Paediatrics (RCH) - Theses
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ItemImproving pain and distress management of children in the emergency department( 2015)This thesis represents a compilation of peer-reviewed papers addressing the care for children in pain or undergoing painful or distressing procedures in the emergency department. After an introductory chapter, papers related to one of several themes are briefly introduced and placed in context with each other. The papers, and their compilation in this thesis, aim to provide guidance for paediatricians and emergency physicians caring for children on how to prepare for and reduce procedural and non-procedural pain and distress. Many aspects of this work, including certain research findings, evolving approaches to pain and sedation management and evidence-based teaching materials, are being used by, or have been implemented in, the Emergency Department at Royal Children’s Hospital and other emergency departments across Victoria, Australia, as well as interstate and overseas.
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ItemA prospective evaluation of symptom based screening for child contact screening and management of tuberculosis in Yogyakarta, Indonesia( 2013)Children who are in close contact with a case of tuberculosis (TB) have a high prevalence of infection with Mycobacterium tuberculosis (M. tuberculosis).Infected children, and in particular young infants, are at high risk of developing severe disseminated TB such as tuberculous meningitis or miliary TB, which is associated with high mortality rates.Screening and management of children who are in close contact with a case of pulmonary TB has the potential to increase TB case finding and prevent disease. This is universally recommended but rarely implemented in TB endemic settings. The WHO recommends a symptom based screening approach that may improve implementation at the primary care level. The main aim of the study was to prospectively evaluate the performance of symptom based screening approach for child contact screening and management. A prospective cohort study of children who were close contacts of a pulmonary TB patient in Yogyakarta, Indonesia, was conducted from August 2010 to December 2012. Clinical assessment, tuberculin skin test and chest X ray (CXR) were performed on all eligible children irrespective of symptoms at baseline. Sputum smear and culture or other appropriate investigations were performed only in children with suspected TB. Following assessment, children were assessed as having TB disease, latent TB infection (LTBI) or TB exposed only. They were treated appropriately as TB disease or with isoniazid preventive therapy (IPT) if they did not have TB and were less than 5 years of age, as per WHO guidelines. All children were followed for 12 months to evaluate response to therapy if diagnosed as TB at baseline evaluation, or to monitor for the development of TB among those without disease at baseline. The effectiveness and cost of the symptom-based screening approach was compared to other possible screening approaches. Data were further analysed to determine factors associated with the risk for infection with M. tuberculosis and with TB disease, to evaluate adherence to IPT, to describe CXR findings and to measure inter-observer agreement in the interpretation of CXR findings in the context of child contact screening and management. At baseline evaluation, of 269 child contacts, 8% had TB disease, 38% had LTBI and 64% were TB exposed only. The results of further evaluations and follow up showed that symptom-based screening provides a simple, effective and low-cost approach to child TB contact management that can be implemented at the primary health care setting. An important strength of this study was that it observed outcomes in the cohort for 1 year with a very low rate of lost to follow up. We identified that children who had close contact with a TB case that was sputum smear-positive case or female were most likely to be infected with M. tuberculosis. We observed that none of 99 children who were provided IPT at baseline developed TB in the first year of observation. Incomplete adherence to IPT was common, and problems related to health care service were identified as possible barriers to adherence. The majority of CXRs of child contacts were normal but there was substantial disagreement between reviewers on the quality and the findings of the CXR. This study provides original data from a prospective and comprehensive evaluation of the symptom-based screening approach. The findings support implementation of contact screening and management at a primary care level, with implications for global efforts to detect and prevent TB in children.
