Melbourne School of Population and Global Health - Theses

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    Epidemiology of adult chronic cough
    Zhang, Jingwen ( 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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    The role of short-term grass pollen exposure in allergic disease and lung health
    Idrose, Nur Sabrina ( 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.