Melbourne School of Population and Global Health - Theses
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ItemThe role of short-term grass pollen exposure in allergic disease and lung health( 2023-02)Background: Australia has one of the highest prevalence of allergic diseases. Although the mortality rate is low, allergic conditions are associated with significant burden. Environmental risk factors of allergic diseases include exposure to aeroallergens such as pollen. In Australia, temperate grass pollen is the primary seasonal aeroallergen. Research Gaps: Although it is well-established that temperate grass pollen can trigger asthma hospitalisations, its relationship with lung function and airway inflammation at a community level is understudied. Furthermore, no study to date has considered the short-term associations between pollen exposure and food allergy. Studies on selective populations have shown that eczema can be exacerbated with increasing ambient pollen exposure, but population-based studies are lacking. Moreover, the evidence on the potential effect modification by individual and environmental factors on the associations is scarce. Aim: I investigated the associations between short-term grass pollen exposure and lung function, airway inflammation, food allergy and eczema across different age groups within the community and identified potential effect modifiers of these associations. Methods: My doctoral research utilised a systematic review methodology and original data from large population-based cohorts: HealthNuts, The Melbourne Atopy Cohort Study (MACS) and the Tasmanian Longitudinal Health Study (TAHS). Grass pollen exposure was assessed either using daily concentrations or the season as a proxy measure of exposure. Where daily pollen data were available, exposure was investigated on the day of exposure (lag 0) and up to three days before (lag 3). Statistical modelling was performed accounting for the distribution of the model residuals, the functional form for the associations between the exposure and outcomes, and confounders. Interactions with individual and environmental factors were explored using likelihood ratio tests. Results: Research Question 1 – The systematic review showed that outdoor pollen exposure is an important risk factor for type-2 inflammation in the upper and lower airways in people with ever asthma and/or seasonal allergic rhinitis, but the evidence on lung function was limited (Chapter 3). Research Question 2 – Increasing grass pollen concentrations were associated with reversible obstructive lung function deficits in children with allergic disease, the greatest risk of exacerbation in food allergic children (Chapter 5). Research Question 3 – There was evidence of a relationship between increasing grass pollen concentrations, and subsequent airway inflammation (1-2 days after the exposure) and lung function deficits (2-3 days after the exposure). Adults and individuals with co-existing allergic diseases were especially vulnerable. (Chapter 6). Research Question 4 – Peak grass pollen season was associated with lower pre- and post-bronchodilator lung function in smokers with allergic respiratory disease, those exposed to higher traffic-related air pollution, with co-existing allergic diseases or with poor adherence to inhaled corticosteroids (Chapter 7). Research Question 5 – Persistent grass pollen exposure over 4 days was associated with increased odds of food skin-prick test reactivity and eczema flares in children, but the impact was greater if peanut allergy was already present (Chapter 8). Conclusions: My work has significant public health and clinical implications. Notably, there was evidence of association between ambient grass pollen exposure, and subsequent lung function impairment and airway inflammation in both children and adults, mainly on the large and medium-small sized airways. There was also an association with post-bronchodilator measures in middle-aged adults, implying that the pathology in this age group may be distinct from classic, reversible asthma. Furthermore, the negative health impacts of short-term grass pollen exposure may extend to non-respiratory allergic diseases such as food allergy and eczema. Lastly, I identified high-risk groups who were more vulnerable to grass pollen, which were adults, smokers with allergic respiratory disease, those exposed to higher traffic-related air pollution, with allergic co-morbidities or with poor adherence to inhaled corticosteroids.
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ItemAssociations between dietary factors, lung function and bronchial responsiveness in middle-aged and older Australians( 2020)Studies of relationships between dietary factors, lung function and bronchial responsiveness (BR) are limited and findings inconsistent. My aim was to investigate these relationships in middle-aged and older adults. A secondary aim was to identify a more suitable statistical method to assess factors associated with BR and compare its findings to those from the common regression model of the log-transformed dose-response slope (logDRS). I used data from two cross-sectional studies – the Tasmanian Longitudinal Health Study (TAHS) 2010 follow-up and the Chronic Obstructive Pulmonary Disease (COPD) Study. The TAHS is a respiratory study of Tasmanian school children born in 1961. In 2010-2012, an asthma and bronchitis enriched subsample completed spirometry, a methacholine challenge and a questionnaire. I used a linear mixed model (LMM) to examine “known” predictors of BR and compared the findings to those from regression of the logDRS. I used multivariable linear regression to investigate associations between fruit and vegetable intakes and lung function and LMMs to examine associations with BR. The COPD study is a population-based cross-sectional study of adults aged 45-69 years living in inner south-east Melbourne. A random subsample completed spirometry, a methacholine challenge, and questionnaires including a semi-quantitative food frequency questionnaire. I derived dietary patterns from nutrient intakes using principal component analysis and calculated an energy-adjusted dietary inflammatory index (E-DII) as a measure of the inflammatory potential of the diet. I examined associations between these dietary factors and lung function and BR using linear regression and LMMs, respectively. I explored sex, BMI, smoking, asthma status and atopy as effect modifiers of these associations. Results from the LMM differed to those from regression of the logDRS. In particular, sex predicted BR in the regression model but not the LMM. I found relationships between several dietary factors and lung function in those with current asthma only. In this group, higher vegetable intake, higher intakes of a “high potassium & magnesium” dietary pattern, indicating a diet high in fruits, vegetables and wholegrains, and higher intakes of a “low calcium & sugars” dietary pattern, indicating a diet high in vegetables and low in sugar and dairy products, were associated with better lung function. A higher E-DII, indicating a more proinflammatory diet high in animal products and low in fruits and vegetables, was associated with poorer lung function. I also found higher fruit intake was associated with increased BR. Conversely, in those with current asthma, higher scores for several dietary patterns were associated with less BR. In conclusion, I demonstrated results from an LMM can differ to those from regression of the logDRS, and recommend using the LMM to investigate factors associated with BR. My findings suggest a diet low in animal products and high in fruit, vegetables and wholegrains may be beneficial for lung function in adults with asthma. Therefore, a dietary modification program in this group may improve lung function and reduce the prevalence and severity of asthma and COPD. However, further studies are needed to establish causality of the diet-lung function associations and clarify relationships with BR.
