Paediatrics (RCH) - Theses
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ItemEnd-organ consequences of the Fontan circulation( 2022)The Fontan procedure is the last in a series of staged surgical procedures offered to children born with complex congenital heart disease in whom a two-ventricle repair is not feasible. Since its first description, the Fontan procedure has undergone a number of technical modifications which have further improved survival and reduced associated morbidity. Due to improved survival, the number of people living with a Fontan circulation is growing, and the average age is increasing. However, with more patients surviving into adulthood we are unfortunately seeing that many will develop complications. Ventricular dysfunction, circulatory failure, atrioventricular valve (AVV) regurgitation, cardiac arrhythmias, protein-losing enteropathy, plastic bronchitis and thromboembolic phenomena have all been increasingly recognized as potential complications after the Fontan operation. Hepatic fibrosis, cirrhosis and hepatocellular carcinoma have also been described, as well as renal dysfunction in the form of reduced glomerular filtration rate (GFR) and microalbuminuria. The aim of this thesis was to (i) characterize the prevalence and severity of hepatic and renal complications in patients with a Fontan circulation, (ii) identify potential risk factors that may contribute to the development of hepatic and renal complications after the Fontan procedure, and (iii) inform screening practices for end-organ complications in these patients. In this thesis I have demonstrated that: (i) the majority of patients with a Fontan circulation have non-invasive evidence of liver fibrosis by early adulthood, (ii) a smaller but significant proportion of patients will be diagnosed with liver cirrhosis by early adulthood, (iii) a minority of patients will develop hepatocellular carcinoma, which may occur in adolescence or early adulthood, (iv) history of cardiac arrhythmia or AVV failure is associated with an increased risk of advanced liver disease, (v) mild renal dysfunction is common in patients with a Fontan circulation, however, does not appear to negatively impact mid-term outcomes, (vi) creatinine based estimated GFR should be interpreted with caution in children with a Fontan circulation, and tends to over-estimate true or measured GFR in children and adults with a Fontan circulation, (vii) many of the patients who were found to have hepatic or renal dysfunction were identified on routine screening. This thesis has drawn attention to the significant proportion of patients with a Fontan circulation who will develop hepatic or renal dysfunction during long-term follow-up. These findings encourage us to consider the implications of end-organ dysfunction on the medical management of a population that is growing in numbers and age. This work emphasizes the importance of routine surveillance in identifying those with significant liver and kidney dysfunction after the Fontan procedure, and identifies a number of potentially modifiable risk factors for more advanced disease. In the absence of any proven pharmacological treatment for these complications, it is likely that optimisation of the Fontan circulation itself in combination with the avoidance of secondary end-organ insults will be the key to minimising the burden of hepatic and renal disease in this population.
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ItemAtrioventricular valve function during single ventricle palliation( 2021)Single ventricle anomalies encompass a spectrum of the most severe congenital heart disease. Staged surgical palliation culminates in the Fontan circulation, wherein the functional single ventricle pumps blood to the systemic circulation and returning blood flows passively through the pulmonary circulation, without the support of a subpulmonic ventricle. Surgical modifications and advancements in non-operative management have led to a significant decline in early mortality following the Fontan operation. As such, the population of patients living with a Fontan circulation is expected to double over the next 20 years, including a growing proportion of patients surviving well into adulthood. Due to inherent anatomical and physiological limitations, the Fontan circulation is characterised by elevated systemic venous pressure and reduced cardiac output. Atrioventricular valve (AVV) regurgitation impairs pulmonary venous return leading to increased post-capillary venous pressures and further increasing systemic venous pressure. Furthermore, AVV regurgitation increases the volume load on the single ventricle which can lead to ventricular dilatation and impaired function. Studies have demonstrated that AVV regurgitation and AVV surgery are associated with worse clinical outcomes during the initial stages of single ventricle palliation, but little is known about the cumulative impact of AVV regurgitation and AVV surgery over the lifetime of patients undergoing single ventricle palliation. The aim of this thesis was to (i) determine the cumulative incidence of, and risk factors for, moderate or greater AVV regurgitation during the lifetime of patients undergoing Fontan palliation, (ii) determine the impact of moderate or greater AVV regurgitation on clinical outcomes in patients with a Fontan circulation, and (iii) determine the impact of AVV surgery on long-term AVV competency and clinical outcomes in patients undergoing single ventricle palliation. The studies contained within this thesis were conducted with data primarily from the Australia and New Zealand Fontan Registry, which is the largest database of Fontan survivors in the world. In this thesis I have demonstrated that: (i) there is a high rate of moderate or greater AVV regurgitation during the lifetime of patients with a Fontan circulation, (ii) risk factors for moderate or greater AVV regurgitation and AVV surgery include right ventricular (RV) dominance, atrioventricular septal defect (AVSD), mitral atresia, right atrial isomerism, aortic atresia, and prior AVV repair, (iii) moderate or greater AVV regurgitation in patients with a Fontan circulation is associated with an over two-fold increased risk of death or transplantation, but only in patients with RV dominance, (iv) in patients with AVSD and a Fontan circulation, the high rate of moderate or greater AVV regurgitation is primarily due to the anatomy of the common AVV, and is not impacted by ventricular dominance, (v) AVV surgery itself is not a risk factor for death or transplantation in patients with a Fontan circulation, but rather it is the patient’s characteristics necessitating AVV surgery that are associated with an increased risk of death or transplantation, (vi) patients with tricuspid valve repair failure are at high risk of death or transplantation, but successful tricuspid valve repair improves transplantation-free survival rates in patients with moderate or greater AVV regurgitation, (vii) patients with functional AVV regurgitation and impaired ventricular systolic function are at increased risk of death or transplantation after AVV repair, (viii) AVV closure is a safe and effective surgical technique for management of AVV regurgitation in patients with a Fontan circulation and two AVVs, where the diminutive valve is regurgitant. This thesis has revealed the enormous burden of AVV regurgitation and AVV surgery in patients with a Fontan circulation. In doing so, it has drawn attention to AVV regurgitation as one of the most important issues in the management of patients undergoing single ventricle palliation. Ultimately, by improving our understanding of the incidence and natural history of AVV regurgitation, this thesis will improve the long-term outcomes of many patients living with a single ventricle circulation.
