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Prieto Gaez, Miguel Dario

University of British Columbia

Patients with cystic fibrosis (CF) have an elevated lifetime risk of infection and disease caused by nontuberculous mycobacteria (NTM). Infection with NTM can be associated with faster decline in lung function for people living with CF. Diagnosis and treatment of pulmonary NTM disease (NTM-PD) remains challenging as there are no accurate estimates of the burden, there is no way to predict progression to disease and the therapeutic guidelines lack high quality evidence for recommendations. In this thesis, we began by estimating the overall burden of NTM infection and disease in the CF population through a systematic review of prevalence and incidence. We included all available data from registries and observational studies and found a pooled estimate of NTM infection point prevalence of 8%. We identified geographical region and sample size as determinants of heterogeneity in our analysis. Also, we found that estimates were more accurate for NTM infection caused by the Mycobacterium avium and Mycobacterium abscessus complexes individually. However, we could not identify other sources of heterogeneity due to the lack of primary reporting of microbial identification methods and screening approaches. Next, we explored the impact of host gene expression on the progression to pulmonary NTM disease (NTM-PD) in a cohort of patients with NTM infection (n = 42). We conducted an RNAseq experiment using whole blood close to the time of first NTM growth and conducted differential gene expression using DESeq2. Our results show that patients who progressed to NTM-PD had higher expression of genes that are associated with innate immunity and inflammation. These findings contrast with results of non-cystic fibrosis studies in humans that show decreased lymphocyte and immune responses in NTM-PD. However, the pro-inflammatory state of the CF lung and the higher bacterial burden observed in CF, could explain this contradictory result. Overall, in this biomarker discovery study, we identified several functional pathways that may play a role in progression to NTM-PD n the CF population, providing a basis for future biomarker discovery studies.

Text

2023-05-31

Attribution-NonCommercial-ShareAlike 4.0 International

http://hdl.handle.net/2429/81543

Experimental Medicine

University of British Columbia

UBCV

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