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ItemEpidemiology of obstructive sleep apnoea: diagnosis, prevalence, comorbiditis, and risk factors( 2019)Obstructive sleep apnoea (OSA) occurs due to repetitive partial or complete upper airway obstruction during sleep and may lead to generalised hypoxia and/or arousals from sleep. OSA has both direct and indirect health and economic costs. However, design of public health interventions to control OSA is constrained by some critical gaps in knowledge. OSA is widely regarded to be highly prevalent but the reported prevalence estimates vary widely. The last population prevalence study in Australia was performed nearly twenty-five years ago. New estimates on population prevalence and the comorbidities associated with OSA would help better understand the burden of disease. Several OSA-screening questionnaires have been recommended for use in primary care settings in Australia, but these questionnaires have not been validated in the Australian primary-care population. Although OSA is seemingly associated with some chronic disorders such as cardiovascular and cerebrovascular disorders, metabolic disorders, respiratory disorders and psychiatric disorders, evidence for some associations are limited. Furthermore, the currently known modifiable risk factors for OSA are limited and rarely based on longitudinal evidence. No childhood risk factors are known for OSA. Given these knowledge gaps, during my doctoral work I aimed (1) to determine the validity of commonly known OSA-screening-questionnaires, (2) to describe the prevalence of OSA and its co-morbidities in the general population, and (3) to describe some potential early-life and lifetime risk factors for OSA. My specific objectives were (a) to systematically summarise the current evidence on the validity of the common OSA questionnaires for which such systematically synthesised evidence was unavailable, (b) to determine the validity of some common OSA-screening-questionnaires to detect OSA among middle-aged Australian adults, (c) to systematically summarise the available evidence on the prevalence of OSA in the adult general population including in age and sex- specific subgroups, (d) to describe the prevalence and associated chronic co-morbidities of OSA in middle-aged Australian adults, (e) to determine the role of lifetime lung function trajectories on OSA in adult life, and (f) to determine the role of childhood respiratory risk factors on OSA in adult life. To achieve the first aim, I systematically synthesised the literature on the validity of the Berlin questionnaire (Chapter 3). The evidence on the validity of the other questionnaires were already synthesised at the time I commenced this work. The included studies reported varied sensitivity and specificity based on the OSA assessment method used. I then used the data from the Tasmanian Longitudinal Health Study (TAHS) to validate the Berlin (BQ), STOP-Bang and OSA-50 questionnaires against type-4 sleep studies (Chapter 6). To determine if the flow-based AHI or ODI is more suitable as the reference standard, I investigated their agreement in detecting and classifying OSA (Chapter 6 [6.1]). I found that ODI identified more clinically significant OSA than flow-based AHI. Unlike in the previous studies that relied only on conventional AHI/ respiratory disturbance index (RDI)/oxygen desaturation index (ODI) cut-off levels for the reference test, I derived and used a new reference standard, namely, ‘clinically-relevant OSA’ that included moderate-severe OSA (ODI≥15) and mild (ODI≥5) OSA with symptoms as a combined group, as this is the group that needs to be captured for clinical management. I found that all three questionnaires were not clinically useful on their own (sub-optimal sensitivity and specificity) in a simulated primary-care sample but could be used to rule-in OSA (high specificity) when combined with Epworth sleepiness scale (Chapter 6 [6.2]). I also found that OSA-50 and STOP-Bang had a moderate sensitivity and low specificity and BQ had low sensitivity and moderate specificity, at the recommended thresholds, in the general population (Chapter 6 [6.3]). The trade-off between sensitivity and specificity remain a limitation of their practical use. To achieve the second aim, I systematically synthesised the literature on the prevalence of OSA (Chapter 4). I found that the prevalence of OSA varied between population subgroups and the OSA assessment methods. I then used the data from the Ten to Men study to determine the prevalence of doctor diagnosed OSA in Australian men and its co-morbidities (Chapter 7 [7.1]). I found that the prevalence increased from 2% in younger adults to 8% in the middle-age and that OSA was associated with several chronic cardiovascular, metabolic, respiratory and psychiatric disorders. Using data from the TAHS, I found the prevalence of medically-confirmed OSA to be 5% and probable OSA as determined by the STOP-Bang questionnaire to be 15% (Chapter 7 [7.2]). Medically-confirmed OSA as well as probable OSA were associated with several co-morbidities as seen in the Ten to Men study. Furthermore, I investigated how nocturnal-asthma-like symptoms and bronchial hyper-reactivity (BHR) contribute to the association between OSA-risk and current-asthma using the data from TAHS. I found no evidence for any role of BHR in this association but found some evidence for some nocturnal asthma symptoms to be suggestive of undiagnosed OSA. To achieve the third aim, I investigated how OSA is related to lifetime lung function trajectories and childhood respiratory risk factors using longitudinal data from the TAHS. I found that three trajectories were associated with both probable OSA (defined using STOP-Bang questionnaire) and medically-confirmed OSA (Chapter 8 [8.1]). Frequent childhood lower respiratory tract infection, asthma and lung function trajectories were associated with probable OSA (Chapter 8 [8.2]). Overall, my findings have significant public health, clinical and research implications and significantly advanced the current knowledge in this area. My assessment between ODI and flow-based AHI is the first such evidence and suggest that ODI should be preferred in clinical practice. Current OSA screening-questionnaires could be useful in epidemiological research but not as clinical tools. This calls for development of better screening methods. My findings challenge the current recommendations for OSA screening at primary-care and I make suggestions as to how this process could be improved. The high prevalence of OSA in general, and in males and elderly, and its association with other priority chronic disorders provide public health foci for interventions. The demonstrated role of nocturnal respiratory symptoms in the OSA-asthma association suggests the need for clinical vigilance for undiagnosed OSA in patients with nocturnal symptoms. Furthermore, the evidence for association of lung function trajectories and childhood risk factors with OSA advances the current knowledge and provides platforms for future research to delineate the seemingly complex pathophysiology and natural history of OSA.
