Melbourne School of Population and Global Health - Theses
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ItemEpidemiology of adult chronic cough( 2023-10)Background: Cough is common in adults and has major impacts on individuals’ physical and mental health, and a high economic burden. Cough is a heterogenous condition and clinical guidelines recommend classifying or phenotyping cough by its duration (i.e., acute, subacute, and chronic cough) and the underlying conditions causing the cough (e.g., asthmatic cough, reflux cough, etc.). Diagnosing and treating the underlying conditions responsible for cough is often challenging, as sometimes no underlying conditions can be identified and treating the conditions may not fully resolve the cough. Therefore, using cough-related symptoms to explore heterogeneity can be simpler and more practical. Research Gaps: The heterogeneity of cough in the general adult population is poorly understood as most studies have recruited patients from cough clinics, reducing the generalisability of the findings. Furthermore, several studies have been published to investigate the longitudinal risk factors of cough in adults, but the evidence has not been systematically synthesised. There is also inadequate and inconsistent evidence on some risk factors of cough such as occupational exposures and ambient air pollution. This inconsistency may stem from the use of standard definitions of cough (i.e., chronic cough, chronic phlegm, and chronic bronchitis) which may not fully capture the heterogeneity of cough. Aim: My overall aim was to investigate the risk factors for and heterogeneity of cough in the general adult population. My specific objectives are: i) to systematically synthesise the evidence on longitudinal risk factors for adult cough; ii) to investigate the heterogeneity of cough based on cough-related symptoms (i.e., denoted as cough subclasses in my thesis) among a middle-aged population; and iii) to investigate the associations between potential risk factors and the novel cough subclasses identified in the previous objectives. Methods: My doctoral research utilised systematic review methodology and original data from the population-based Tasmanian Longitudinal Health Study (TAHS) that followed participants from age 7 to 53 years. Latent class analysis was used to identify cough subclasses in middle age based on cough-related symptoms. Clinical features of different cough subclasses were described using prevalence with logit-transformed 95% confidence intervals (CIs) and were compared using t-tests or chi2 tests. Occupational exposures were coded into a Job-Exposure Matrix (JEM) using data from participant work history calendars. Markers of ambient air pollution were derived from the residential addresses of participants using satellite-based land-use regression models. Multinomial logistic regression models were performed to assess associations between exposures and the cough subclasses, after adjusting for confounders. Logistical regression models were used for the standard cough definitions (chronic cough, chronic phlegm, and chronic bronchitis) to enable comparisons with the results from my newly identified cough subclasses. Results: In Chapter 3, I present my findings from the systematic review and meta-analysis. It found heterogeneous definitions of chronic cough used in the literature. Asthma, persistent smoking, and lower education were consistently associated with an increased risk of chronic cough in adults with little to moderate heterogeneity. There was inconsistent evidence for risk factors such as occupational exposures and ambient air pollution and substantial heterogeneity was observed across primary studies precluding any meta-analysis for these factors. In Chapter 5, I present my novel classification of six cough subclasses in a middle-aged general population using latent class analysis. Each of the cough subclasses had distinct clinical features cross-sectionally and longitudinally from childhood to middle age. The subclasses were labelled as “minimal cough”, “cough with colds only”, “cough with allergies”, “intermittent productive cough”, “chronic dry cough”, and “chronic productive cough”. In Chapter 6, I report my findings on the associations between occupational exposures and my novel cough subclasses. Specific occupational risks were identified for different cough subclasses, which were not fully captured when using standard cough definitions as outcomes. These included associations between aromatic solvents and chronic dry cough; biological dust and allergic cough; and herbicides, other solvents, and productive cough. In Chapter 7, I report my results of associations between ambient air pollution and my novel cough subclasses. There was a linear, dose-response relationship between ambient nitrogen dioxide (NO2) and productive cough (intermittent and chronic), as well as fine particulate matter with an aerodynamic diameter <= 2.5um (PM2.5) and chronic dry cough. These associations were present even in a low polluted setting as the pollution levels in this study were lower than the Australian National Environment Protection Measure. Conclusions: The identified novel cough subclasses have largely addressed the heterogeneity of cough in the community as shown by their distinct clinical characteristics cross-sectionally and longitudinally. Distinct associations between occupational exposures, ambient air pollution, and cough subclasses were uncovered, which were not detected by the standard cough definitions. Future studies should consider adopting a similar framework to address the heterogeneity of cough in general populations. This will help generate better quality evidence to inform individualised clinical management of cough.
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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.