Paediatrics (RCH) - Theses
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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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ItemPlatelet physiology and function in neonates and children on extracorporeal membrane oxygenation (ECMO)( 2019)Extracorporeal membrane oxygenation (ECMO) is a modified form of heart-lung machine that aims to provide short- to-medium length of support to patients with cardiac and/or respiratory dysfunction. Children represent the majority of the ECMO population. While increasing experience and technical improvements for ECMO over the years have seen some improvement in outcomes, the rates of morbidity and mortality remain high in this population and many complications are related to bleeding and thrombosis. Platelets are a key element of the coagulation system. Platelet dysfunction can cause coagulopathy in adults on ECMO, however, the association between modification of platelet function and coagulopathy remains unknown for children. This study hypothesised that there are platelet-specific differences: I.) for paediatric patients on ECMO according to their age, pathway onto ECMO and duration of ECMO that could be associated with the development of bleeding or thrombosis during ECMO and II.) at different sites in a paediatric ECMO system. This study aimed to characterize the molecular indices of circulating platelets in the paediatric ECMO population using whole blood flow cytometry approach: 1) To examine and compare the effect of a patient’s pathway onto ECMO on platelet phenotype and function and their associations with the development of bleeding or thrombosis during ECMO. 2) To examine and compare the effect of a patient’s age on platelet phenotype and function and their associations with the development of bleeding or thrombosis during ECMO. 3) To examine and compare the effect of a patient’s duration of ECMO on platelet phenotype and function and their associations with the development of bleeding or thrombosis during ECMO. 4) To examine and compare the site-specific differences for platelet phenotype and function in the paediatric ECMO system. A total of 22 paediatric patients [median (interquartile range): 0.34 (0.01 – 3.38) years] were included in this study. Citrated whole blood samples were collected and a whole blood flow cytometry method was developed for the evaluation of platelet phenotype and function in the setting of ECMO. The platelet assays were standardized to ensure minimal pre-analytical activation. By using multiple thrombin receptor activator peptide 6 (a thrombin mimic) concentrations, the platelet panels also showed sensitivity to detect subtle changes in platelet response. The multifaceted flow cytometry panels allowed simultaneous evaluation of platelets for their phenotype, function and interactions with monocytes and neutrophils. Such approach to investigate platelet-specific changes from different aspects suits well for the ECMO population, representing a complex group of patients. These results showed that the whole blood flow cytometry assay is a reliable and useful platelet function test for paediatric ECMO patients. Results from the analysis for platelet-specific markers within the first 24 hours showed no difference in platelet phenotype and function between patients from different pathways onto ECMO and different ages. However, the association of platelet-specific changes and the development of clinical events during ECMO were different according to a patient’s age and pathway onto ECMO. Patients who had cardiopulmonary bypass before coming onto ECMO and had bleeding had increased platelet integrin GPIIb/IIIa receptor expression and reduced circulating neutrophil-platelet aggregates level compared to patients who had no bleeding during ECMO. In contrast, patients who had no cardiopulmonary bypass before coming onto ECMO and developed bleeding had reduced platelet response compared to those who had no bleeding during ECMO. Conversely, increased lysosome release was observed for children with thrombosis and may indicate the presence of a protective mechanism against increased thrombus formation. Duration of ECMO had been recognized as an important factor affecting the outcome of paediatric ECMO patients. The results showed an increased level of von Willebrand factor (VWF) receptor and reduced platelet response for granule exocytosis with increasing number of days on ECMO (Day 2 vs. Day 5). Most importantly, such platelet-specific changes that involved GPIb/IX/V receptor and granule release with increasing duration of ECMO were only observed in patients who had bleeding but not in patients without bleeding after five days on ECMO. In addition, elevated circulating monocyte-platelet aggregates level was only observed in patients who had thrombosis but not for those without thrombosis. Together, these results suggested a link between pathway onto ECMO/age/duration of ECMO, bleeding/thrombosis and platelet dysfunction. Hence, markers relevant to the platelet-specific changes could be used as the indicators for increased bleeding or thrombosis risk for paediatric patients during ECMO. Platelet phenotype and function were also compared at different sites in the ECMO system to identify the site-specific differences of platelet-specific changes that have not previously been investigated in a paediatric ECMO system. In the setting of mechanical circulatory support, shear and oxidative stress are known to modify platelet phenotype via integrin GPIIb/IIIa and GPIb/IX/V receptors and increase platelet response via multiple platelet activation pathways. The results demonstrated that platelet phenotype and function were different at different sites in a paediatric ECMO system. The platelet-specific changes observed included the modification of platelet phenotype via increased VWF and integrin GPIIb/IIIa receptor expression, increased platelet activation through the activation of the integrin GPIIb/IIIa receptor and higher platelet responsiveness at the post-oxygenator site compared to the pre-oxygenator site. However, the exact cause of the site-specific differences of platelet phenotype and function remained to be identified. In summary, this study demonstrated the feasibility of using whole blood flow cytometry method with multifaceted platelet-specific panels as a reliable platelet function test in paediatric patients on ECMO. Platelet-specific changes could be associated with the development of bleeding or thrombosis during ECMO. In addition, platelet phenotype and function were different at different sites in a paediatric ECMO system. Together, this study provides new insights for the circuit-related platelet-specific changes and the understanding of how modifications of platelet phenotype and function that are dependent on patient’s factors may be associated with coagulopathy in children on ECMO.
