Paediatrics (RCH) - Theses

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    The epidemiology and risk factors of anaphylaxis and food-induced anaphylaxis worldwide
    Wang, Yichao ( 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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    Environmental and genetic risk factors for food allergy in children with Asian ancestry
    Suaini, Noor Hidayatul Aini Bte ( 2019)
    Epidemiological and genetic studies on food allergy to date have focused primarily on the Caucasian population. This is despite emerging evidence that food allergy appears to be rising in Asian countries, alongside the increasing Westernisation and urbanisation in these countries. Even less is known about Asian migrants living in Western countries. A population-based study on food allergy found the risk of food allergy to be three times higher in infants of East Asian ancestry than infants of Caucasian ancestry. It is thought that infants growing up in Australia are exposed to environmental agents that have a differential effect on the immune system depending on their genetic background. However, the influence of specific genetic and environmental risk factors is currently unknown. It is also unclear if the increased risk of food allergy translates to higher risk of other allergic diseases later in childhood. The main objective of this thesis is to identify specific environmental and genetic factors on the risk of food allergy in the Asian population living in Australia. This thesis aims to quantify the prevalence of, and identify risk factors for food allergy and allergic comorbidities in the Asian population. An additional aim is to identify genetic variants that increase the risk of food allergy in the East Asian population and compare this to the Caucasian population living in Australia. This thesis primarily used data and samples from the longitudinal HealthNuts study where 5,276 1-year-old infants attending council run vaccination sessions across Melbourne were recruited. Skin prick tests to a range of food were carried out on infants and those with a wheal size less than 1 mm underwent an oral food challenge. The 1-year-old infants were followed up again at age 6 years and data collected at this follow-up visit were also used for analyses in this thesis. Additionally, data collected from a Growing Up in Singapore Towards Healthy Outcomes (GUSTO) birth cohort was also used to compare the risk factors and prevalence of allergic diseases between East Asians living in Melbourne and East Asians living in Singapore. This thesis reports that Australian-born children with East Asian parents have a higher burden of allergic rhinitis, eczema and aeroallergen sensitisation but not asthma, in the first six years of life compared to children of Caucasian ancestry. Moreover, children with IgE-mediated food allergy and eczema in infancy were 3 times more likely to have asthma and 2 times more likely to have allergic rhinitis at age 6 years, irrespective of ancestry. Additionally, East Asian children living in Melbourne have a higher risk of food allergy compared to East Asian children living in Singapore. Despite delayed introduction of allergens into the diet compared to the Asian population in Melbourne, Asian children in Singapore had less food allergy. While eczema rates were lower in Singapore than in Melbourne, early onset eczema was associated with an increased risk of food allergy in both Singapore and Melbourne. In terms of genetic risk factors, a systematic review conducted as part of this thesis identified several genes of interest known to be involved in immune regulation, cell function and epidermal barrier function. However, studies were of varied quality and the reproducibility of findings for the same SNPs were minimal. Some of the highly re-producible genes identified from the literature include HLA, FLG and IL13. Additionally, there was also a paucity of studies carried out in the Asian population that were able to elucidate underlying mechanisms for the differential food allergy risks observed in the population. This highlighted the need for genetic studies focused in this population. This thesis found that HLA rs7192 minor allele was associated with increased risk of peanut allergy in the Caucasian population but not East Asian population. Among sensitised children with two East Asian born parents, those with the minor allele for rs231735, rs231804 or rs11571291 (all CTLA4) have a reduced risk of egg allergy. The findings of this thesis identify Asian children living in Australia as a high risk allergic group not just in infancy but throughout early childhood. As a multifactorial disease, both environmental and genetic factors are known to contribute to the pathogenesis of food allergy. Therefore, it may be that the increased risk of food allergy observed in genetically predisposed East Asian children living in Melbourne unmasked upon exposure to environmental risk factors.