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ItemRisk factors for and outcomes of lung function deficits throughout the lifespan( 2019)Good lung function is essential for general health and longevity. The lungs are responsible for providing oxygen to meet the metabolic demands of the body and expelling waste products of cellular respiration. They also play a critical role in maintaining acid-base balance. Impaired lung function imposes significant health issues. Chronic obstructive pulmonary disease (COPD) in late adulthood is responsible for the largest burden. Across the life course, lung function passes through different phases (development, growth, plateau, and decline). Lung function is influenced by multiple risk factors that act at different periods, which together form a complex web contributing to lifetime risk. Understanding how particular risk factors influence each phase as well as the lifetime trajectory of lung function and the consequences of these impairments is critical for evidence-based strategies to promote lung health and prevent lung diseases. However, such understanding is limited. Specifically, some major gaps in this literature include: how reduced lung development and growth in early life influence the risk of COPD and its phenotypes in later life; how multiple early life factors interact and predict long-term lung function deficits and COPD; how adult life factors interact with genetic and early life factors to influence lung function decline; and what are the determinants and consequences of different lifetime lung function trajectories. In this thesis, I aim to investigate risk factors for, and outcomes of, lung function deficits throughout the life course, using data from the Tasmanian Longitudinal Health Study (TAHS). My specific objectives are (1) to investigate the association between childhood lung function and asthma-COPD phenotypes in middle age, (2) to identify childhood respiratory risk factor profiles that influence lung function and COPD development in middle age and to examine the causal pathways involving potential mediators and effect modifiers, (3) to establish trajectories of lung function from childhood to the sixth decade and to investigate the association between identified lung function trajectories and both early life determinants and subsequent COPD risk, and (4) to investigate how interactions between major adverse exposures in adulthood, early life respiratory risk factors and potential genetic factors may influence lung function decline in middle age. In chapter 4, I present my findings that lower lung function at age seven years predicted higher risk of COPD and asthma-COPD overlap syndrome (ACOS) in middle age, independent of personal smoking. In particular, I found that being in the lowest quartile of the ratio of forced expiratory volume in 1 second to forced vital capacity (FEV1/FVC) at age seven years was associated with a 5.8 fold and 9.8 fold increase in the risk of COPD and ACOS, respectively. In chapter 5, I present my results identifying six distinct profiles of childhood respiratory risk factors. These risk profiles were associated with differing risks of reduced lung function and COPD in middle age. Among four risk profiles associated with increased risk of lung function deficits and COPD in middle age, the “frequent asthma, bronchitis, allergy” profile was found to be the most “at risk” group. The associations between this profile and COPD and reduced lung function were largely mediated through adult active asthma (62.5% for COPD), with some mediation through reduced childhood lung function (26.5% for COPD). I also found that the association between the “frequent asthma, bronchitis, allergy” profile and middle-aged lung function was aggravated by personal smoking. In chapter 6, I present my results identifying six distinct trajectories of FEV1 from the first to the sixth decade of life, using group-based trajectory modelling. I found that three “unfavourable” trajectories were associated with an increased risk of COPD and collectively contributed 75% of the COPD burden at the sixth decade. Two of the six trajectories were novel and contradict the long-held paradigm that lung function established in childhood tracks through life. I also found that childhood factors including childhood asthma, bronchitis, pneumonia, hayfever, eczema, parental asthma and maternal smoking during childhood predicted membership of the three unfavourable trajectories. In chapter 7, I report my findings that current smoking, current adult asthma, occupational exposures, and living close to major roads were associated with accelerated decline in post-bronchodilator FEV1 and FEV1/FVC, suggesting a predisposition to subsequent airflow obstruction; while body mass index (BMI) gain and incident obesity were associated with both FEV1 and FVC decline, suggesting a predisposition to restrictive lung deficits. Notably, I observed interactions between childhood factors and personal smoking and occupational exposure to vapors/gases/dusts/fumes (VGDF). In particular, accelerated lung function decline associated with current smoking and occupational VGDF was accentuated for those with low childhood lung function, a glutathione-S-transferase M1 (GSTM1) null genotype, or exposure to maternal smoking. Overall, my thesis findings have advanced the current knowledge of the influence of lifetime risk factors on lung function deficits across the life course and their consequences. My findings provide a basis for developing tools that clinicians could use to predict/assess long-term lung health for a child based on his/her exposure patterns. They also provide further impetus for close clinical monitoring of children with impaired lung function. From the public health perspective, my findings suggest that preventing impaired lung function from early life, avoiding unfavourable lifetime lung function trajectories, and promoting favourable lung function trajectories would reduce the burden of lung function impairment, particularly in relation to COPD. My findings also highlight the need for an integrated and comprehensive “life course” preventive strategy, taking into account genetic and lifetime environmental risk factors, and their interactions.