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ItemThe epidemiology and risk factors of anaphylaxis and food-induced anaphylaxis worldwide( 2019)Anaphylaxis is a severe allergic reaction that is rapid in onset and may cause death. There are increasing reports from individual countries and regions on anaphylaxis prevalence or incidence; however, there has been no systematic summary of the worldwide evidence among the paediatric population. An increasing rate of hospital admissions for food-induced anaphylaxis was observed in Australia from 1993 to 2012, especially among young children. Although rising rates of anaphylaxis have also been reported in other western countries, little is known about the time trends in Asian regions. Time trends of adrenaline auto-injectors (AAI) prescription is a good supplement surrogate for the time trends of anaphylaxis risk in the community. Some studies reported time trends of AAI prescription internationally, such as USA, UK and Canada; however, there is little information on the time trends of AAI prescription or dispensing in Australia in recent years. Previous international studies have reported that ethnicity is associated with the risk of anaphylaxis. Food allergy was found to be more common in children born in Australia with Asian parents than children born in Australia with Caucasian parents. However, it is not known whether ethnicity is also a risk factor for the development of anaphylaxis and food-induced anaphylaxis in Australia. Food allergy is an important cause of anaphylaxis. People with food allergy have a high risk of anaphylaxis, but not all of them will have an anaphylactic reaction. It is hence crucial to know the risk factors of having anaphylactic reactions in the food allergic population. Few studies have examined risk factors for food-induced anaphylaxis in food-allergic children. The characteristics of children with food allergy who are more likely to experience anaphylaxis are unknown. Therefore, this thesis aims to describe the worldwide incidence and prevalence of anaphylaxis and identify risk factors for anaphylaxis and food-induced anaphylaxis in both the general population and the food-allergic population. Firstly, I conducted a systematic review to describe the incidence and prevalence of anaphylaxis in children worldwide. I found a high heterogeneity between studies which limited the interpretation of an overall combined incidence and prevalence. I found increasing time trends of all-cause anaphylaxis and food-induced anaphylaxis in children from included studies and studies in developing areas were underrepresented. By using hospital admission data for anaphylaxis from the Hospital Authority of Hong Kong, I reported increasing time trends of both all-cause anaphylaxis and food-induced anaphylaxis in the paediatric population in Hong Kong between 2001 and 2015. By analysing AAI dispensing data from the Australian Pharmaceutical Benefits Scheme (PBS) database, I found an increasing incidence rate of patients with AAI in Australia from 2005 to 2014. Different trends were reported by sex, age and state. I found a shift towards more AAI prescriptions being provided by general practitioners (GPs) rather than specialists in most regions in Australia. By using the data from the School Entrant Health Questionnaire in Victoria, Australia, I investigated the risk factors of anaphylaxis in the general population. I found an association between Asian ethnicity and anaphylaxis risk in children living in Australia and identified the high-risk group (Australian-born children with Asian-born mothers) for anaphylaxis. Lastly, I used data from the HealthNuts study to explore the frequency and risk factors of anaphylaxis in food allergic children from a community setting. I found a high frequency of experiencing anaphylactic reactions (11.5%) in the preceding 12 months in children with food allergy. In summary, the results presented in this thesis have provided further knowledge on the epidemiology of anaphylaxis and food-induced anaphylaxis in the general population and identified important predictors of anaphylaxis in the general population and the food allergic population. The identification of these essential predictors has important implications for the management of anaphylaxis and will improve our understanding of the development of anaphylaxis.
