Fungal colonization and infection in cystic fibrosis : prevalence, consequences and intervention

Abstract: Background: Cystic fibrosis (CF) is an inherited progressive disease affecting multiple organs. The main cause of death in CF is related to the respiratory complications. Inflammation and infection, triggered by colonizing microorganisms in CF airways, cause structural lung damage resulting in respiratory failure and death. Isolation of bacteria and fungi from the CF respiratory tract is common. While the role of bacteria has been studied extensively, fungi have received less attention and their impact on the CF progressive lung disease has not been established yet. In this thesis we aimed to thoroughly study the fungal epidemiology, consequences and parameters that may impact the fungal outcomes in CF. Methods: Study I and II were 16-year longitudinal retrospective single center studies. Study I consisted of two parts. The descriptive part of the study encompassed data on the fungal prevalence, diversity and variation over time. In the second part, the impact of the most common fungi; C. albicans, C. dubliniensis and A. fumigatus on lung function was assessed using linear mix model. In study II, we determined the impact of A. fumigatus colonization and eradication on lung function. The impact of the first acquisition of A. fumigatus on the annual predicted decline in lung function was analyzed by a using linear mixed model and the natural logarithm of the percentage of predicted forced expiratory volume in 1 second (ppFEV1). The impact of colonization and eradication was analyzed by calculating the ratios of ppFEV1 for a specific condition divided with ppFEV1 of the compared condition. Study III was a prospective one-year multicenter study. A multivariate regression analysis was used to identify risk factors associated with chronic colonization with A. fumigatus. Study IV was also a prospective multicenter study aimed to determine the impact of lumacaftor/ivacaftor on the microbiological outcomes as well as on a number of clinical parameters. Linear models were used for continuous outcomes, logistic models for dichotomous variable and Poisson models for count variables. Results: The three most common fungi were C. albicans (63%), A. fumigatus (22%) and C. dubliniensis (11%). During the study period (16 years), the fungal prevalence and diversity increased. Interestingly, persistent colonization with C. albicans, A. fumigatus or C. dubliniensis for three consecutive years was associated with a significant decline in lung function with 2.6%, 4.9% and 7.6% decrease in ppFEV1 respectively. Regarding A. fumigatus, the most common mold, the annual predicted decline in lung function increased from –1.8% per year to –2.3% after the first acquisition. Furthermore, within the same individual lung function was 4.3% and 7.9% lower when A. fumigatus persisted for two and three consecutive years. Patients who eradicated A. fumigatus, with or without treatment, and remained free from A. fumigatus in the respiratory cultures for two consecutive years displayed 9.9% and 14.5% higher lung function compared with patients who continued to culture A. fumigatus two and three years in a row. Inhaled antibiotics was a risk factor for chronic colonization with A. fumigatus with 11% increasing risk for each month of use of inhaled antibiotics. Treatment with lumacaftor/ivacaftor, improved lung function, nutrition status and inflammatory parameters. Furthermore, antibiotic and antifungal treatment decreased after initiation of the treatment with lumacaftor/ivacaftor. However, the key microorganisms such as P. aeruginosa, S. aureus and A. fumigatus did not change with lumacaftor/ ivacaftor treatment one year after the onset of the treatment. Other less common bacteria such as Streptococcus pneumoniae and Stenotrophomonas maltophilia became less common while C. albicans, Penicillium species and Scedosporium apiospermum were more prevalent. Conclusion: The results from our studies highlighted the potential impact of fungi in the course of CF lung disease. Unexpectedly, a negative association between Candida species, which have been considered as harmless colonizer, and lung function was observed. Because of the study design, causality cannot be determined. Despite the improvement in cardinal clinical outcomes after introducing lumacaftor/ivacaftor, it did not impact the prevalence of A. fumigatus or other key pathogens in CF in short-term emphasizing the importance to continue monitoring patients treated with CFTR modulators with regards to microbiological outcomes.