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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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.