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ItemUnderstanding the epidemiology of tuberculosis in adolescence( 2018)Despite the availability of curative treatment since the 1940s, tuberculosis (TB) remains a leading cause of morbidity and premature mortality worldwide. TB-related risks vary markedly throughout the life course; adolescence is characterised by a dramatic increase in the risk of developing TB, a fact that has been appreciated since the early 20th century. Evidence is emerging that adolescents and young adults with TB are also at increased risk of adverse outcomes, particularly premature disengagement from care. However, the epidemiology of TB in adolescence and young adulthood is an almost entirely neglected topic in the literature. This thesis aimed to provide a detailed account of the epidemiology of TB in adolescents and young adults in modern epidemics. This body of work is composed of five distinct projects: a systematic review of epidemiologic estimates for TB in young people; an estimate of the number of young people who develop TB globally each year; descriptive analyses of case-based TB surveillance data from two high burden settings, the Western Cape province of South Africa and the Philippines; and a narrative review of epidemiologic considerations in building age-structured mathematical models of TB transmission with a demonstration. The systematic review identified 26 studies from 19 countries; 2 prospective cohort studies of TB incidence and 24 prevalence surveys. TB prevalence among adolescents and young adults varied substantially but was very high in some settings. By analysing global TB surveillance data from 2012, 1.8 million adolescents and young adults were estimated to have developed TB that year, suggesting that they experienced 17% of incident TB cases globally that year. Case-based surveillance data from the Western Cape province of South Africa and from the Philippines each confirmed a substantial escalation in the burden of TB throughout adolescence, and an increasing proportion of patients with a transmissible form of TB. Adolescents and young adults living with HIV in South Africa were at high risk of prematurely disengaging from TB treatment. Incorporating what is known about the age-related epidemiology of TB into a simple mathematical model showed that that older adolescents are likely to make a disproportionate contribution to TB transmission. This fact is not captured by current mathematical modelling practice, and recommendations for addressing this issue are provided. Adolescence is a highly dynamic period with regard to TB epidemiology. Adolescents and young adults face a dramatic increase in the risk of TB as they mature, and physiological and social factors combine to create a high risk of onward transmission from this age group. Because of the disproportionate impact of high transmission rates on younger people and the age structure of populations in high TB burden settings, adolescents and young adults are a population of particular importance in intense TB epidemics. Improving the prevention and management of TB among these age groups is critical in order to both safeguard their health and strengthen TB control globally. Whether we can eliminate TB in the coming decades will hinge in large part on better prevention and management of TB among the current generation of young people.
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ItemThe epidemiology and aetiologies of the severe epilepsies of infancy( 2016)The severe epilepsies of infancy (SEI) are a group of infantile-onset seizure disorders characterised by frequent seizures, abnormal EEG and pharmacoresistance to anti-epileptic therapy. SEI include well-described epilepsy syndromes such as early infantile epileptic encephalopathy (EIEE), epilepsy of infancy with migrating focal seizures (EIMFS) and West syndrome. Cognitive outcome is often poor, due to effects of seizures, the underlying aetiology, and antiepileptic drugs (AEDs) on the developing brain. There is an urgent need for novel treatments. Where effective therapies are available, such as epilepsy surgery for brain malformations, treatment can be life-changing. Given that developmental outcomes may be significantly improved in the context of optimal seizure control at an early age, determining the underlying cause of SEI early in life is paramount. The aetiologies of SEI are heterogeneous; a large number of acquired and genetic brain disorders are reported. In many infants, the cause remains unknown despite investigation, and is presumed to be genetic. With the emergence of next generation sequencing (NGS) techniques such as whole exome sequencing (WES), a rapidly growing number of genetic causes of SEI is now recognised and gene discovery is ongoing. The genetic epidemiology of SEI has not been studied and the relative importance of each genetic cause is not known. Brain malformations, chromosomal abnormalities, inborn errors of metabolism and some genetic disorders can be diagnosed with technologies currently available in clinical practice. Studies of WES and other NGS techniques in epilepsy populations have shown that these techniques identify