Melbourne School of Population and Global Health - Theses
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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.