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Dong, Kang

University of British Columbia

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.

Text

2023-10-31

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/82821

Experimental Medicine

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/