Factors influencing patient outcomes in idiopathic pulmonary fibrosis in Australia

Background:
Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease with a median survival of 3 to 5 years from diagnosis, and is characterized by a severe symptom burden, progressive lung function decline, and increased mortality. Treatment options for IPF are limited, and indeed some treatments may even have been counterproductive, with the widely used combination of prednisone, azathioprine, and N–acetylcysteine over a few decades ultimately demonstrated to increase risk of death. Recently, management guidelines for treatment of IPF focus on the new antifibrotic medications (pirfenidone and nintedanib) that may slow progression of the disease, but evidence regarding the impact on survival is limited. There is a need to investigate how mortality from IPF has been influenced by changing trends in management guidelines, patient characteristics, and other factors. In addition, there is a need to assess the influence of varying factors on IPF outcomes globally and by extension, in Australia.
With that backdrop in mind, this PhD research project aimed to assess the effect of various factors on IPF outcomes in a cohort of Australian patients. To achieve this, five key studies were conducted. The specific aims for each study are:
1. To investigate the recent trends in mortality and survival for IPF and factors affecting these trends.
2. To identify the presence of ITB in observational studies examining associations between the use of antifibrotic therapy and survival in people living with IPF and illustrate how ITB may affect the effect size estimates of those associations.
3. To examine the impact of long–term exposures to low–level concentrations of air pollution on lung function and progression–free survival in an Australian cohort of people living with IPF.
4. To provide the prevalence estimates over a broader range of comorbidities in an Australian cohort of people living with IPF and explore the impact of comorbidities on mortality.
5. To estimate the relative contribution of comorbidities to health–related quality of life (HRQoL) and examine the magnitude of the effects of the number and type of comorbidities on HRQoL of people living with IPF in Australia.
Thesis Outlines, Methods, Summary of Key Results:
This research thesis comprises of eight chapters in total, with Chapters 3–7 presenting each of the five key studies arising from this PhD project. Specifically, Chapter 1 provides a comprehensive background on the disease burden and key aspects of management of IPF relevant to this thesis. The chapter also highlights the specific contribution of each of the five key studies included in this thesis to bridge the substantial evidence gaps on factors influencing patient outcomes in IPF. Chapter 2 provides a summary of the methods used in this thesis, mainly focusing on study designs, data sources, study participants, and data collection.
Chapter 3 presents a systematic review and meta–analysis on mortality and survival trends for IPF, suggesting the age–standardised IPF mortality to range from ~0.5 to ~12 per 100,000 population worldwide since 2000. Additionally, the pooled 3–year and 5–year survival rates were 61.8% (95% confidence interval [CI] 58.7 to 64.9) and 45.6% (95% CI 41.5 to 49.7), respectively. There were promising results demonstrating an improvement in survival after 2010 which may be attributable to newly available antifibrotic therapy; however, the true effect of IPF–related antifibrotic therapy reported in observational studies, could be overestimated by ITB, which is further investigate in Chapter 4. This study has added to the evidence for summary estimates of the mortality and survival of IPF internationally that may help stimulate future studies to consider the issues related to surveillance, disease control, and development of new therapies.
Chapter 4 illustrates how ITB can affect effect size estimates of IPF–related antifibrotic therapy. Findings presented in this chapter suggests that the time–fixed method (hazard ratio [HR] 0.55, 95% CI 0.47 to 0.64) and exclusion method (HR 0.79, 95% CI 0.67 to 0.92) overestimated the effectiveness of antifibrotic therapy, in comparison with the time–dependent method (HR 0.93, 95% CI 0.79 to 1.09). This study adds to the evidence for addressing the influence of ITB in IPF studies and recommends appropriate methods to ensure the survival effects of various IPF treatments are estimated more precisely in future observational studies.
Chapter 5 provides a comprehensive assessment of the impact of air pollution on lung function and progression–free survival in Australians living with IPF, suggesting that living near a major road and increased fine particulate matter (<2.5µm, PM2.5) exposure were both associated with an increased rate of annual decline in diffusing capacity of the lungs for carbon monoxide (DLco), while there was no significant association observed with nitrogen dioxide (NO2). There was also no significant association between air pollution and progression–free survival. This study contributes important evidence for the detrimental effects of air pollution on lung function in people with IPF living at low–level concentrations of air pollution.
Chapter 6 explores the prevalence of comorbidities and related outcomes in an Australian cohort of IPF. This study demonstrated that nearly 90% (n=598) of participants had at least one comorbidity. Pulmonary hypertension was associated with an increased risk of mortality (HR 1.35, 95% CI 1.03–1.75). Obesity and asthma were associated with a decreased risk of mortality (for obesity: HR 0.72, 95% CI 0.58–0.89; for asthma: HR 0.56, 95% CI 0.42–0.76). Identification of key comorbidities in people living with IPF, with optimised management may ultimately lead to improved patient outcomes.
Chapter 7 examines the relative contribution of comorbidities to determine HRQoL in IPF, suggesting that comorbidities had a significant impact on HRQoL of people living with IPF, with markedly negative impacts on their health state utilities and physical health. This study adds important evidence and advocates for a holistic approach to the care of people with IPF including better managing their comorbidities which could lead to improved HRQoL.
Chapter 8 presents the conclusions of this thesis and highlights future directions for IPF research.
Conclusion: In conclusion, this thesis provides five key studies to improve our understanding of a selected set of factors influencing patient outcomes in an Australian cohort of people living with IPF. This will provide critical evidence for consideration in future studies, particular those related to the development of effective therapies and preventative interventions to manage IPF with the aims of improving health outcomes for people living with IPF.