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ItemThe role of occupational exposure on chronic obstructive pulmonary disease in middle-aged adults( 2017)Chronic Obstructive Pulmonary Disease (COPD) contributes significantly to the global burden of disease. COPD is characterized by the presence of fixed airflow obstruction (AO) as measured by spirometry and defined by irreversible reduction in the post-bronchodilator (BD) ratio between the forced expiratory volume in one second and forced vital capacity (FEV1/FVC). Chronic bronchitis, chronic respiratory symptoms and lung function decline over time are also significant predictors of COPD. However, they are also considered separate conditions as these may exist with normal lung function. Smoking is the main risk factor for COPD but a large number of people with COPD are never smokers, so other factors are contributing to the disease burden. Occupational exposure is one of the known important preventable risk factor for this disease. Understanding how occupational exposures contribute to the overall risk of COPD in the general population is essential to be able to gain a greater understanding of COPD etiology and to be able to identify high-risk occupational groups. Population-based studies have found evidence of a relationship between some occupational exposures and COPD. However, a critical review of literature presented in Chapter 2, identified that studies to date investigating these relationships have had some significant limitations including lack of post-BD measurement, limited use of lifetime work history and cumulative exposure assessment. Furthermore, some common occupational exposures with known respiratory impacts have not been investigated in relation to fixed AO with adequate consideration of asthma and lung function decline. Therefore, the aim of my doctoral work was to investigate the effects of occupational exposures on COPD using robust definitions of COPD, chronic bronchitis, and lung function decline and to explore if any effect modification existed. My systematic review and meta-analyses (Chapter 3) identified an association between low exposure to mineral dust and high exposure to gases/fumes and COPD, and both low and high exposure to biological dust and mineral dust were associated with chronic bronchitis. This work further helped to identify some of the major gaps in the literature that I have addressed in my subsequent analysis. In Chapter 4, I used data from the population-based Tasmanian Longitudinal Health Study (TAHS). Lifetime work history calendars were collected at age 45 years, and occupational exposures were assigned using the ALOHA plus Job Exposure Matrix and defined as ever exposed and cumulative exposure-unit years. Multivariable linear and logistic regressions were used to investigate the associations adjusting for possible confounders. In Chapter 5, I examined the associations between occupational exposure and COPD defined by fixed AO, chronic bronchitis, and respiratory symptoms. I found consistent significant associations between ever exposure and cumulative exposure-unit years to pesticides and herbicides and fixed AO, chronic bronchitis, and respiratory symptoms. I also found evidence of effect modification by current asthma for the association between biological dust, mineral dust, and gases/fumes and fixed AO. In Chapter 6, I examined the association between exposure to solvents and metals and COPD as defined by fixed AO and gas transfer factor. I found an association between ever exposure to metals and fixed AO. Interestingly I also found an association between increasing cumulative exposure-unit years to chlorinated solvents and fixed AO and fixed AO plus low DLco but only in women, not in men. In Chapter 7, I investigated the association between occupational exposures and lung function decline between age 45 and 50 years. I found an association between both ever exposure and cumulative exposure-unit years to aromatic solvents and a greater decline in lung function. I also found that increasing cumulative exposure-unit years to aromatic solvents were associated with a greater lung function decline in women, but not in men. Collectively these findings have strengthened and have filled some major gaps in our understanding of the links between overall occupational exposure and the development of COPD in an adult population. I have confirmed in my study that exposure to pesticides is a risk factor for COPD with solvents and metals exposure also linked to an increased risk of COPD. Importantly, my findings suggest that women are at a greater risk of COPD when exposed to solvents. These findings lead me to make several important public health recommendations. Firstly, workplaces need to be monitored to ensure exposure to pesticides and solvents is reduced via adequate ventilation, storage, and usage solutions. Secondly, occupational groups with regular and high exposure to these chemicals need to be encouraged to utilize personal protective equipment, together with routine monitoring. By implementation of these control measures, the burden of COPD caused by occupational exposures has the potential to be reduced.
