicians completed survey 3. Over 70% felt confident providing up-to-date FP knowledge, 67.7% "often" or "always" provided verbal information, and 35.4% "often" or "always" provided written information. Clinicians desire improvement in FP practice. The toolkit provided significant perceived and actual benefits.

A Conceptual Framework: The Musical Self as a Unique Pathway to Outcomes in the Acute Pediatric Health Setting.

This article reports on a project at the Royal Children's Hospital Melbourne in which the music therapy team synthesized their practice and related theories to propose a new conceptual framework for music therapy in their acute pediatric setting. The impetus for the project was the realization that in the process of producing key statements about the non-musical benefits of music therapy, the cost was often the suppression of information about the patient's unique musical potential as the major (mediating) pathway from referral reason, to music therapy, and to effective outcomes. The purpose of the project was to articulate how this team of clinicians conceive of the patient's musical self as the major theoretical pathway for music therapy in an evidence-based acute medical setting. The clinicians' shared reflexive process across six months involved robust directed discussion, annotation of shared reading, and documentation of all engagement in words and diagrams. The outcome was a consensus framework including three constructs: the place of music in the life of the infant, child, and young people, Culture and Context, and Musical Manifestations. The constructs were tested in a clinical audit, and found to be robustly inclusive. In addition to the conceptual framework, this project serves to demonstrate a process by which clinical teams may reflect on their individual practice and theory together to create a consensus stance for the overall service they provide in the one setting.

Oesophageal atresia: Are "long gap" patients at greater anesthetic risk?

Long gap oesophageal atresia occurs in approximately 10% of all oesophageal atresia infants and surgical repair is often difficult with significant postoperative complications. Our aim was to describe the perioperative course, morbidity, and early results following repair of long gap oesophageal atresia and to identify factors which may be associated with complications. This is a single center retrospective cohort study of consecutive patients with oesophageal atresia undergoing surgical repair at The Royal Children's Hospital Melbourne from January 2006 to June 2017. Two hundred and thirty-nine consecutive oesophageal atresia infants included 44 long gap oesophageal atresia infants and 195 non-long gap infants. A high rate of prematurity (24.7%), major cardiac (17%), and other surgically relevant malformations (12.6%) was found in both groups. The median age at oesophageal anastomosis surgery was 65.5days for the long gap group vs 1day for the oesophageal atresia group (mean difference 56.8days, 95% CI 48.1-65.5days, P<.01). Surgery for long gap oesophageal atresia included immediate primary anastomosis (n=10), delayed primary anastomosis (n=11), oesophageal lengthening techniques (n=12) and primary oesophageal replacement (n=6). Long gap oesophageal atresia was not associated with an increased incidence of difficult intubation (OR 2.8, 95% CI 0.6-22.1, P=.17), intraoperative hypoxemia (OR 1.6, 95% CI 0.6-4.5, P=.32), or hypotension (OR 0.9, 95% CI 0.5-1.8, P=.81). The surgical duration (177.7 vs 202.1minute, mean difference [95% CI], 28 [5.5-50.4minutes], P=.04) and mean duration of postoperative mechanical ventilation (107 vs 199.8hours, mean difference [95% CI], 91.8 [34.5-149.1hours], P<.01) were shorter for the non-long gap group. Overall in-hospital mortality was 7.5% (15.9% long gap vs 5.6% non-long gap oesophageal atresia OR 1.1, 95% CI 0.4-3.4, P=.85). Long gap oesophageal atresia infants have a similar incidence of perioperative complications to other infants with oesophageal atresia. Current surgical approaches to long gap repair, however, are associated with longer anesthetic exposures and require multiple procedures in infancy to achieve oesophageal continuity.