the aetiology in 10-50% of undiagnosed patients. No study has specifically looked at the yield in SEI, and no population-based studies have been reported. The yield and cost-effectiveness of NGS for SEI at a population level remains unknown, and access to genetic testing is currently poor in most regions of the world. This population-based study of SEI in Victoria, Australia aimed to study the incidence and determine the aetiologies, electroclinical phenotypes and other phenotypic characteristics of SEI. As part of a particular focus on genetic aetiologies, the study aimed to identify genetic causes in infants with SEI of unknown aetiology using WES, and determine the yield and cost of early genetic testing relative to current standard diagnostic pathways for investigation of SEI aetiology. Infants with SEI born in Victoria during 2011-2013 were identified by a comprehensive state-wide search of multiple sources. Infants with potential SEI were identified by review of all electroencephalogram (EEG) reports on children under two years old during 2011-2015 (n=4505), and search of neonatal intensive care unit (NICU) databases for neonates with seizures born 2011-2013 (n=379). Hospital records of infants with potential SEI from the three main paediatric hospitals in Victoria, The Royal Children’s Hospital (RCH), Monash Health (MMC) and The Austin Hospital, and the two NICUs not co-located with a paediatric hospital, The Royal Women’s Hospital (RWH) and The Mercy Hospital for Women (MHW), were reviewed to confirm clinical and demographic inclusion criteria were met. SEI was defined as epilepsy onset before age 18 months, frequent seizures (> daily for a week or > weekly for a month), epileptiform EEG and pharmacoresistance (failed 2 appropriate anti-epileptic therapies); infantile spasms were automatically included. In infants with confirmed SEI, medical records, EEG recordings and brain magnetic resonance imaging (MRI) were reviewed to determine each infant’s epileptic syndrome, outcome at two year old, and aetiology. Clinical assessment and WES were performed if aetiology or electroclinical phenotype was unknown. 114 infants with SEI were ascertained. The incidence of SEI in Victoria is 51/100,000 live births/year. West syndrome/infantile spasms was the most common epileptic syndrome, with an incidence of 33/100,000 live births/year. EIMFS and EIEE had incidences of 4.5 and 3.6/100,000 live births/year respectively. At two years old, 18 (16%) infants were deceased. 86/98 (90%) survivors had delayed development, and 46/98 (47%) ongoing seizures. All infants whose presenting epileptic syndrome was EIEE, early myoclonic encephalopathy (EME) or EIMFS at epilepsy onset were deceased or had severe developmental impairment. Normal development was seen in 9/64 (14%) infants who presented with West syndromes/infantile spasms or a unifocal epilepsy, and only two were deceased. The aetiology was identified in 76 (67%) and unknown in 38 (33%). Fourteen (12%) infants had an acquired brain insult such as hypoxic-ischaemic encephalopathy or perinatal stroke. The remaining infants had genetic or presumed genetic aetiologies. Brain malformations were identified in 31 (27%), including focal cortical dysplasia (FCD) in 14 (12%). Six (5%) infants had metabolic disorders and nine (8%) had chromosomal abnormalities. Sixteen (14%) had single gene disorders, including 11 (10%) with disorders of ion channel function (channelopathies). Aetiology was known from clinical testing in 61 (54%). Research MRI review identified the cause in a further 4 (4%) and research genetic testing in 11 (10%). Among 86 (75%) infants with no aetiological diagnosis prior to epilepsy onset, the highest yield investigations were MRI and genetic testing, which identified the cause in 25/85 (29%) and 16/50 (32%) respectively. 13/50 (26%) infants had a genetic variant of unknown significance (VOUS) identified on WES; these are being further investigated. Modelling of diagnostic pathways showed that performing WES early in the diagnostic pathway and reducing the amount of metabolic testing increases diagnostic yield for less cost compared with the current standard diagnostic pathway. Approximately 1:2000 infants have SEI, equating to over 150 new cases of SEI in Australia per year. Outcomes for seizure control, development and survival are poor. Brain malformations were the most common cause, were under-recognised, and should be considered in those with unknown aetiology, especially in those with West syndrome or unifocal epilepsy. Channelopathies were the most common group of single gene disorders. Next-generation genetic testing and high quality brain imaging improved diagnostic yield, with implications for treatment and reproductive counselling, and should be implemented early in the diagnostic pathway in clinical practice. Future work will focus on identifying the aetiology in the remaining infants, determining the genetic basis of brain malformations causing SEI, and studying the yield of other NGS and brain imaging techniques to improve the rate of early diagnosis. This work will inform research into development of novel and targeted treatments for these devastating disorders.