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ItemThe contribution of outdoor fungal spores to child and adolescent asthma hospitalisations: lung function and airway inflammation( 2017)Outdoor fungal spores are among the most common aerobiological particles in the air we breathe. Although a limited number of outdoor fungal species are recognised as exacerbating agents of a number of allergic and respiratory conditions, their contribution towards asthma exacerbation is unclear, particularly among children and adolescents. Moreover, we have limited understanding of the impacts that inhaled fungal spores have on lung function or airway inflammation, which may be pre-clinical signs of asthma exacerbation. Therefore the aim of my doctoral research is to examine whether there are associations between common outdoor fungal spores and child and adolescent asthma hospitalisations, and also to explore if short term exposure to ambient fungal spores is associated with lower lung function or airway inflammation. In Chapter 2, a comprehensive literature review highlights that there are significant knowledge gaps in the contribution of outdoor fungal spores to child and adolescent asthma hospitalisations, lung function and airway inflammation. In order to address some of these gaps, my specific research objectives of this doctoral research were to: (a) systematically synthesise the current evidence as to whether outdoor fungal spores were significant triggers of child and adolescent asthma exacerbations resulting in health service attendances; (b) investigate if there were associations between short term exposure to outdoor fungal spores and child and adolescent asthma hospitalisations; (c) explore if any of these associations were modified by air pollutants, grass pollen, age group, sex, presence of human rhinovirus infection, or fungal sensitisation status; (d) investigate if there were associations between outdoor fungal spores and lower lung function or airway inflammation, and (e) explore if any associations were modified by air pollutants or pollen, age group or fungal sensitisation status. In Chapter 3, my systematic review found that only a small number of studies have been conducted, predominantly in countries located in the northern hemisphere. Children with fungal sensitisation appeared to be at greater risk of asthma hospitalisations. Severity of asthma exacerbation may vary between fungal spore taxa. There were inconsistent findings, possibly due to the lack of accounting for other significant triggers of asthma exacerbations. In Chapter 5, my ecological case-crossover study of child and adolescent asthma hospitalisations in south-west Sydney found that there were associations with Coprinus, Periconia, Chaetomium, Ganoderma and Cerebella, with same day and lagged effects. There was evidence of effect modification by sex, with girls demonstrating stronger associations with Cladosporium, Coprinus and Chaetomium than boys. Age also acted as an effect modifier with older adolescents, demonstrating stronger associations with Coprinus and Ustilago/smuts than those aged under 14 years. In Chapter 6, my case-crossover study of child and adolescent asthma hospitalisations in Melbourne found associations between ambient Alternaria, Coprinus, Drechslera and Leptosphaeria, with signs of same day and lagged effects. These associations were independent of having a human rhinovirus respiratory infection. There was some evidence that Cladosporium sensitisation acted as an effect modifier. In Chapter 7, my cross-sectional study of a high allergy risk cohort comprising of children, adolescents and adults found differing associations between outdoor fungal spores and lower lung function and presence of airway inflammation. Fungal sensitisation acted as an effect modifier with some fungi and parameters of lung function and markers of airway inflammations. Overall, this research has contributed to filling some of the gaps in our current understanding of the contribution of outdoor fungal spore exposures to child and adolescent asthma hospitalisations, lower levels of lung function and airway inflammation. This research demonstrates that the contribution of outdoor fungal spores may be under-estimated. Importantly, species that have not been previously found to be associated with asthma exacerbations, but are genetically related to well-known fungal triggers of asthma exacerbation, may warrant further investigation. Future research needs to improve the modelling of dispersion and distribution of outdoor fungal spores on spatial and temporal levels. The development of reliable and standardised fungal reagents for detection of allergic sensitisation is needed. The presence of fungal spores in the air is important for the ecosystem, and may not be controlled on a large scale, but understanding how to prevent their effects on respiratory health will benefit public health.
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ItemAssociations between biomarkers in exhaled breath condensate (EBC) and allergic disease phenotypes and lung function( 2016)Asthma is a common chronic disorder of the airways that involves a complex interaction of airflow obstruction, bronchial hyperresponsiveness and underlying airway inflammation. It is increasingly clear that asthma is a heterogeneous group of conditions (phenotypes) with common symptoms. The underlying mechanisms of different phenotypes are not clearly understood and the treatment responsiveness and causative factors are likely to vary between phenotypes. The increasing interest in airway inflammatory biomarkers assessment has led to the development and evolution of tools to measure these biomarkers which identify various asthma phenotypes. Exhaled breath condensate (EBC) is a totally non-invasive, easy to perform, feasible and inexpensive method for sampling lung and airways fluid, which reflects the airway epithelial lining fluid (ELF). EBC comprises a variety of airway inflammatory mediators, such as oxidative stress and pH, which provides non-invasive indicators of ongoing biochemical and inflammatory activity in the airways. Although EBC samples the entire respiratory tract from the mouth to the alveoli, the precise origin of each sampled molecule cannot be determined. A number of studies have assessed the relationship between EBC biomarkers and adult airway diseases, such as asthma. However, these studies have had limited sample sizes and, as a result, were unable to compare associations between numerous phenotypes of airway diseases. It remains possible that the associations with EBC biomarkers may change with age, but this has not been examined in a single study using the same methods. Furthermore, previous studies have been conducted in clinical populations rather than epidemiologic settings. Therefore, the overall aim of this PhD research was to assess the associations between oxidative stress biomarkers and pH in EBC and asthma phenotypes, rhinitis phenotypes, atopic sensitisation, lung function and objective markers of airway inflammation, including bronchial hyperresponsiveness (BHR) and the fraction of exhaled nitric oxide (FeNO), in both the early adulthood and middle-aged groups. Within this thesis, cross-sectional analyses nested within the two Australian longitudinal studies have been performed. These studies are: (1) The Melbourne