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ItemNovel approaches to the immunodiagnosis of childhood tuberculosis( 2012)Approximately one-third of the global population is infected with Mycobacterium tuberculosis (MTB). Despite a number of advances, tuberculosis (TB) remains one of the diagnostically most challenging diseases. For almost a century, the tuberculin skin test (TST) was the only method available to identify latent TB infection (LTBI). However, the TST has variable sensitivity and limited specificity. In 2002, a new generation of immune-based tests, interferon-γ release assays (IGRA), were licensed for clinical use. IGRA rely on the detection of interferon-γ produced by sensitised T cells in response to stimulation with relatively MTB-specific antigens. Since these are absent from all BCG vaccine strains and most non-tuberculous mycobacteria, it is assumed that IGRA have greater specificity than the TST. However, increasing data cast doubt on the performance of IGRA, especially in the paediatric setting. Two constellations are particularly common in children: (a) discordance between TST and IGRA results (ie TST+/IGRA- or-TST-/IGRA+), and (b) indeterminate IGRA results. The underlying basis for discordance remains unknown and it is uncertain which of the test results accurately reflects the true TB infection status. Both indeterminate and discordant IGRA results present a considerable management dilemma in clinical practice. The principle hypothesis of this thesis was that a detailed analysis of mycobacteria-specific cellular immune responses would provide insights into the origins of discordance, and provide important information to enable the development of improved immunoassays for the diagnosis of TB. This thesis begins with a systematic review of the literature on the performance of IGRA in children, highlighting the lack of evidence supporting the hypothesis that prior BCG vaccination and exposure to non-tuberculous mycobacteria are the primary cause of common discordance (TST+/IGRA-). The next chapter describes the development of whole blood assays that enable detailed analyses of mycobacteria-specific immune responses. It also describes the development of a complex multi-colour flow cytometric procedure for simultaneous analysis of major T cell surface markers (CD3, CD4, CD8), T cell memory markers (CD45RA, CCR7) and intracellular cytokines (IFN-γ, IL-2, TNF-α, IL-17), as well as the optimisation of Luminex bead-based cytokine assays used to determine mycobacteria-specific cytokine responses in supernatants. The subsequent chapters describe the results of a clinical study in children at risk of TB infection that used these methods. The data show that individuals with common discordance are a heterogeneous group, comprising both TB-uninfected and TB-infected cases. A number of mycobacteria-specific cytokine responses that have the potential to improve diagnostic assays for TB were identified. Importantly, the results indicate that certain cytokine responses can identify TB infection, and also discriminate between LTBI and active TB. Furthermore, the results show that the proportion of mycobacteria-specific single-positive TNF-α+ CD4+ T cells differs significantly between uninfected children, those with LTBI and those with active TB. The discovery of biomarkers that can simultaneously identify TB infection and determine disease stage is an important breakthrough, as existing immune-based TB tests are unable to distinguish between disease stages. This represents a significant advance in TB diagnostics, with the potential to be developed for use in low-resource settings where better TB tests are needed most.
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ItemCerebral palsy in Victoria: a population-based study( 2012)BACKGROUND AND AIMS: This thesis reports an exploration of the epidemiology of cerebral palsy in Victoria and a comparison of Victorian data with data from other populations. Each of six broad aims related to a particular area of investigation and thesis chapter. The aims were to describe 1) the frequency of cerebral palsy in Victoria, 2) overall temporal trends and by gestational age group, 3) clinical characteristics, including motor type, topographical pattern, and motor severity, 4) accompanying disorders and impairments, 5) neuroimaging patterns and their relationship to perinatal variables and clinical characteristics, and 6) survival. METHODS: The Victorian Cerebral Palsy Register was used to extract data on individuals born in Victoria with non-postneonatally acquired cerebral palsy based on specific criteria for each chapter. A systematic review of the literature was also undertaken to enable comparison of classification, definitions, and epidemiological data with the Victorian data. RESULTS: The decade-specific prevalence of cerebral palsy in Victoria was 1.6 per 1000 live births for the 1980s, 1.8 for the 1990s and 1.7 for 2000-2004. In comparison, the range of prevalence estimates from 33 surveillance systems was 1.8-4.0 per 1000 for 1990s birth cohorts and 1.2-3.0 per 1000 for 1980s cohorts; no methodological or population factors explained the wide variability. The rate of cerebral palsy in Victoria increased during the 1980s and early 1990s, particularly for extremely preterm infants, but also for infants born at term. The data suggest a reversal of this trend from the mid-1990s for both term and extremely preterm infants, a finding