Melbourne School of Population and Global Health - Theses
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ItemLifetime asthma and the development of fixed airflow obstruction( 2023-05)Asthma is a major public health problem worldwide and its prevalence has risen considerably over recent decades. Asthma prevalence in Australia is among the highest in the world and thus has been recognised as an Australian National Health Priority Area since 1999. There is now established evidence that asthma has adverse effects on lung health over the life course and strategies aimed at improving long-term outcomes are urgently needed. The natural history of asthma is influenced by complex interactions between genetic and environmental factors. Despite extensive research in this area over recent decades, many uncertainties remain. An important limiting factor has been the lack of suitable prospective studies with follow-up from childhood (when asthma is most prevalent) into middle-age (when respiratory complications manifest clinically). To address these knowledge gaps, my doctoral work utilises data from the Tasmanian Longitudinal Health Study (TAHS), the world’s largest and longest-running population-based study of respiratory disease. The primary aim within my thesis is to characterise the natural history of asthma and its cumulative effects on lung health over the life course, focusing on a complication known as fixed airflow obstruction. I also aim to evaluate strategies which might improve these outcomes in asthma, and to validate novel methods of detecting these complications earlier in the disease process. The findings of this work will have important clinical and public health implications, with the overall objective of improving asthma outcomes in Australia and worldwide. In chapter 4, I present a study on the diagnostic utility of bronchodilator responsiveness (BDR) as a test for adult asthma, both with and without fixed airflow obstruction (FAO). I provide specific data on the sensitivity and specificity of commonly-used BDR cut-offs, and additional normative data on BDR ranges in a general population cohort. In chapter 5, I present my findings that asthma follows five longitudinal pathways (phenotypes) from childhood to middle-age, each associated with different risks of developing FAO. Importantly, I found that even apparently remitted asthma was associated with FAO in middle-age, despite an absence of symptoms. In chapter 6, I present my findings of several biomarkers which hold prognostic value in adults in spontaneous asthma remission. I showed that abnormal serum cytokine profiles (Th2-high and Th2-low) were associated with accelerated lung function decline in these individuals. In chapter 7, I present the findings of a systematic review and meta-analysis showing that long-term use of inhaled corticosteroids (ICS) are associated with modest, age-dependent improvements in lung function children and adults with asthma. In chapter 8, I present my findings that lung function thresholds can accurately identify individuals at high-risk of developing FAO in the future. I describe a particular threshold of pre-BD FEV1/FVC < 10th percentile as accurately identifying 88% of individuals who developed COPD over an 8-year follow-up period, while excluding 87% of individuals who did not. Collectively these findings provide new insight into the complex relationship between asthma and lung function over the life-course, with a particular focus on the development of FAO. My work highlights lifetime asthma as a potentially-modifiable risk factor for FAO, and describes the high-risk subgroups in whom early detection and prevention strategies might be beneficial.
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ItemThe impact of household risk factors and their interactions with antioxidative stress genes on respiratory health( 2019)Background: Asthma affects people of all ages and is associated with a substantial impact on both the individual and the community, yet there are few effective strategies to prevent its development or persistence. This is because the aetiology of asthma and factors influencing its progression or remission are currently poorly understood. Asthma primarily affects lung function. Progressive lung function decline associated with asthma is well-recognised but has not been commonly investigated as an outcome in asthma studies. Knowledge on the critical factors influencing maximal development of lung function in childhood is scarce. The development of asthma and allergic diseases is very complex and believed to be influenced by multiple genetic and environmental factors that may influence asthma risk from pre-conception through to adult life. A range of strategies modifying environmental exposures have been trialled to potentially reduce the risk of asthma, with many studies finding no evidence of substantial benefit, or only limited benefit, from the interventions. Additionally, although some genes are associated with increased asthma risk, the associations are small and only explain a small percentage of the large asthma burden. There is evidence of some gene-environmental interactions, but these relationships are varied and complex and have not yet been fully investigated or understood. Elucidating the interactions between environmental risk factors and genetic factors and their associations with respiratory outcomes in both childhood and adulthood may help identify asthma prevention strategies. The main aim of my PhD work was to investigate one group of gene-environment interactions; the relationship between oxidative exposures and antioxidant genes on asthma and lung function. Specifically, I investigated the associations between various household environmental oxidant exposures and respiratory outcomes from childhood to middle age and examined whether those associations were modified by Glutathione s-Transferase (GST) genes, which are known buffers of oxidative stress. Methods: I used a range of methods to address my research aims, including a systematic literature review and data analyses of two longitudinal cohort studies: the Melbourne Atopy Cohort study (MACS), and the Tasmanian Longitudinal Health Study (TAHS). MACS began as a randomised controlled trial investigating the effects of infant formulas at weaning and, has subsequently become a prospective birth cohort. Initially, 620 pregnant women were recruited between 1990 and 1994. The MACS children have now been followed up to 18 years of age. The TAHS is a population-based study of respiratory disease spanning from childhood to adulthood. The study began in 1968, recruiting 8,583 Tasmanian school children born in 1961 (approx. 