Atopy Cohort Study (MACS), a study of individuals with a family history of allergic disease (defined as the early adulthood group in this thesis); and (2) The Tasmanian Longitudinal Health Study (TAHS), a population-based study (defined as the middle-aged group in this thesis). EBC samples were collected at the 18-year follow-up of MACS and the BHR LAB Study of the 5th-decade follow-up of TAHS. Using these data, this thesis contributes knowledge to the field, specifically addressing the following issues: Methodological issues from the laboratory analysis of EBC biomarkers Findings from this doctoral research showed that EBC biomarkers were influenced by the long period of storage, particularly for hydrogen peroxide (H2O2). The vast majority of analysed samples for H2O2 were shown to be below the lower limit of detection (LOD). In addition, both decreased levels of EBC total nitric oxide products (NOx) and increased EBC pH were associated with a long period of sample storage. Therefore, the duration of sample storage was adjusted for in all analyses presented in this thesis. Associations between EBC NOx and different phenotypes of asthma and rhinitis, sensitisation, lung function, BHR and FeNO This PhD research showed that atopic asthma and atopic rhinitis phenotypes were associated with higher levels of EBC NOx. Also, atopic sensitisation was related to increased levels of EBC NOx and this association was stronger in individuals with poly- aero-sensitisation. These findings were generally consistent across the two age groups. In the early adulthood group only, elevated levels of EBC NOx were associated with reduced pre- and post-BD FEV1/FVC. Additionally, EBC NOx was not related to BHR and FeNO. Therefore, EBC NOx may be considered a marker for allergic airway inflammation in different age groups. Associations between EBC pH and different phenotypes of asthma and rhinitis, sensitisation, lung function, BHR and FeNO Reduced EBC pH was associated with the presence of asthma and strongly associated with severity of asthma symptoms, as well as atopic asthma and atopic rhinitis in the early adulthood group. Also, similar associations were observed in those with atopic sensitisation, particularly in those who were sensitised to more than one tested allergen. However, none of the above associations were observed in the middle-aged group, suggesting that these effects may be age-dependent. Alternatively, it may be due to differences in methods used between the projects (e.g. degree of deaeration of the sample post collection). In addition, there were no associations between EBC pH, lung function, BHR, and FeNO in either project. These findings suggest that associations between airway acidification and asthma and sensitisation phenotypes may be influenced by the age of an individual. Conclusion Overall, my doctoral work observed some novel and interesting associations. Results from this thesis will aid the current understanding of an underlying inflammatory process, help to discriminate between different phenotypes of airway diseases and help guide future research. Although EBC is a promising method, it lacks appropriate standardisation and reference values and is therefore not currently suitable for use in clinical practice.
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ItemImpact of traffic related air pollution on asthma, allergic diseases and lung function( 2016)Traffic related air pollution (TRAP), the most common type of air pollution in urban areas, has been hypothesised to increase the risk of asthma and allergic diseases. However, epidemiological studies investigating the associations of TRAP exposure and these outcomes have found inconsistent results. These inconsistencies can be partially explained by genetic variations associated with regulating oxidative stress. Therefore, the aim of my doctoral work is to investigate the effects of TRAP exposure on asthma, allergic diseases and lung function while examining these effects are modified by Glutathione S-Transferase (GST) polymorphisms. Polymorphisms of GST genes which are associated with regulating oxidative stress pathways are of special interest because of the biological mechanisms which play an important role in modulating inflammatory responses triggered by reactive oxygen species. In Chapter 2, a critical review of the literature revealed that there are major knowledge gaps in the effects of TRAP exposure on asthma, allergic diseases and lung function, and their interactions with GST polymorphisms. Hence, the specific research aims of the present thesis were to: (i) systematically synthesise the evidence for the association between early life TRAP exposure and the risk of asthma, hay fever and allergic sensitisation during childhood and adolescence, (ii) investigate the relationship between TRAP exposure during first year of life and asthma and hay fever to late adolescence, (iii) investigate the relationship between current annual TRAP exposure and current asthma in middle aged adults and asthma, allergic sensitisation and lung function, (iv) investigate the association of the effect of TRAP exposure over five years in adults and outcomes of asthma and lung function, and to examine if GST gene polymorphisms modify the associations in aims ii, iii and iv. In Chapter 3, my systematic review and meta-analyses of birth cohort studies found that: long term exposure to particulate matter less than 2.5 µm in diameter (PM2.5) or black carbon from birth associated with asthma incidence in childhood, and early life exposure to PM2.5, black carbon or nitrogen dioxide (NO2) exposure were associated with a trend of increased risk of asthma incidence throughout childhood. In Chapter 4, my work in the Melbourne atopy cohort study (MACS), a birth cohort of children with family history of allergic diseases showed that, early life TRAP exposure defined as the cumulative length of major roads within 150 metres of each participant’s residence during the first year of life associated with increased risk of asthma and wheeze at the age of 12 years in carriers of Glutathione S-Transferase theta1 (GSTT1) null genotype. In Chapters 6 and 7, I used two proxies for TRAP: (i) mean annual NO2 exposure, estimated for current residential addresses using a validated land use regression model or (ii) living less than 200 metres from a major road. In Chapter 6, I found that current mean annual exposure to NO2 was associated with increased risk of aero-allergen sensitisation. In addition, current mean annual NO2 and living less than 200 metres from a major road were associated with increased risk of wheeze. In this group of middle age adults, living less than 200 metres from a major road was associated with lower levels of pre- and post-BD FEV1. Carriers of the GSTT1 null genotype had an increased risk of asthma and allergic outcomes when exposed to TRAP compared to GSTT1 non null genotype. In Chapter 7, I found that exposure to higher levels of NO2 over five years was associated with increased risk of asthma. Furthermore, over a five year period, living less than 200 metres from a major road was associated with asthma, wheeze and lower levels of FEV1, FVC and FEV1/FVC. Increased risk of asthma and wheeze associated with living less than 200 metres from a major road over five years was more marked in carriers of the GSTT1 null genotype. Overall, the present thesis has contributed significantly to the current knowledge of TRAP exposure, asthma, allergic diseases and lung function. Consistently, GSTT1 null genotype carriers exposed to TRAP showed an increased risk of these outcomes. The overarching goal being to establish an integrated strategy to improve air quality especially in urban areas, which will benefit the community and reduce the burden of asthma, allergic diseases and poor lung function. An integrated plan can be adopted in controlling TRAP in urban areas including; providing efficient public transport network, use of clean fuel in vehicles, reducing house densities near major roads and vehicles should be monitored regularly for emissions. In setting future air quality guidelines high-risk groups should take into account including genetically susceptible populations and standards should consider lower levels of air pollution which can cause potential adverse health outcomes in these vulnerable subgroups.