Long Term Risk of Severe Retinopathy in Childhood-Onset Type 1 Diabetes: A Data Linkage Study

To determine the relationship between glycaemic control trajectory and the long term risk of severe complications in people with type 1 diabetes mellitus, as well as the effects of paediatric and adult HbA 1c levels. Data linkage study of data for adults with childhood-onset type 1 diabetes (diagnosed during 1975–2010) who had transitioned from paediatric diabetes care at the Royal Children's Hospital (Melbourne) to adult diabetes care at the Royal Melbourne Hospital during 1992–2013. Severe complications were categorised as severe diabetic retinopathy (SDR), chronic kidney disease, ulceration or amputation, and death. Mean HbA 1c levels were calculated for the paediatric and adult periods. Four glycaemic control trajectories were defined according to mean paediatric and adult HbA 1c levels: stable low (paediatric and adult HbA 1c ≤ 66 mmol/mol); improving (paediatric HbA 1c > 66 mmol/mol, adult HbA 1c ≤ 66 mmol/mol); worsening (paediatric HbA 1c ≤ 66 mmol/mol, adult HbA 1c > 66 mmol/mol); and stable high (paediatric and adult HbA 1c > 66 mmol/mol). 503 eligible participants (253 men) were identified, 26 (5.2%) of whom had at least one severe complication, including 16 with SDR (3.2%). No-one in the stable low group, but 4% of the improving, 1% of the worsening, and 7% of the stable high groups developed SDR. Higher mean paediatric (per 10.9 mmol/mol increase: odds ratio [OR], 2.9; 95% CI, 1.9–4.3; P < 0.01) or adult HbA 1c levels (OR, 2.1; 95% CI, 1.4–3.1; P < 0.01) were associated with increased risk of SDR, as was longer duration of type 1 diabetes (per additional year: OR, 1.3; 95% CI, 1.2–1.5; P < 0.01). SDR was associated with higher paediatric HbA 1c levels, independent of glycaemic control during adulthood; it was not documented in patients with a stable low glycaemic control trajectory.

Bone mineral density is related to lung function outcomes in young people with cystic fibrosis-A retrospective study.

Improvements in the medical management of cystic fibrosis (CF) in recent years have resulted in increased prevalence of long-term sequelae of the condition, such as low bone mineral density (BMD) and hence an increased risk of fractures in later life. Aim To explore the interaction between BMD and lung function, nutrition, and genotype. This study was a retrospective audit of 202 children with CF from August 2000 to January 2016 to investigate associations between BMD Z-scores with clinical status, nutrition, and genetics using dual-energy absorptiometry X-ray data from the Royal Children's Hospital Melbourne, Australia. Severity of both lung disease (P < 0.0001) and nutritional status (P < 0.05) was found to be strongly associated with BMD Z-scores. This is the biggest study to date to provide further evidence that the severity of pulmonary disease is related to BMD in CF patients and therefore screening guidelines for bone health in children with CF should target individuals with the poorest clinical status.

Risk Factors for Peri-Procedural Arterial Ischaemic Stroke in Children with Cardiac Disease.

Improved survival of children with congenital heart disease has led to increasing focus on neurodevelopmental outcome, as close to half of the infants undergoing cardiac surgery are affected by neurodevelopmental disability. Stroke is particularly important as it frequently results in permanent neurologic sequelae. The aim of this study was to investigate risk factors for peri-procedural arterial ischaemic stroke (AIS) in children with cardiac disease. A retrospective case-control analysis of children aged<18years with radiologically confirmed AIS following a cardiac procedure admitted to the Royal Children's Hospital Melbourne between 1993 and 2010. Each case was matched with two controls with similar cardiac diagnosis, procedure type, age and date of procedure. Demographics and peri-procedural data were collected from medical records and departmental database. Fifty-two cases were identified. Multivariable analysis identified post-procedural infection (OR 6.1, CI 1.3-27, p=0.017) and length of ICU stay (OR 4.0, CI 1.4-11, p=0.009) as risk factors for AIS. Although the study is limited to a single-centre cohort, length of ICU stay and post-procedural infection were identified as risk factors for AIS. These findings demonstrate these factors to be important areas to focus attention for stroke prevention in children with cardiac disease.

Atrioventricular block after ASD closure

ObjectiveSecundum atrial septal defect (ASD) is a common congenital heart defect. There is limited data on both early and late atrioventricular (AV) block post ASD closure. The aim of this...