98.8% of the Tasmanian population for 1961 births). Extensive follow-ups of initial participants were conducted in 2002 and 2012, respectively, when participants were in their 40s and 50s. Both the MACS and the TAHS collected a substantial amount of exposure and outcome data at multiple ages over the lifespan through questionnaires and clinical testing, providing a great opportunity to address questions concerning gene-environment interactions and respiratory health outcomes. I investigated the following oxidative exposures: early life tobacco smoke, early life paracetamol, heating and cooking facilities, mould, long term and current active and passive tobacco smoke. Previous evidence suggests that these common home environmental exposures are associated with increased oxidative stress, and therefore, their impacts are likely to be modified by GST genes. So, in conjunction with these exposures, I investigated potential interactions with GST gene polymorphisms at two significant developmental stages: during lung function growth in childhood and adolescence, and during lung function decline in middle age. Research Gaps: Firstly, I systematically reviewed the current evidence on interactions between indoor air pollution and GST genes in association with allergies, asthma and lung function (Aim 1: Chapter 3). I then conducted a study to examine the interactions between early life tobacco smoke exposure and GST genes on asthma and lung function in childhood and adolescence using Melbourne Atopy Cohort Study (MACS) data (Aim 2: Chapter 5). Another study on the potential interactions between paracetamol use before 2 years of age and GST genes in association with asthma and lung function in later life was performed using MACS data (Aim 3: Chapter 6). In this study, I adjusted for early life exposure to respiratory infections, an important confounding factor which has not been adjusted for by many previous studies. Finally, I conducted a study using data from the TAHS to investigate similar associations in middle-age (Aim 4: Chapter 7). In this analysis, I identified seven longitudinal exposure profiles using Latent Class Analysis (LCA) methods with common household air exposures including heating and cooking types, mould exposure, passive and active smoking. I then determined the associations between these risk profiles and respiratory outcomes, and whether these profiles were modified by GST genes. Linear and logistic regression were used to investigate these associations. Results: Aim 1. My systematic review of the relationship between indoor air pollution, GST genes and asthma identified 22 eligible studies, with 15 finding some evidence of gene-environment interactions. Overall, carriers of GSTM1/T1 null and GSTP1 Val105 genotypes exposed to indoor air pollution, were more susceptible to developing asthma and reduced lung function. However, these findings were more consistent in studies of children compared to studies of adults (Chapter 3). Aim 2. I found evidence that early life tobacco smoke exposure was associated with an increased risk of asthma, reduced lung function growth between 12 and 18 years, and reduced lung function at 18 years, with girls appearing to be more susceptible than boys (master research program). I also found an interaction between early life tobacco smoke exposure and GST genotypes on lung function at both 12 and 18 years. Carriers of GST null mutations and GSTP1 Ile/Ile alleles were more susceptible to tobacco smoke in early life, and these associations were not found in carriers of other GST genotypes (Chapter 5). Aim 3. I found some evidence that early life paracetamol use may be associated with impaired lung function and increased risk of asthma in adolescence after adjustment for the frequency of early life respiratory tract infections. Interaction analysis suggested that these associations were only for carriers of GSTM1 null and GSTP1 Ile/Ile genotypes, I did not find evidence for carriers of other GST genotypes (Chapter 6). Aim 4. I found that the exposure profiles of “Wood heating”, “All gas”, “Wood heating/smoking” and “Wood heating/gas cooking” were associated with persistent asthma and greater lung function decline by age 53 years. Carriers of GSTP1 Ile/Ile genotypes had a greater risk of asthma at age 53 years with exposure to “All gas” and “Wood heating/smoking” compared to a reference group (reverse cycle air conditioning, electric cooking and no smoking). Carriers of GSTM1 null and GSTP1 Ile/Ile genotypes had a greater risk of accelerated lung function decline when exposed to “Wood & gas heating/gas cooking/smoking” and “Wood heating/gas cooking” compared this reference group. These associations were not observed in carriers of other genotypes (Chapter 7). Conclusions: My work identified several household risk factors associated with the progression of asthma, limited maximal lung function development in childhood, or accelerated lung function decline in adulthood. Additionally, this work provides evidence on interactions between household exposures and GST polymorphisms and has contributed significantly to our understanding of gene-environment interactions in relation to respiratory health. These findings highlight the importance of considering potential gene-environment interactions in studies that investigate exposures associated with lung oxidative stress. These findings have the potential to inform guidelines and preventive strategies, especially for people who are at increased risk.
