Bradley Quon

The landscape of Cystic fibrosis (CF) is changing. Historically, it was a disease mainly affecting children, but now there are more adults living with CF with many additional health problems and evolving needs. The thesis aims to assess the impact and burden of CF in British Columbia (BC).The Canadian CF Registry (CCFR) and multiple administrative data sources were utilized to evaluate an annual, open provincial CF cohort from 2000 to 2017. Epidemiological and clinical trends were summarized. The Global Burden of Disease methodology was used to quantify the overall burden of CF attributed to lung impairment, complications/comorbidities, and mortality. Health care resource use and costs were summarized. A fixed CF cohort was followed from 2009 to 2017 to evaluate characteristics associated with frequent high-cost CF users.The incidence rate of CF has slightly increased (average annual percentage change : +2.9%, 95% CI: -0.1 to +5.9) while the birth incidence rate declined (AAPC: -2.4%, 95% CI: -4.2% to -0.5%) since 2000. The prevalence rate has grown over time (AAPC: +2.1%, 95% CI: +1.7% to +2.5%). Survival outcomes have improved and more growth in the prevalence of CF (up to 50%), specifically in the adult CF population is expected. The clinical status has also improved with less occurrence of severe or advanced lung disease and an overall improvement in lung function over time. The total burden of CF has declined over time (Disability Adjusted Life Year rate: -12.3%, 95% CI: -2.7% to -20.9%) primarily due to a reduction in premature mortality. Despite this progress, morbidity due to other CF-related complications and comorbidities has been slowly rising (AAPC: +1.0%, 95% CI: -1.4% to +3.5%) and disproportionately affects adults. Health care resource use and inflation-adjusted costs have also increased during this time, driven by the rising costs of adult care and medications. Frequent high-cost users represent 17% of the cohort but accounted for 32% to 45% of the overall total health care costs. Moderate-to-severe lung impairment, transplantation, liver cirrhosis with portal hypertension, and female sex were the main factors associated with frequent high-costing CF individuals.

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Pulmonary exacerbations (PEx) are common in cystic fibrosis (CF) and are significant risk factors for lung disease progression. PEx are often diagnosed when a patient presents to clinic with increased respiratory symptoms and decreased lung function. However, changes can sometimes be subtle or the patient can be a poor perceiver of their symptoms, potentially leading to missed or delayed diagnosis of PEx. Blood-based biomarkers reflective of the host immune response and inflammatory activity have the potential to predict PEx in CF. However, due to the poorly defined pathophysiology of PEx, individual candidate biomarkers are unlikely to capture the full spectrum of immune and inflammatory responses in CF. The central hypothesis of this thesis is that by profiling molecules (protein, transcripts, and modifier genes) in blood with unbiased high-throughput ‘omics’ technologies, we can identify blood-based biomarkers to predict PEx risk and PEx-related treatment outcomes in CF. First, I assessed changes in blood proteins in response to IV antibiotic treatment for PEx. Early changes in IGFR2 were associated with symptom improvement by the end of treatment, suggesting its potential to act as a predictive marker of symptomatic treatment response in CF PEx. I further identified blood biomarker candidates (genes and proteins) from CF individuals with paired stable and PEx samples. Based on these candidates, a 16-gene panel and a 9-protein panel were developed predictive of imminent PEx risk (AUCs of 0.88 and 0.83, respectively). I then evaluated blood proteins to predict azithromycin treatment response in CF individuals. Early changes in serum calprotectin were predictive of PEx risk by day 168, indicating that serum calprotectin represents a promising predictive biomarker to identify individuals who derive benefit from azithromycin treatment. Finally, I investigated genetic modifiers of PEx risk in pre-school children with CF and identified the SLC9A3 variant as significantly associated with the risk of PEx. In summary, I showed that blood-based biomarkers could reliably predict response to treatment and PEx risk in CF individuals, which allows for more personalized monitoring and earlier diagnosis and treatment of CF PEx.

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