DISCUSSION
had pancreatic insufficiency and were colonized with P. aeruginosa to a larger extent which may indicate a more advanced lung disease in this group of patients. Interestingly, longitudinal studies reported a lower lung function at baseline and prior to the colonization with A. fumigatus compared to controls (9, 113). These may indicate that CF patients with advanced lung disease are more susceptible for colonization with A. fumigatus. On the other hand, an exaggerated and detrimental immune response has been reported in CF epithelial cells when they were exposed to A. fumigatus implying the potential pathogenicity of A.
fumigatus (93). Study I&II showed that within the same individual lung function was lower when the patient was colonized compared to when not being colonized. In this analysis, patients were their own control in order to reduce the impact of potential confounders.
Additionally, in study I we adjusted for potential confounders that may impact lung disease severity such as colonization with P. aeruginosa, CFTR genotype, age and treatment with IV antibiotic courses as a surrogate for lung exacerbation rates. It could also be argued that the decline in lung function was induced by other factors. CF is a complicated disease, and a number of factors may impact the trajectory of the lung disease such as patients’ adherence, colonization with non-tuberculosis mycobacteria or other bacteria, environmental factors and modifier genes.
Yeast has traditionally been considered as an innocent colonizer and its potential impact on CF lung progression is hardly studied. Study I demonstrated a negative association between colonization with C. albicans and C. dubliniensis and lung function. The decline in lung function was most pronounced in patients colonized C. dubliniensis, which was unexpected.
Again, the causality cannot be determined in the current study. To the best of our knowledge our study is the first to highlight the potential virulence associated with C. dubliniensis colonization. A former study pointed out that the prevalence of C. dubliniensis in CF airways was as high as the prevalence in the oral cavity of HIV infected patients (145). The rationale behind this similarity have not been explained yet but indicates similar defects in host immunity against C. dubliniensis. Thus, studies on the antifungal immune response induced by C. dubliniensis persistence in the CF airways are warranted.
The identification of Candida species from the airways does not require treatment according to Clinical practice guidelines for the management of Candidiasis “Growth of Candida from respiratory secretions usually indicates colonization and rarely requires treatment with antifungal therapy (strong recommendation; moderate-quality evidence” (169). A case series presented eleven patients with a history of chronic sputum production and finding of Candida species from the respiratory tract showed a symptomatic improvement with antifungal
was recommended in patients with a history of mucus and suggested reevaluating the clinical practice guidelines for the management of Candidiasis. The results in study I, together with two former studies, raised the potential virulence of Candida species (10, 11). In 2016, Chotirmall reviewed these two studies and encouraged future therapeutic trials (171). The pros and cons of treatment need to be studied more in-depth. Importantly, there is a strong clinical need to obtain more information on the indications for treatment, the choice of antifungal agents, the route of administration, the treatment duration and most importantly the goal of treatment.
The fungal- fungal and fungal- bacterial interactions in CF is not fully understood. Study I demonstrated that patients who were co-colonized with C. albicans, C. dubliniensis, A.
fumigatus and P. aeruginosa simultaneously exhibited a more pronounced decline in lung function than when they were colonized with each species individually. Similarly, several studies reported that co-colonization with A. fumigatus and P. aeruginosa was associated with a distinct deterioration in lung function (7, 111, 172). The interaction between P.
aeruginosa and A. fumigatus in CF airways has been studied with conflicting results. In vitro studies, both mutual inhibitory and promotive interactions have been reported (173-175). In a review article the authors concluded that P. aeruginosa impede the growth of fungi by producing toxic peptides and inhibiting iron uptake and that fungi inhibit P. aeruginosa by their products (175). To resolve this issue, it is essential to perform additional studies on the pathophysiology of fungi in the CF airways, the host response, fungal-fungal as well as fungal-bacterial interactions.
In study II we evaluated the role of colonization as well as the eradication of A. fumigatus.
Patients who eradicate A. fumigatus and continued to have negative cultures for A. fumigatus the following two years displayed a higher lung function compared to patients who continued to recover A. fumigatus for two or three years in a row. Again, this study cannot reveal if the better lung function observed in the eradication group is a consequence or a cause. To answer this question a prospective and preferably randomized clinical trial is required.
Identifying CF patients at risk to develop fungal colonization may help clinicians to monitor these patients more closely. Study III, which had a prospective design, showed that inhaled antibiotics was strongly associated with chronic colonization with A. fumigatus. Inhaled antibiotics have also been presented as risk factor in former retrospective studies (120, 176, 177). Inhaled antibiotics is recommended as maintenance therapy in CF patients chronically colonized with P. aeruginosa and widely used as established treatment in the CF care. Study III highlighted the disadvantage of treatment with inhaled antibiotics and the need to consider
the pros and cons of such treatment. Moreover, in CF patients treated with inhaled antibiotics, a careful monitoring of the fungal outcomes in the respiratory tracts is needed.
CFTR modulators are an effective treatment in CF (71, 72, 178). Despite the improvement in clinical outcomes and reduction in the antibacterial and antifungal treatment burden achieved one year after treatment with lumacaftor/ivacaftor, our study could not show a significant reduction in key bacterial and fungal species, i.e., P. aeruginosa and A. fumigatus.
Other less common bacteria such as S. maltophilia and Achromobacter species, multi drug resistant opportunistic bacteria considering pathogenic in CF, were less prevalent one year after the initiation of lumacaftor/ivacaftor. However, the result should be interpreted with caution because of the low prevalence of these two bacteria in our cohort. Unexpectedly, C.
albicans, Penicillium species and S. apiospermum became more prevalent during treatment.
The role of these fungi is still unclear. We believe that monitoring patients receiving CFTR modulators regarding fungal and bacterial outcomes is needed considering the significant reduction in the bacterial and fungal suppressive treatment in this group of patients.
8.3 METHODOLOGICAL CONSIDERATIONS AND LIMITATIONS OF THE