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ItemNatural history and consequences of food sensitisation: results from two birth cohort studies( 2016)The prevalence of allergic diseases is increasing worldwide, particularly in Australia and other “westernised” countries. More recently, evidence suggests a second wave of the “allergy epidemic”, with an increase in the prevalence of food allergies. Despite intense research in this area, there are numerous questions concerning the potential risk factors for the development of allergic diseases. It has been shown that sensitisation to aeroallergens is strongly associated with allergy progression. However the associations between food sensitisation and the development of allergic conditions remain unclear. Therefore, my doctoral work has investigated the natural history of food sensitisation from infancy up to adolescence in an allergy high-risk cohort. I have also investigated the associations between early life food sensitisation and subsequent probable food allergy, asthma, allergic rhinitis and lung function during later childhood and adolescence. Data from an Australian allergy high-risk cohort (Melbourne Atopy Cohort Study (MACS)), and a German population-based cohort (Influence of Life-style related factors on the development of the Immune System and Allergies in East and West Germany PLUS the influence of traffic emissions and genetics (LISAplus)), were used to address the aims of this thesis. MACS recruited 620 infants with a family history of allergic disease prior to birth. The infants were followed from birth up to 18 years and skin prick test (SPT) was conducted at 6, 12 and 24 months, 12 and 18 years. LISAplus recruited 3,097 neonates from four German cities: Munich, Leipzig, Wesel and Bad Honnef. The participants were followed from birth up to 15 years and serum specific IgE was measured at age 2, 6, 10 and 15 years. In both cohorts, multiple surveys, that assessed the occurrence of allergic disease, were distributed throughout the follow-up period. Using these data along with sensitisation data, this thesis has contributed knowledge to address the following issues: Natural History of food sensitisation from infancy up to 18 years A better understanding of the natural history of food sensitisation provides insight, from a public health perspective, to appreciate the likely subsequent burden of food allergy and other allergic diseases over the life course. Longitudinal data on the natural history of food sensitisation beyond early childhood are scarce. Using MACS data, the prevalence of food sensitisation was found to be highest in infancy and declined after the age of 12 months. In the first two years of life, egg white was the most common food sensitisation followed by peanut and cow’s milk while peanut was the most prevalent food allergen at 18 years. Boys with eczema had the highest prevalences of egg and milk sensitisation throughout the follow-ups. A small proportion of children developed late onset food sensitisation (after the age of 2 years) which was unlikely to be clinically relevant. Consequences of early life food sensitisation Longitudinal birth cohort studies with prospective collection of data are the most appropriate design to evaluate the temporal association between early life food sensitisation and development of probable food allergy, asthma, allergic rhinitis and lung function during later childhood and adolescence. An association between food sensitisation at 12 months and the presence of adolescent food sensitisation and probable food allergy was noted in MACS, with sensitisation to more than one food allergen being the strongest predictor. I also demonstrated that early life sensitisation to food without concurrent aeroallergen sensitisation was associated with increased risk of asthma and allergic rhinitis during later childhood (i.e. 10-12 years) in both the MACS and LISAplus studies. Stronger associations were observed for co-sensitisation to both food and aeroallergen. However, only co-sensitisation to both food and aeroallergens in early life was found to be associated with asthma and allergic rhinitis at 18 years in MACS. These findings support the concept of an “atopic march”, in which early life food sensitisation progresses to later asthma and allergic rhinitis. Moreover, I have demonstrated evidence that sensitisation to food allergens only at 6 or 12 months in MACS was associated with reduced FEV1 in adolescence. Most of the observed effect was a direct association, although early life asthma but not aeroallergen sensitisation mediated these associations in part. However, these associations need to be confirmed in population-based studies as sensitisation was not assessed in the first year of life in the LISAplus study. In conclusion, the results I present in this thesis increase our knowledge of the relationship between food sensitisation and allergic disease. Additionally, they suggest that further efforts to prevent the development of food sensitisation, and hence the progression from food sensitisation to food allergy, asthma, allergic rhinitis and lung function impairment should be explored.