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    Impact of pneumococcal vaccination on carriage in a Fijian population
    Boelsen, Laura Kate ( 2018)
    Streptococcus pneumoniae (the pneumococcus) causes a range of diseases including otitis media, pneumonia and meningitis, and is a major cause of morbidity and mortality in children under five years of age worldwide. Colonisation of the nasopharynx by S. pneumoniae (carriage) is generally asymptomatic and is considered a precursor for pneumococcal disease. S. pneumoniae has several important virulence factors which contribute to colonisation and disease. The most significant of these is the polysaccharide capsule which forms the outer protective layer of the bacterium, with over 90 known capsule types or serotypes. Current pneumococcal conjugate vaccine formulations target 10-13 of the most common serotypes. Pneumococcal vaccines have been effective at reducing pneumococcal disease both directly, by protecting vaccinated individuals, and indirectly through reducing carriage, which lowers transmission of S. pneumoniae to unvaccinated individuals. However, pneumococcal vaccine introduction has also led to serotype replacement whereby serotypes not included in pneumococcal vaccines have become more prominent in carriage and disease. There is some evidence to suggest that species replacement (whereby vaccine introduction leads to increases in other bacterial species sharing the same ecological niche) can also occur. In Fiji, pneumonia and meningitis are a significant burden and S. pneumoniae is a major cause of both diseases. There are two main ethnic groups in Fiji, indigenous Fijians (iTaukei) and Fijians of Indian descent (Indo-Fijian). Significant differences in the burden of disease between ethnic groups have been observed for a number of diseases including invasive pneumococcal disease, which is higher in iTaukei compared with Indo-Fijians. An earlier vaccine trial in Fiji (FiPP) examined reduced-dose schedules and the use of the polysaccharide vaccine (23vPPV) to reduce cost and provide greater serotype coverage. However, the use of 23vPPV in children at 12 months of age was associated with poorer immune responses when challenged at 17 months of age. In this thesis we examined whether 23vPPV use had any long-term effects on nasopharyngeal carriage in the same children now aged 5-7 years. We found no overall effect of 23vPPV on pneumococcal carriage or on carriage of respiratory pathogens (H. influenzae, S. aureus and M. catarrhalis). We found that the carriage rates of all four bacterial species were significantly different between the two ethnic groups. When data were stratified by ethnicity, we found that 23vPPV use in iTaukei children was associated with higher carriage of S. aureus but had no effect on S. pneumoniae carriage. In contrast, 23vPPV use in Indo-Fijian children was associated with lower carriage of S. pneumoniae and had no effect on S. aureus carriage. Given the previous immune hyporesponsiveness observed with the use of 23vPPV and these findings, we conclude that the current WHO recommendations against the use of 23vPPV in children less than 2 years of age are appropriate. Next, we examined whether the 7-valent pneumococcal vaccine (PCV7) had an effect on the microbiome of children of iTaukei and Indo-Fijian descent. No overall effect of PCV7 on the microbiome at 12 months of age was observed, however there were significant differences between iTaukei and Indo-Fijian children in the composition of bacteria within the nasopharynx. After stratifying by ethnicity, PCV7 was associated with lower relative abundance of Streptococcus in iTaukei children and higher relative abundance of Dolosigranulum in Indo-Fijian children. Given Dolosigranulum has been associated with a healthy microbiome, pneumococcal vaccination elicited generally positive effects in both ethnic groups. With the introduction of PCV10 into the infant immunisation program in Fiji, we next examined whether PCV10 had an indirect effect on carriage in adult caregivers. Firstly, we examined whether there was added benefit to sampling the oropharynx in addition to the nasopharynx when using molecular methods for identification and serotyping. Oropharyngeal (OP) samples were more complex than nasopharyngeal (NP) samples, and contained commensal streptococci which caused spurious identification and serotyping results. We found that the inclusion of OP samples did not significantly improve detection of pneumococci compared with NP sampling alone. We next examined the indirect effect of PCV10 introduction in adults using NP samples, finding evidence to suggest that PCV10 reduced vaccine-type carriage three years post-vaccine introduction, particularly in iTaukei adults. Fewer adults had low-density carriage of pneumococci following vaccine introduction, which underpinned an observed increase in pneumococcal density in adults over this time. We found that Indo-Fijian adults had lower carriage of pneumococci than iTaukei adults and carried very little vaccine-type pneumococci. Indirect effects of PCV10 introduction may not have been apparent 3 year after PCV10 introduction and an additional year or years of data would strengthen the evidence for an indirect effect of PCV10 in adults. Taken together, the studies included in this thesis examine direct and indirect effects of several pneumococcal vaccines on carriage in a middle-income setting.