George Patton: global leader in adolescent health

“What's a guy like you doing in a place like this?”, asked a criminologist to George Patton at a meeting on re-engagement for young offenders in Melbourne, Australia, 15 years ago. The colleague was referring to Patton's background in clinical psychiatry and epidemiology, and his work at the Royal Children's Hospital Melbourne. Today, Patton is a Professorial Fellow in Adolescent Health Research at the University of Melbourne and the nearby Murdoch Childrens Research Institute, and his eclectic professional positions have been an asset in his role as Chair of the Lancet Commission on adolescent health and wellbeing. Our future: a Lancet commission on adolescent health and wellbeingUnprecedented global forces are shaping the health and wellbeing of the largest generation of 10 to 24 year olds in human history. Population mobility, global communications, economic development, and the sustainability of ecosystems are setting the future course for this generation and, in turn, humankind.1,2 At the same time, we have come to new understandings of adolescence as a critical phase in life for achieving human potential. Adolescence is characterised by dynamic brain development in which the interaction with the social environment shapes the capabilities an individual takes forward into adult life. Full-Text PDF

Intensive care management of children intubated for croup: a retrospective analysis.

Croup remains the commonest reason for acute upper airway obstruction in children, yet there are scarce contemporary data of airway management in those requiring intubation. We performed a retrospective analysis of the intensive care management of children intubated for croup in two quaternary Paediatric Intensive Care Units: Royal Children's Hospital Melbourne, Australia and Alberta Children's Hospital Calgary, Canada. Patients intubated for less than three days were compared with those intubated for greater than three days. Patients less than 10 kg body weight were compared to those greater than 10 kg. Demographic, clinical and microbiological data were recorded. Seventy-seven cases of croup requiring intubation were identified. The median duration of intubation was 60 hours. Parainfluenza was the most common viral aetiology, detected in 30% of cases. Antibiotics were prescribed in 51% of patients. Corticosteroids were prescribed pre intubation in two-thirds of patients and all post intubation, with the median dose being prednisolone 3 mg/kg/day. Primary extubation failure occurred in 6.5% of patients. Neither the duration of intubation nor patient size were associated with extubation failure. An air leak test was performed in 69% of patients and poorly predicted extubation success. One non-urgent tracheostomy was performed and there was one death from hypoxic ischaemic encephalopathy. Endotracheal tube leak is poorly recorded and may not predict successful extubation.

A longitudinal study of risk and protective factors associated with successful transition to secondary school in youth with ADHD: prospective cohort study protocol.

BackgroundAttention-Deficit/Hyperactivity Disorder (ADHD) has a significant impact on child and adolescent development, especially in relation to school functioning and academic outcomes. Despite the transition to high school being a potentially critical period for children with ADHD, most research in this period has focused on academic outcomes. This study aims to extend previous research by describing academic, school engagement, behaviour and social-emotional outcomes for young people with ADHD in the first and third years of high school and to identify risk and protective factors predictive of differing outcomes across these four domains.Methods and designThe Moving Up study is a longitudinal, prospective cohort study of children with ADHD as they transition and adjust to high school (age 12–15 years). Data are collected through direct assessment and child, parent and teacher surveys. The primary outcome is academic achievement, obtained by linking to standardised test results. Secondary outcomes include measures of behaviour, ADHD symptoms, school engagement (attitudes and attendance), and social and emotional functioning, including depressive symptoms. The mean performance of the study cohort on each outcome measure will be compared to the population mean for same aged children, using t-tests. Risk and protective factors to be examined using multiple regression include a child, family and school factors know to impact academic and school functioning.DiscussionThe Moving up study is the first Australian study prospectively designed to measure a broad range of student outcomes for children with ADHD during the high school transition period. Examining both current (cross sectional) and earlier childhood (longitudinal) factors gives us the potential to learn more about risk and protective factors associated with school functioning in young people with ADHD. The richness and depth of this information could lead to more targeted and effective interventions that may alter academic and wellbeing trajectories for young people at risk of poor outcomes.The study is approved by The Royal Children’s Hospital Melbourne Human Research Ethics Committee (33206). Findings will be disseminated through peer-reviewed journals and conference presentations.

Protocol for a prospective, longitudinal, cohort study of postconcussive symptoms in children: the Take C.A.Re (Concussion Assessment and Recovery Research) study.