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ItemThe health of Australian Aboriginal and Torres Strait Islander adolescents( 2016)The poor health and disadvantage experienced by Aboriginal and Torres Strait Islander (Indigenous) Australians is well described. Almost ten years after the Closing the Gap agreement, the life expectancy gap between Indigenous and non-Indigenous Australians remains ten years. Some gains, however, have been made. Child survival has improved significantly, and as a result, one third of the Australian Indigenous population are now adolescents (aged 10 - 24 years). These young people provide great promise for the health of Indigenous Australians. Their engagement in education and employment can help address the intergenerational cycle of poverty. Given half of all pregnancies to Indigenous mothers occur before the age of 24 years, young people are central to assuring the health of the next generation. Adolescence is also a period where future patterns of health are established, with many health risks (tobacco and alcohol use) and health states (mental disorder, overweight and obesity) having their onset and perhaps most amenable to intervention during this period. To date, however, Indigenous adolescents have largely remained at the margins of health policy, with correspondingly limited investment in their health and wellbeing. One reason for the limited focus on Indigenous adolescent health in policy is likely to be the limited health data to inform priority and need. A common assumption that young people are ‘healthy’ may have contributed to the absence of a reporting framework or defined health indicators for Indigenous adolescent health. The paucity of health data for Indigenous adolescents also reflects limitations of health data systems for Indigenous Australians, which are typically orientated to either child or adult health concerns. Recent national health surveys have, however, included good coverage of Indigenous adolescents and provide an opportunity to better understand their health needs. The quality of administrative datasets with respect to Indigenous ascertainment has also improved. To date, the adequacy of these data or their findings with respect to Indigenous adolescent health have not been examined. This study aimed to describe the health of Australian Indigenous adolescents at a national level so as to better inform policy. Three key methods defined the approach used in this study. In the absence of a reporting framework or indicators, relevant domains of Indigenous adolescent health were first defined using modelled data, policy frameworks and consultation with a broad range of stakeholders. The available data for these domains of health were then identified (including national survey data, mortality data, hospital data and notifiable diseases data), and the best of these available data were selected to define indicators. These indicators were then populated to describe a comprehensive health profile for Indigenous adolescents. Where possible, the health profile amongst Indigenous adolescents was compared to that of non-Indigenous Australians to identify inequities in health. The definition of health in this study included physical and mental health (mortality, health outcomes and health risks) within the broader context of sociocultural wellbeing. Four key findings emerged from the analysis of sociocultural wellbeing. Firstly, Indigenous adolescents were found to experience significant disadvantage across the broad sociocultural determinants of health. Many Indigenous young people lived in socioeconomically disadvantaged, overcrowded homes of insecure tenure. Life stressors were common, including experiences of discrimination and contact with the justice system. Secondly, social roles changed rapidly during adolescence. Compared to non-Indigenous adolescents, Indigenous adolescents transitioned out of education early but were no more likely to transition into employment. Childbearing also occurred earlier for Indigenous adolescent females. Thirdly, the structural social determinants were found to be associated with the wellbeing of Indigenous adolescents, but so too were the ways in which adolescents interacted with their environment and these determinants. For example, Indigenous adolescents who had a voice in important issues or participated in culture were more likely to report wellbeing. Fourthly, almost a third of Indigenous adolescents reported a chronic physical health condition, associated with poorer wellbeing. Analysis of mortality data found that the mortality rate of Indigenous adolescents to be twice that of non-Indigenous adolescents, mortality greatest amongst older adolescents and males. Leading causes of mortality included suicide and road traffic injuries. Indigenous adolescents were also at excess risk of mortality resulting from communicable disease and non-communicable disease (including ischaemic heart disease and rheumatic heart disease) compared to non-Indigenous adolescents. Of significance to policy, 80% of mortality amongst Indigenous adolescents was potentially preventable in the current health system. Four key findings emerged from the analysis of health outcomes. Firstly, Indigenous adolescents experienced a complex pattern of disease and injury. Mental disorder, poor sexual and reproductive health and injury were leading health conditions. Indigenous adolescents also experienced a significant burden of communicable and vaccine preventable diseases. They experienced an early onset of ‘adult’ diseases such as type 2 diabetes and ischaemic heart disease. Additionally, Indigenous adolescents were burdened with diseases such as trachoma, rheumatic heart disease and bronchiectasis, diseases that are otherwise rare in Australia. Secondly, many health outcomes were characterised by significant inequity between Indigenous and non-Indigenous Australians. Rheumatic heart disease, pneumococcal disease, gonorrhoea and type 2 diabetes hospitalisation all had incidence rates amongst Indigenous adolescents more than 10 times that of non-Indigenous adolescents. In contrast, eating disorders, melanoma and allergy were all significantly less likely amongst Indigenous adolescents (important health outcomes for non-Indigenous adolescents in Australia). Thirdly, there was significant inequity in health outcomes within the Indigenous adolescent population. Indigenous adolescents living in remote areas were at excess risk of communicable disease, assault, obstetric complications, rheumatic heart disease and emerging non-communicable disease, whereas those in urban areas were more likely to experience asthma, migraine, epilepsy, allergies and eating disorders. Fourthly, young Indigenous adolescents (10 – 14 years) emerged as a population of particularly complex health need. While health outcomes in this population included those typical to Indigenous children, young Indigenous adolescents also experienced a disproportionate burden of poor sexual and reproductive health, mental disorder, substance-related harm and injury compared to young non-Indigenous adolescents. Finally, the analysis of health risks identified opportunities to address the burden of poor health amongst Indigenous adolescents, but also opportunities to address the downstream health of adults and the health of the next generation. Behaviours such as substance use, poor physical activity and poor-quality diets provide opportunities for behaviour modification and harm minimisation to avert morbidity and mortality related to these exposures. Health states such as obesity, hypertension, iron deficiency anaemia and impaired glucose tolerance may provide targets for health screening and early health intervention. In order to describe sociocultural wellbeing, physical and mental health, this study first assessed the quality of national data. Three key data gaps with respect to Indigenous adolescent health emerged. Firstly, data for young adolescents (10 – 14 years) were limited to what was available from administrative datasets or what was reported by parents or guardians on their behalf. Secondly, what emerged as key health outcomes amongst Indigenous adolescents (mental disorder, sexual and reproductive health and injury) were poorly measured in the national surveys. Thirdly, identification of Indigenous status in administrative datasets remains incomplete. The findings of this study provide the basis for two key recommendations. The first relates to addressing the health needs of Indigenous adolescents. The priority health needs identified in this study would be best met through preventive intervention involving many sectors, including the health system. Existing platforms within the health system that have effectively reached young people, like immunisation, may also provide opportunities to deliver other key health interventions (e.g. sexual health education / provision of condoms with HPV vaccination). There is also a need to invest in further addressing the sociocultural determinants of health, particularly education. Ensuring education in the context of socioeconomic disadvantage, mobility due to insecure housing, high rates of pregnancy during adolescence and poor physical and mental health presents a significant challenge for young people, families, communities, the education and health sector. The second recommendation relates to data systems and how these can be strengthened for Indigenous adolescent health. There is a need to better align national survey content with the needs of Indigenous adolescents, and employ methods that better engage young people and respect their autonomy. There is also a need to strengthen the identification of Indigenous adolescents in administrative datasets. For Indigenous Australians, adolescence is likely to provide many opportunities to assure the health of individuals, communities and the next generation. The findings of this study define some priority areas for action in addressing the health inequity experienced by Indigenous Australians. Further, the defined reporting framework provides a mechanism to monitor the progress in the health of young Indigenous Australians, relevant to broader policy frameworks such as Closing the Gap.