observed in other populations. In general, the proportion of cerebral palsy cases with each motor type, topographical pattern, motor severity level, and associated impairment varied widely between surveillance systems, and there was a lack of consensus on definitions and classifications. Victorian data showed a relative increase in mild motor impairment between 1970 and 2003 and an increase in the proportion of cerebral palsy cases with spastic hemiplegia and diplegia relative to spastic quadriplegia; however, no improvement in survival was seen, even for the most severely affected. The most common imaging finding was periventricular white matter injury (PWMI), a pattern associated with spastic diplegia and hemiplegia, and mild-moderate motor impairment. While PWMI was the primary pattern in children born preterm, it was also common in children born at term. Grey matter injuries and malformations were predominantly associated with term birth, and bilateral brain injuries were associated with poor gross motor function. The majority of focal vascular insults and unilateral malformations resulted in spastic hemiplegia. CONCLUSIONS: Through a series of systematic reviews, this thesis has contributed to a better understanding of issues relating to the definition and classification of cerebral palsy and, in particular, emphasised the potential for these to affect estimates of prevalence and distribution of clinical subtypes. In addition, it has resulted in a deeper understanding of clinical, temporal and neuropathological patterns in cerebral palsy and exemplifies the potential benefits of inclusion of MRI data in epidemiological research into a condition with diverse causal networks and clinical manifestations.
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ItemHealth and development in the 12 months following arterial ischaemic stroke in children( 2012)Background: The breadth of consequences of stroke in children is poorly understood, impacting the targeting of health resources and appropriate measurement of intervention outcomes. Clinical experience suggests children experience functionally disabling consequences following a stroke that change over time. There is limited understanding of the clinical course following diagnosis and factors that impact long-term functional outcome. Aim: This study aimed to: 1) Prospectively measure and describe neurological, language, cognitive and motor abilities of children from acute presentation to 12 months following diagnosis of arterial ischaemic stroke 2) Measure the children’s activity limitations in daily life activities, quality of life, and parent health at 6 and 12 months 3) Explore the relationship between brain capacity markers, cognitive capacity markers, age at injury and environmental factors over a 12 month period 4) Identify factors predictive of functional outcome at 12 months. Method: A prospective single-centre study was undertaken to evaluate the clinical course of 27 children following diagnosis of first arterial ischaemic stroke. The children were evaluated during the acute phase, and at 1, 3, 6 and 12 months following diagnosis across domains of health including neurological function, language, motor, cognitive, social-emotional, adaptive behaviours and quality of life. Family functioning and parent health was also measured and the concerns of the children and parents elicited. Outcomes were explored for the neonatal group (n=6) compared to the older children (aged > 30 days at diagnosis), and the cohort overall. Findings: Neonates had few neurological or detectable health consequences in the first 6 months following diagnosis, however motor impairments and limitations in functional daily abilities were evident by 12 months. In the older age group, a wider range of sequelae was evident. Motor impairments were the most prevalent consequence, and made the most rapid recovery in the first 6 months. Fine motor difficulties emerged over time. Social, behavioural and communication limitations were evident by 12 months. None of the children aged older than 30 days at diagnosis returned to their pre-morbid levels of functional daily ability by 12 months. The health-related quality of life of the older children was impacted, particularly psychosocial health. Parent health was impaired, and burden on the family was sustained through the first 12 months following diagnosis. Functional outcome at 12 months was predicted by the presence or absence of a speech deficit at the time of symptom onset, and one month fine motor or cognitive abilities. Socio-economic status also contributed to functional outcome. Conclusions: The consequences of stroke in children are diverse, can appear over the months following diagnosis, and may continue to emerge beyond the 12 month surveillance period of this study. Measures of impairment only detect a limited range of sequelae. Activity limitations, and participation and quality of life restrictions are prevalent. The impact of the stroke can also extend to the broader family. Health resources need to be targeted to long-term surveillance of this population, to address changing needs in daily life (including home, school and community activities) and parent and family health. Further prospective multi-centre studies of larger populations will enable prognostication of outcome, and the exploration of the individual and environmental mechanisms that contribute to variations in clinical course and outcome.