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ItemEstablishing predictive indicators, or biomarkers, of aminoglycoside nephrotoxicity and the Incidence of ototoxicity in children up to six years with cystic fibrosis (PIANO-CF extension)( 2019)Cystic Fibrosis (CF) is an autosomal recessive condition caused by a mutation in the cystic fibrosis transmembrane regulator (CFTR) gene. It is commonly known as a disease affecting the lungs. Advances in screening, diagnosis and treatment of CF have led to enormous improvements in outcomes and life expectancy. Since pulmonary outcomes are better for patients from centres with aggressive and early use of antibiotic therapies, patients now have an earlier and longer lifetime exposure to antibiotics. People with CF are often treated with prolonged courses of aminoglycosides (AGs), for which known adverse effects include nephro- and ototoxicity. The resulting increase in longevity and ageing of the CF population has led to a paradigm shift from a focus on the lungs to management of a complex multi-system disease. The CFTR gene is abundantly expressed in the kidney, which has been considered ‘spared in CF’. However, renal complications are emerging in childhood with adolescents developing renal impairment and presenting with kidney failure. Correspondingly, renal impairment in CF has been largely attributed to nephrotoxic antibiotic exposure and, in particular, to AGs. Most importantly, it is necessary to recall the time before these complications were observed to understand the risk factors and how the development of renal impairment and kidney failure can be arrested. Acute kidney injury (AKI) is common in people treated with an intravenous AGs yet assessing the prevalence of AKI is difficult and complicated by a multitude of definitions. Serum creatinine is considered the ‘gold standard’ for the detection of AG-induced nephrotoxicity in AKI classification systems, yet it is neither specific nor sensitive and has many limitations, particularly in CF. Predictive indicators and novel renal biomarkers may allow earlier detection of AG-induced nephrotoxicity and provide an opportunity to mitigate risk, the progression AKI and subsequent renal impairment and chronic kidney disease. The primary aim of this study was to investigate predictive indicators and novel renal biomarkers of AG-induced nephrotoxicity in young children with CF in the setting of acute AG exposure. We also sought to uncover whether expression of novel renal biomarkers differed between children with CF and healthy controls—and whether previous AG exposure played a role in this. The secondary aim of this study was to investigate hearing impairment and whether there was a correlation between hearing impairment and cumulative intravenous AG exposure. The predictive indicators that were studied include serum cystatin C, serum magnesium, fractional excretion of magnesium and urinary beta-2-microglobulin. The novel renal biomarkers that were studied include kidney injury molecule-1, neutrophil gelatinase-associated lipocalin, interleukin-18, liver-type fatty acid binding protein and fibroblast growth factor-23. All novel renal biomarkers were measured in urine and for a small cohort, we additionally measured kidney injury molecule-1 and neutrophil gelatinase-associated lipocalin in serum. We also studied hearing at three time points, investigating hearing impairment and ototoxicity in young children with CF in the setting of acute intravenous AG exposure, with longitudinal follow-up up to approximately one year. In children with CF and acute intravenous AG exposure, we observed AKI, no significant change in estimated glomerular filtration rate, hypomagnesaemia with increased fractional excretion of magnesium that resolved, no correlation between serum creatinine and serum cystatin C and significant changes in urinary kidney injury molecule-1 and urinary neutrophil gelatinase-associated lipocalin. A comparison of gentamicin and tobramycin showed significant differences with higher fractional excretion of magnesium, when corrected for difference in dose, and higher levels of kidney injury molecule-1 in children who received gentamicin. Children with CF showed hyperfiltration and increased fractional excretion of magnesium at baseline. There was a large difference in the novel renal biomarkers (urinary kidney injury molecule-1, urinary neutrophil gelatinase-associated lipocalin and urinary fibroblast growth factor-23) between children with CF and healthy controls, irrespective of previous intravenous AG exposure. Hearing impairment was observed on 12% of tests; 7% of which was considered ototoxicity. We did not observe a correlation between hearing impairment and cumulative intravenous AG exposure. This is the first study of predictive indicators, novel renal biomarkers and long-term hearing follow-up in young children with CF. Our findings challenge the traditional view that the kidney is ‘spared’ in CF and suggest that the kidney in CF is different from the normal kidney, which may represent CF-related kidney disease. The results of this study suggest that novel renal biomarkers may be useful for detection of AG-induced nephrotoxicity in CF; however, they must first be understood in this population, as they differ significantly from healthy controls. Additionally, these findings provide insight into the rate of hearing impairment in young children with CF and challenge the traditional view that cumulative intravenous AG exposure increases the rate of hearing impairment. Further considerable work is required to better elucidate the comorbidities of kidney disease and hearing impairment faced by patients with CF. This study has informed on previously under-recognised phenomena and shown that the kidney is involved in CF. Further research in this field should better explicate the role of CFTR in the kidney, the extent of hyperfiltration and the expression of novel renal biomarkers in older children and adults with CF. With regard to hearing outcomes, future studies should consider how to screen for hearing impairment and how to ameliorate auditory ototoxicity using otoprotective agents.