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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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ItemThe epidemiology of infantile eczema( 2011)Eczema is a common disease of early childhood which can have major effects on a child's development and quality of life. The prevalence of eczema has been rising over the past few decades and is particularly high in Australia. The rise in eczema prevalence is occurring too rapidly to be explained by genetic factors alone, however environmental factors that can explain the rise in eczema have yet to be fully elucidated. An important aspect of eczema epidemiology is the progression from eczema to other allergic disease. The prevalence of food allergy among infants with eczema from the general community is not known, whilst the idea of a progression from eczema to asthma in an 'atopic march' is controversial. It is unclear whether there is a causative role for eczema or skin barrier dysfunction in the development of sensitisation and IgE-driven disease. In my PhD, I investigated three aspects of eczema epidemiology in infancy: the current prevalence of eczema; potential risk factors for eczema; and the progression from eczema to IgE sensitisation, IgE-mediated food allergy, and atopic asthma. To address my research questions, I drew on data from two large, Australian observational studies. The HealthNuts Study has recruited approximately 5300 twelve-month-old infants (as of mid-2011) from the community in Melbourne, Australia, with the aim of measuring the current prevalence and finding risk factors for allergic disease in infancy. This thesis examines data for the first 3405 participants. All infants were examined for eczema, underwent a skin prick test to common food allergens (cow's milk, hen's egg, peanut, sesame and/or shellfish) to measure sensitisation (2mm wheal or greater). Uniquely, IgE-mediated food allergy was confirmed among sensitised infants using standardised oral food challenge protocols, under medical supervision. Parents of participating infants provided information about their child's history of eczema and potential risk factors for allergic disease. To explore the association between eczema and atopic asthma, I drew on data from the Tasmanian Longitudinal Health Study. This study is one of the longest running asthma studies in the world: over eight thousand Tasmanian children were first sampled at age seven years, in 1968, and over five thousand were followed-up most recently in 2004, at age approximately 44 years. A sub-sample of the 2004 participants underwent sensitisation testing to a panel of common inhalant allergens, which permitted phenotyping of adult asthma into atopic and non-atopic forms. My results show that eczema remains a common childhood disease: approximately one in three infants (38.5%) are affected. Certain aspects of the HealthNuts Study methodology lend support to this being one of the most valid estimates of infantile eczema prevalence for an urban population: a high response rate, broad sampling frame, and information about eczema collected even among families who declined participation in the study. The strongest risk factors for eczema that I could identify related to socio-demographic factors, rather than easily-modifiable factors. Male sex (OR 1.4, 95% CI 1.2, 1.6), maternal eczema (OR 2.1, 95% CI 1.7, 2.7) and paternal eczema (OR 1.8, 95% CI 1.4, 2.5) were strong predictors of infantile eczema risk. Additionally, infants of East Asian ethnicity were found to be at greater risk of eczema than infants whose parents were born in Australia (a largely Caucasian population) (OR 1.6, 95% CI 1.3, 1.9 for each parent born in East Asia). This was in spite of the East Asian parent group having a lower prevalence of allergy compared to Australian-born parents: hence there is evidence for gene-environment interactions which trigger an eczema susceptibility among East Asian migrants to Melbourne. I found no evidence for a role in the causation of eczema for several factors associated with microbial exposure or the maternal or infant diet. One exception was maternal consumption of peanut during breastfeeding, which was associated with a decreased risk of infantile eczema (OR 0.8, 95% CI 0.6, 1.0). Maternal consumption of probiotics was associated with an increased risk of infantile eczema, however this was explained by a trend towards probiotics consumption among mothers who have eczema, asthma and/or allergic rhinitis. Infant consumption of antibiotics- a factor that has been associated with an increased risk of eczema in multiple studies- was not plausibly a causative factor for most cases of eczema, as eczema onset usually preceded antibiotic use. Furthermore, the crude association between infant antibiotic use and eczema was largely explained by the increased need for treatment of skin infections among patients with eczema. There has been intense interest in the potential role of vitamin D deficiency as a risk factor for food allergy and asthma. My PhD research does not, however, support a role for vitamin D in causing a child's eczema to occur: the prevalence of eczema did not vary by season of birth; serum vitamin D levels were comparable at age 14 months