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ItemThe ‘Kids Sleep Study': effects of an infant sleep intervention at 6 years of age: follow-up of a randomised controlled trial( 2011)BACKGROUND: Behavioural sleep problems in infancy are highly prevalent. They increase the risk of maternal depression symptoms and predict later child sleep problems, which in turn are associated with adverse mental and general health outcomes for children and parents. Controlled trials demonstrate that behavioural sleep techniques effectively reduce infant sleep problems and associated maternal depression symptoms in the short- to medium-term. However, theoretical concerns remain that these techniques harm child-parent attachment and lead to later child emotional and behaviour problems. Although they are yet to be empirically tested, these concerns are potentially causing harm, as are some practitioners who hold these concerns, by discouraging the use of effective behavioural management strategies. The capacity for behavioural techniques to have long-lasting benefits on child, child-parent and maternal outcomes to school-entry age is also unknown, because studies are yet to examine whether early child sleep problems predict these later outcomes. AIMS: Part 1 aimed to determine whether an infant behavioural sleep program caused lasting harms or benefits at child age 6 years (school-entry) to: (1) attachment-related, (2) sleep and (3) maternal mental health outcomes. Part 2 aimed to determine whether early child sleep problems (4, 12 and 24 months) predicted (4) child sleep, and (5) secondary child, child-parent, and maternal outcomes at child age 6 years, after accounting for concurrent child sleep problems. METHODS: This study drew on a pre-existing population-based cluster controlled trial of a behavioural sleep intervention (n=328, ISRCTN48752250), which recruited infants with parent-reported sleep problems at 7 months from six socioeconomically diverse Melbourne (Australia) local government areas. The original study compared an intervention comprising behavioural sleep strategies delivered by well-child nurses at 1-3 individual consultations at child age 8-10 months, with usual care. The current study revisited children and their mothers at child age 6 years with a parent questionnaire and direct assessment in the family home. Part 1 analysed data as a randomised controlled trial follow-up. Based on the results of Part 1, Part 2 pooled trial arms to analyse data as an epidemiological cohort. Aims were analysed using unadjusted and adjusted regression modelling (linear for continuous outcomes, logistic for binary outcomes) controlling for known confounders selected a priori, where possible. RESULTS: Families retained at 6 years (n=225, 69%) were more likely to speak English than those lost to follow-up (84% versus 74%, p=0.03). There was no evidence of attrition bias between groups. Part 1: There was no evidence of a difference between groups for any attachment-related, sleep or maternal mental health outcome. Although power was limited to detect effect sizes ≥0.4 standard deviations between groups, 95% confidence intervals tended to centre on equivalence and there was no pattern of effect across the sample estimates toward harms or benefits. Part 2: Early sleep problems at individual time points (4, 12, 24 months) rarely predicted outcomes at 6 years, but, when measured as an ordinal persistent count (1, 2, 3 or 4 sleep problems at these ages, taking a single sleep problem at 7 months as the reference category), demonstrated an increasing dose-response relationship with later child, child-parent and maternal outcomes, with evidence strongest for child outcomes. CONCLUSION: This brief behavioural sleep intervention was effective in the short- to medium-term and safe to use in the long-term, at least to five years post-intervention. Parents and health professionals can feel confident using and offering behavioural strategies to manage infant sleep in the second six months of life. In a sample selected for infant sleep problems at 7 months, recurring or persistent early child sleep problems predisposed children and their mothers to poorer outcomes at 6 years. Health professionals need to offer, and parents need to be able to access, strategies that adapt to the changing nature of child sleep problems as the child develops.