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ItemIntragenic DNA methylation and neurodevelopmental outcomes in children with fragile X-related disorders( 2019)The type and severity of clinical involvement in children with fragile X syndrome (FXS) and disorders related to premutations (PM) of the fragile X mental retardation 1 gene (FMR1), herein collectively denoted as fragile X-related disorders (FXDs), is highly variable. Multiple molecular factors contribute to the heterogeneity of neurodevelopmental outcomes. Increased intragenic DNA methylation (DNAm) in blood of the fragile X-related epigenetic element 2 (FREE2) region, located at the FMR1 exon 1/intron 1 boundary, was associated with lower intellectual functioning in a cohort of female children and adults with FXS and with neuro-cognitive and psychiatric phenotypes in women with PM. Nevertheless, FREE2 DNAm has not yet been investigated in exclusively paediatric male and female FXDs cohorts. The overarching aim of this thesis was to explore FREE2 DNAm and neurodevelopmental outcomes of Australian male and female children with FXDs. Matrix assisted laser desorption/ionization time-of-flight mass spectrometry and methylation specific-quantitative melt analysis were used to analyse FREE2 DNAm in venous blood, buccal epithelial cells (BEC) and retrieved newborn blood spots (NBS). In addition, FMR1 mRNA levels in blood were assessed using real-time polymerase chain reaction (PCR) relative standard curve method. The evaluation of the neurodevelopmental outcomes concentrated on direct clinical assessment of intellectual functioning and autism spectrum disorder (ASD) symptom severity. Intelligence Quotient (IQ) scores were corrected for floor effect using the Whitaker and Gordon (WG) extrapolation method. The findings highlighted the variability of the clinical presentation of children with PM. Results also showed that compared to sex-matched paediatric controls, children with FXS had significantly higher levels of FREE2 DNAm levels in blood and BEC and, within the FXS group, higher FREE2 DNAm levels in blood correlated with lower FMR1 mRNA levels. In children with FXS, the application of the WG method effectively addressed the floor effect inherent in standardised intelligence scales, unmasked inter-individual variability in IQ scores and uncovered significant associations between intragenic DNAm and neurodevelopmental outcomes. Strength and statistical significance of these epigenotype-phenotype relationships varied based on sex, position of the differentially methylated sites, tissue analysed, assay used and neurodevelopmental domain investigated. The most significant finding was in males with FXS, for whom higher levels of BEC FREE2 DNAm were associated with lower WG-corrected Full Scale IQ (cFSIQ) and Performance IQ (cPIQ) scores. Finally, findings showed that the best-performing FREE2 biomarker had sensitivity, specificity, negative and positive predictive values of 100% for detection of full mutation alleles in NBS of males and females with FXS. Additionally, this study revealed that for males with FXS, FREE2 DNAm in NBS was significantly associated with lower cFSIQ and cPIQ scores obtained in childhood and adolescence. This is the first study in any monogenic neurodevelopmental disorder associated with intellectual disability, showing that a perinatal epigenetic biomarker is significantly associated with paediatric neuropsychological outcomes. In conclusion, the results of this thesis contribute to the characterisation of the neurodevelopmental outcomes in children with FXDs, provide evidence that FREE2 DNAm is a sensitive epigenetic biomarker significantly associated with the variability of intellectual functioning in male children with FXS, and may have implications for the development of new methylation specific tests for earlier diagnosis with potential prognostic applications.