between infants with and without eczema; mother's with a history of vitamin D deficiency were no more or less likely to have a child with eczema; and there was no association found between maternal sun exposure and eczema incidence. My results suggest that sun exposure and vitamin D may have a role in modifying eczema severity, with increased maternal sun protection in pregnancy associated with a reduced eczema severity score at age 14 months. I found that infants with eczema were at greatly increased risk of an IgE-mediated food allergy to peanut, egg white or sesame. One in five infants with eczema were allergic to one or more of these foods at age 14 months, compared to one in twenty-five infants without eczema. Increasing eczema severity and a younger age at eczema onset were risk factors for food allergy among infants with eczema, as were increasing socio-economic status and East Asian ethnicity. Pet ownership, on the other hand, decreased the odds of food allergy among infants with eczema by 40-50%. I found no evidence for a role of skin barrier function at non-lesional skin at age 14 months as a mechanism by which sensitisation to food allergens may occur, however I found some evidence of skin barrier dysfunction at eczema lesion sites. As well as being a highly prevalent condition of early childhood, I found that eczema was associated with long-lasting sequelae. Infants and young children with eczema were highly likely to have atopic asthma that was current in middle age, particularly when allergic rhinitis was also experienced. There was no association between eczema and non-atopic asthma. Whether or not there is a causal link between eczema and other atopic disease, there is great need to understand the natural history of eczema in the atopic march and to counsel patients accordingly.
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ItemThe epidemiology of egg allergy and other IgE-mediated food allergies in infants( 2010)IgE-mediated food allergy often develops early in life and has a major impact on the quality of life of the child and its family. Recent increases in the prevalence of food allergy, which have occurred too rapidly to be explained by genetic factors alone, suggest that environmental factors may play an important role. Potential candidates include maternal and infant diet and infant microbial exposures. However, few studies to date have examined risk factors for food allergies. I investigated the prevalence and risk factors for egg allergy, the most common IgE-mediated food allergy in infants, within the HealthNuts study. HealthNuts is an ongoing population-based cross-sectional study of 12-month-old infants in Melbourne, Australia. As part of the study, parents reported on infant feeding and other environmental exposures. All infants subsequently received a skin prick test for four foods including egg white and those with a wheal size ≥ 1mm underwent an oral food challenge with raw egg white. This thesis includes data from the first 2,600 infants included in the study, which is due to complete recruitment in April 2011. Among infants participating in the HealthNuts study, there was a high prevalence of egg allergy (9.3%, 95% CI 8.2-10.5). There was no evidence that maternal dietary factors were associated with infant egg allergy. Of the infant dietary factors examined, only timing of egg introduction was associated with egg allergy risk. Introduction of cooked egg into the infant diet at 4-6 months of age was associated with a 3-fold decreased risk of egg allergy compared with introduction after 12 months of age. Other infant dietary factors previously suggested to be associated with general allergy risk, namely duration of breastfeeding and age at introduction of first solid foods, were not associated with egg allergy. Factors previously associated with increased microbial exposure, including siblings, childcare and pet ownership, were associated with a reduced risk of egg allergy. There was evidence of a dose-response effect for siblings and egg allergy, with an increasing number of siblings associated with a further reduction in egg allergy: one sibling, OR0.72 (95% CI 0.53-0.97), two siblings OR 0.57 (95% CI 0.35-0.92) and three or more siblings OR 0.47 (95% CI 0.20-1.09). Attending childcare before 7 months of age was associated with a reduced risk of egg allergy compared with never having attended childcare (OR 2.05, 95% CI 0.97-4.35), while there was no evidence of a protective effect of childcare attendance between 7-12 months of age. Having either a cat or dog at home at one year of age was associated with a reduced risk of egg allergy among infants with a history of eczema (OR 0.49, 95% CI 0.31-0.78) but not among those without a history of eczema (OR 1.01, 95% CI 0.62-1.62). My results show that egg allergy is common in infants and suggest several possible risk factors related to infant diet and potentially microbial exposures which may help to explain recent rise in food allergy prevalence. The protective effect of introduction of egg at 4-6 months of age has implications for infant feeding guidelines internationally and, if confirmed, suggests that changes in infant feeding practices could have the potential to reduce the prevalence of egg allergy.