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ItemAssociation between early life liquid diet and allergic disease and lung function outcomes( 2016)During my doctoral work I have investigated the effect of early life liquid diet (duration of breastfeeding, fatty acid composition of breast milk and formula feeding) on allergic diseases and lung function outcomes during late childhood and adolescence, including assessment of possible mediators for these associations. Worldwide, the prevalence of allergic diseases has increased over recent decades. Australia has a high prevalence of these conditions. Allergic diseases are immune mediated and the maturation of the immune system occurs during early life. It is believed that gene and environment factors play a major role in developing or protecting against these diseases. Early life exposures have been hypothesised to influence the risk of developing allergic diseases, as they may have an impact on the developing immune system. While it is currently not clear how to reduce the incidence of allergic disease and improve the lung function outcomes, it is possible that modification of early life dietary exposures may play a role. The focus of my doctoral work is to explore the associations between early life liquid diet (breast and formula feeding) and allergic disease (asthma, eczema and allergic rhinitis) and lung function outcomes. The aim of this work is to determine if modification of early life liquid diet (breast milk and formula milk) may influence the risk of allergic diseases and later childhood lung function outcomes, which may then inform preventive strategies. The main liquids that an infant is exposed to in the first months of life are breast milk and formula milk. It is plausible that these first dietary exposures can impact on allergic disease outcomes. It is recommended by many health care organisations that a baby be exclusively breastfed for at least four months, while some organisations recommend six months of exclusive breastfeeding. Despite these recommendations, the actual duration of breastfeeding remains quite variable. The constituents of breast milk change due to a variety of reasons, such as mother’s diet and the needs of the child. Breast milk, especially colostrum, is rich in biologically active substances. Infant formulas can contain different base protein sources and variable degree of hydrolysis. These differences in the constituents of breast milk and between infant formulas may potentially influence the incidence of allergic disease. Within my thesis, I have both used systematic reviews of the published and utilised the data arising from the Melbourne Atopy cohort Study (n=620) to address key gaps in the evidence base of early life liquid diet and allergic diseases and lung function outcomes. In brief, Melbourne Atopy Cohort Study (MACS) started as a randomised controlled trial of three different types of formula (soy, partially hydrolysed whey and a conventional cows’ milk formula). Only infants with first degree relative with a family history of allergic diseases were eligible to be enrolled in the MACS. While the MACS commenced as a randomised controlled trial, I have also used MACS as a birth cohort study to assess associations between non-randomised exposures and allergic disease outcomes. Using the available data within the MACS, and by systematically synthesising the available literature, I have addressed three objectives. Objective 1: To determine if duration of breastfeeding is associated with lung function outcomes In my systematic review, I found breastfeeding was associated with improved lung function outcomes in childhood. The available evidence suggests this improvement is most apparent on the outcome of forced vital capacity (FVC). My original analysis of MACS data did not support this finding, as I observed very few associations between breastfeeding and lung function outcomes. In my analysis of this high risk cohort, I did observed some evidence that greater duration of exclusive, but not total breastfeeding, was associated with greater mid expiratory flow (MEF), a possible marker of small airway function, and this association was partly due to children with prolonged exclusive breastfeeding having a greater attained height. Objective 2: To determine the associations between colostrum and breast milk poly unsaturated fatty acids and allergic diseases and lung function outcomes Based on my systematic review, the available evidence on the association between poly unsaturated fatty acids n-3 and n-6 on allergic disease outcomes is inconclusive. From my original analysis I observed that a higher level of n-3, especially in colostrum, was associated with an increased risk of allergic diseases and reduces lung function outcomes. This was an unexpected finding. Objective 3: The effect of three types of infant formula (soy formula, partially hydrolysed whey formula and cows’ milk formula) on allergic diseases and lung function outcomes - results of the randomised controlled trial There was no clinically significant protective effect on allergic diseases outcomes from either intervention formula (partially hydrolysed whey or soy formula) compared to cow’s milk formula. However, there was some evidence regarding protection from cows’ milk sensitisation at the 12 years follow up. In conclusion: My conclusions are based on the two systematic reviews, where I systematically searched and summarised the available literature, and also the results of three discrete original data analyses based on the MACS birth cohort. Both my review paper and the original paper based on the associations between breastfeeding and the lung function outcomes found some evidence that breastfeeding may be beneficial for lung function outcomes, although the evidence for a beneficial effect of breastfeeding in my original data analysis was much less pronounced than what had been previously reported in the literature. The available evidence on breast milk fatty acids on allergic disease outcomes was inconclusive but the original analysis did show n-3 having detrimental effects. Therefore, introduction of n-3 PUFA to maternal diet should be performed cautiously. The evidence to suggest pHWF or soy formula improving lung function outcomes or decreases allergic diseases compared to cow’s milk formula is not strong enough to make recommendations.