IntroductionA substantial minority of children who sustain a concussion suffer prolonged postconcussive symptoms. These symptoms can persist for more than 1 month postinjury and include physical, cognitive, behavioural and emotional changes. Those affected can develop significant disability, diminishing their quality of life. The precise prevalence of postconcussive symptoms following child concussion is unclear, with heterogeneous and at times conflicting results published regarding factors that predict children at risk for developing long-lasting postconcussive symptoms. The aim of the Take C.A.Re (Concussion Assessment and Recovery Research) study is to provide an in-depth multidimensional description of the postconcussive recovery trajectories from a physical, neurocognitive and psychosocial perspective in the 3 months following concussion, with a focus on the early postconcussive period, and identification of factors associated with prolonged recovery.Methods and analysisTake C.A.Re is a prospective, longitudinal study at a tertiary children's hospital, recruiting and assessing patients aged 5–<18 years who present to the emergency department with a concussion and following them at 1–4 days, 2 weeks, 1 month and 3 months postinjury. Multiple domains are assessed: postconcussive symptoms, balance and coordination, neurocognition, behaviour, quality of life, fatigue, post-traumatic stress symptoms, parental distress and family burden. ‘Delayed recovery’ is operationalised as the presence of ≥3 symptoms on the Post Concussive Symptoms Inventory rated as worse compared with baseline. Main analyses comprise analysis of variance (recovery trajectories, delayed vs normal recovery groups) and regression analyses of predictors of recovery (preinjury, acute and family factors).Ethics and disseminationEthical approval has been obtained through the Royal Children's Hospital Melbourne Human Research Ethics Committee (33122). We aim to disseminate the findings through international conferences, international peer-reviewed journals and social media.Trial registration numberACTRN12615000316505.

Arterial ischemic stroke in children with cardiac disease.

To describe the spectrum of cardiac disorders, timing in relation to interventional procedures, and outcome in children with cardiac disease and arterial ischemic stroke (AIS). Children younger than 18 years with cardiac disease and radiologically confirmed AIS admitted to the Royal Children's Hospital Melbourne between 1993 and 2010 were retrospectively identified using ICD-9 and ICD-10 searches. Seventy-six children with cardiac disease and radiologically confirmed AIS were identified with the median age at diagnosis of 5 months (interquartile range 0-58). Cardiac lesions included cyanotic congenital heart disease (CHD) in 42 (55%), acyanotic heart disease in 24 (29%), cardiomyopathies/myocarditis in 6 (8%), infective endocarditis in 3 (4%), and primary arrhythmias in 3 (4%). Stroke occurred following cardiac procedures in 52 patients (68%): 41 post cardiac surgery (4.6 strokes per 1,000 surgical procedures) and 11 post cardiac catheterization (1.7 strokes per 1,000 catheterizations). The median time from procedure to diagnosis of stroke was 3 days (interquartile range 2-7), with 68% (95% confidence interval 58%-79%) of strokes estimated to occur within the periprocedural period. Prevalence of periprocedural stroke varied by diagnostic category, but was most common in patients with cyanotic CHD undergoing palliative surgery (22/2,256, 1%) (p < 0.005). There were 3 AIS-related deaths, and 54 survivors (84%) had persisting neurologic deficits. Infants with cyanotic CHD were most frequently affected by AIS during the periprocedural period. Prospective cohort studies are required to determine effective primary and secondary prevention strategies.

Fergus Cameron: getting the big picture in childhood diabetes

Fergus Cameron: getting the big picture in childhood diabetes

Ear for recovery: protocol for a prospective study on parent–child communication and psychological recovery after paediatric injury

IntroductionOne in six children who have been admitted to hospital with an injury develop persistent stress symptoms that put their development at risk. Parents play a crucial role in children's...

Etiology of Brain Attacks in Children

Investigators at the Royal Children's Hospital Melbourne, Australia, studied the presenting features, scope, and prevalence of conditions causing brain attack symptoms in children aged 12 month to 18 years presenting to a tertiary pediatric ED.

Audit of Referrals for Labial Appearance Concerns at the Royal Children's Hospital Melbourne: From 2000 Onwards

Audit of Referrals for Labial Appearance Concerns at the Royal Children's Hospital Melbourne: From 2000 Onwards