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ItemAlternative pneumococcal vaccination schedules for infants in Fiji and pneumococcal epidemiology( 2010)This thesis documents the pneumococcal disease burden and the results of a Phase II pneumococcal vaccine trial in the low middle income country, Fiji. The overall objective was to gather sufficient evidence for the Fiji Ministry of Health to decide whether to introduce the pneumococcal vaccination into its national schedule and define an appropriate and affordable vaccination strategy. The nasopharynx is the main reservoir for pneumococci and plays an important role in the spread of the organism. Studies of nasopharyngeal carriage offer insights into the pneumococcal disease burden in a community, particularly for potential serotypes which may cause pneumonia, and are a convenient way of determining the level of antibiotic resistance among pneumococcal isolates circulating in a population. The first study, a cross-sectional pneumococcal nasopharyngeal carriage survey of healthy children aged 3-13 months, was undertaken to document the prevalence of pneumococcal nasopharyngeal carriage, risk factors for carriage, serotypes and antimicrobial susceptibility patterns of carried pneumococci in healthy young children in Fiji (Chapter 3). Pneumococcal nasopharyngeal carriage was common in Fijian children. Penicillin resistance was documented for the first time, and, as a result, first-line treatment for meningitis was altered. A low proportion of carriage serotypes were included in the 7-valent pneumococcal conjugate vaccine. Invasive pneumococcal disease is an important cause of morbidity and mortality, particularly in the very young and the elderly. The introduction of the 7-valent pneumococcal conjugate vaccine in the national immunisation schedule in the USA has resulted in an impressive reduction in infant invasive pneumococcal disease. In addition, the vaccine has had a more than expected herd immunity effect on invasive pneumococcal disease in the elderly and other age groups. Chapter 4 reports on a study that aimed to document age-specific burden of invasive pneumococcal disease including clinical syndromes, underlying conditions, serotype distribution, and the potential protection against invasive pneumococcal disease and chest X-ray confirmed pneumonia by 7-valent pneumococcal conjugate vaccine in Fiji. The annual invasive pneumococcal disease incidence was comparable to countries of similar socioeconomic status. Being indigenous Fijian was an independent risk factor for disease. Underlying conditions were common and the case fatality rate was high particularly in the elderly population. For every, 1.930 and 128 infants vaccinated, one death and one case respectively, would be prevented in those <5 years, by introduction of universal immunisation with the 7-valent conjugate vaccine. A Phase II vaccine trial was undertaken to document the safety, immunogenicity and impact on pneumococcal carriage of various pneumococcal vaccination regimens combining one, 2, or 3 doses of 7-valent pneumococcal conjugate vaccine in infancy (Chapters 5 to 10). In order to broaden the serotype coverage, the additional benefit of a booster of 23-valent pneumococcal polysaccharide vaccine at 12 months of age was also assessed. To address the theoretical concerns of hyporesponsiveness to 23-valent pneumococcal polysaccharide vaccine following re-challenge, the immunological responses at 17 months of age to a small challenge dose of 20% of 23-valent pneumococcal polysaccharide vaccine (mPPS) in children who had or had not received the 23-valent pneumococcal polysaccharide vaccine at 12 months of age was undertaken. The immunogenicity following a 2 or 3 dose 7-valent pneumococcal conjugate vaccine primary series was similar for many serotypes. A single 7-valent pneumococcal conjugate vaccine dose would offer protection in the first 12 months of life for many serotypes. The one or 2 dose 7-valent pneumococcal conjugate vaccine schedules induced immunologic memory, with memory responses following 23-valent pneumococcal polysaccharide vaccine being most profound for children who had received only a single dose of 7-valent pneumococcal conjugate vaccine previously, compared with the 2 or 3 dose groups. Following the 23-valent pneumococcal polysaccharide vaccine booster, there were significant responses for all 23 serotypes which persisted for at least 5 months following vaccination. However despite higher antibody concentration at 17 months in children who had received 23-valent pneumococcal polysaccharide vaccine at 12 months, the response to a re-challenge was poor to all 23 serotypes compared to children who did not receive the 12 month 23-valent pneumococcal polysaccharide vaccine. This indicates immunological hyporesponsiveness or non-responsiveness. This effect occurred regardless of pre-mPPS antibody levels and prior 7-valent pneumococcal conjugate vaccine exposure. The addition of 23-valent pneumococcal polysaccharide vaccine at 12 months had no impact on carriage, despite the substantial boosts in antibody levels observed and despite significantly higher opsonophagocytic activity and antibody avidity comparing pre- and post-levels. In summary, a substantial burden of pneumococcal disease in Fiji was found. The 7-valent pneumococcal conjugate vaccine would provide limited coverage of invasive disease compared to its use in affluent countries. Two doses of 7-valent pneumococcal conjugate vaccine have similar immunogenicity as 3 doses although a single dose still provides some protection. The 23-valent polysaccharide vaccine booster was found to be immunogenic but re-challenge resulted in hyporesponsiveness. Further research evaluating the potential of reduced dose schedules using the newer conjugate vaccines with an early conjugate booster would be recommended.