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ItemA longitudinal study of atopy, asthma and lung function from birth to 18 years in a high risk birth cohort( 2012)Background: The global burden of allergic disease, including asthma, eczema and allergic rhinoconjunctivitis is still increasing. Of these, asthma is the most important in terms of morbidity, mortality and financial cost. Asthma is a global problem, estimated to affect 300 million people worldwide. Childhood asthma is the most common chronic disease of children in many westernized countries including Australia. We currently have no effective strategies to prevent development or persistence of asthma. A range of strategies have been trialled, including avoiding environmental triggers (dust mites, animal dander), modification of mothers’ and infants’ diets and randomized controlled trials of anti-inflammatory medications in children at high risk. To date, the results have been disappointing with very modest, if any, impact found. The lack of preventive strategies appears to be related to a poor understanding of asthma aetiology. There are many areas of controversy regarding the early life risk factors for the development of childhood asthma. Asthma is believed to result from a complex interaction between genetic, environmental and biological factors. Of these, the only consistent major risk factors to emerge to date are a family history of atopy or asthma, an individual history of atopy, early childhood eczema, environmental tobacco smoke and viral infections in early childhood. Asthma is known to be a heterogeneous disease in childhood, so that poor classification of asthma groups, or phenotypes, may be part of the reason for the lack of results within and inconsistent findings between studies. There is a critical need for studies which can provide a solid basis for accurate classification of asthma phenotypes as well as investigating plausible risk factors for the development and persistence of asthma. To address questions concerning the classification of asthma phenotypes and the natural history of asthma and allergic disease, along with genetic and environmental factors which may influence aetiology and progression, it is important to use the evidence provided by longitudinal studies. In longitudinal studies, especially birth cohorts with frequent ascertainment of potential aetiological exposures and allergic disease outcomes, it is possible to determine the temporal relationship between exposures and outcomes. This thesis addressed some of the issues in asthma and allergic disease research using data from a longitudinal birth cohort study. The Melbourne Atopy Cohort Study comprises 620 children who were selected before birth for familial allergic disease. These children were very closely followed in the first 2 years of life with 18 telephone interviews. They had yearly follow-ups between ages 3 and 7 and again at ages 12 and 18. Additionally they had clinic testing including cord blood, skin prick testing, and respiratory function testing. The three main objectives which I researched within the MACS were: Objective 1: To document the natural history of wheeze in early childhood (from birth to 7 years) and to use this information to identify longitudinal wheeze phenotypes and to identify potential risk factors for these phenotypes Objective 2: To determine the impact of longitudinal wheeze phenotypes on subsequent respiratory function, respiratory symptoms and allergen sensitization Objective 3: To identify early life risk factors for childhood and adolescent asthma and allergic disease Conclusions: I addressed three broad research areas and 9 specific research questions and to contribute to the existing literature concerning allergic disease in childhood. Firstly through defining childhood wheeze phenotypes using latent class analysis, I defined 5 wheeze classes and confirmed the presence of the newly discovered intermediate onset wheeze phenotype. Additionally, I found distinct patterns of associations with specific early-life factors for each wheeze phenotype. Furthermore, I investigated the respiratory and allergic outcomes of these phenotypes up to 18 years of age. An important finding of this analysis was that children who wheeze transiently in early life do not have an increased risk of allergic disease or sensitization, or any deficit in respiratory function by age 18 when compared to never/infrequent wheezers. Conversely, persistent wheezing phenotypes in childhood (including early persistent, intermediate and late onset) were associated with reduced growth in FEV1 over adolescence and persistent lung function deficits. These findings highlight the importance of categorizing early childhood wheeze in asthma research and the detrimental effects of persistent wheeze on adolescent respiratory health. Furthermore, investigating two specific early life factors: sensitization and pet keeping, I have shown that sensitization to dust mite at ages 1 or 2 years is a good predictor for long-term wheeze and that the presence of a cat or dog at birth in high risk families is not a risk factor for allergic disease in the child, and in fact may reduce the risk of asthma or hay fever by 12 years.