Aspergillus and allergic bronchopulmonary aspergillosis in children and young people with cystic fibrosis

Background Aspergillus infection is common in children and young people with cystic fibrosis (CF), yet there is poor understanding of its significance and long-term impact, leading to variable diagnosis and treatment. The overall aim of the research presented in this thesis is to gain a greater understanding of Aspergillus infection in children and young people with CF, specifically to evaluate clinical predictors and long-term outcomes, and to consider future perspectives. Objectives The work presented in this thesis, focussing on Aspergillus infection in children and young people (0 to <18 years old) with CF, aims to 1) provide a comprehensive literature review, 2) assess the long-term outcomes of infection, 3) identify clinical predictors for allergic bronchopulmonary aspergillosis (ABPA), 4) establish whether Aspergillus infection is a risk factor for severe coronavirus disease 2019 (COVID-19), 5) provide a perspective on factors behind the early termination of the cASPerCF randomised controlled trial, and to 6) provide a commentary on future directions. Methods Three observational studies are presented in this thesis. Two longitudinal cohort studies were undertaken with anonymised UK CF Registry (UKCFR) data from 2009 to 2019 from patients aged 8-17 years in 2009-2010 (n=1675 and n=1612). The main longitudinal analyses used were linear mixed-effects models and complementary log-log regression models. The third observational study, a European CF Society Patient Registry (ECFSPR) study (n=1099), was completed using anonymised data collected from 22 countries from 2019-2021. Logistic regression models were used to assess the association between pre-existing Aspergillus colonization and/or ABPA and COVID-19 severity. Results The longitudinal effects study UKCFR shows that ABPA was significantly associated with increased decline in lung function, whereas Aspergillus colonization was not associated with increased decline in lung function in children with CF. The clinical predictors for ABPA UKCFR study demonstrates an association of lower lung function, Aspergillus colonization and Pseudomonas aeruginosa infection with subsequent development of ABPA, whereas there was a negative association between ivacaftor treatment and development of ABPA. The ECFSPR study identified an association between pre-existing Aspergillus colonization and ABPA and increased COVID-19 associated hospitalization. Conclusions The results demonstrate the importance of Aspergillus infection in children and young people with CF. ABPA, but not Aspergillus colonization, worsens long-term lung function decline. Key clinical predictors for ABPA were found and for the first time a protective association of ivacaftor and ABPA was shown. Pre-existing Aspergillus colonization and ABPA is a risk factor for COVID-19 associated hospitalisation.