Group and collaboration

Collaboration: Paul Verweij, Frank van de Veerdonk, Roger Bruggeman (Centre of Expertise in Mycology Radboudumc/CWZ (ESRC))

PhD Student: Nico Janssen

Project description

Invasive fungal infections are clinically increasingly problematic due to several factors. Firstly, the incidence of fungal infections has increased over the years. In part, this is due to the growing number of patients with immunodeficiencies, e.g. due to immunosuppressive drugs or infection with the human immunodeficiency virus (HIV). Furthermore, patients with certain congenital or otherwise acquired immunodeficiencies are more susceptible to fungal infections. However, some patients with fungal infections do not have a clearly discernible immune defect or this defect may only be discovered after specialized laboratory testing (e.g. in patients with chronic pulmonary aspergillosis (CPA), and influenza-associated aspergillosis (IAA)). Most of these invasive fungal infections are still associated with significant morbidity and mortality.

Secondly, antifungal resistance is on the rise. Because relatively recently new and less toxic antifungal drugs have been developed, the use of antifungals for prophylaxis, empirical and directed therapy has increased with the unwanted side effect of increasing resistance and selection of (intrinsically) less susceptible fungi. Also, the use of antifungals in agriculture has led to increasing numbers of resistant isolates obtained from the environment. Because of the limited number of classes of antifungals, this development impedes treatment.

To optimize clinical care for patients with invasive fungal infections and to address these issues, the Center of Expertise in Mycology Radboudumc/CWZ (EMRC) was established. In this Center, patients with difficult-to-treat fungal infections can be enrolled by their treating physician from anywhere in the Netherlands to be discussed in our multidisciplinary meeting (once every two weeks) and are seen in the outpatient clinic. In this project, different fungal infections will be addressed, but the main focus will be on CPA (due to the highest number of patients discussed and seen suffering from this disease) and influenza-associated aspergillosis.

In this project, we aim to:

1. Inventory which fungal infections are discussed in the EMRC multidisciplinary meeting, reflecting the mycological problems posed most frequently to clinicians in the Netherlands;
2. Determine the prevalence and incidence of antifungal resistance in clinical isolates from patients with invasive fungal diseases and to identify clinical factors associated with resistant pathogens (e.g., occupational exposures, a job in the agricultural sector); also, to determine the effect of antifungal resistance on clinical outcome of these infections;
3. Characterize immunological defects in patients with invasive fungal infections and no known underlying immune deficiencies by evaluating the cytokine response, reactive oxygen species production and leukocyte killing capacity with regard to fungi; this will probably pertain mostly to CPA patients (in which no clear underlying immune defect has been described as of yet, predisposing patients to the opportunistic pathogenAspergillus);
4. Participate in the POSA FLU trial, in which prophylactic posaconazol (an antifungal agent) is evaluated for its ability to prevent IAA in patients admitted to the intensive care unit with a severe influenza infection; in this study, we will also evaluate genetic factors predisposing patients to develop IAA and genes important in determining the serum concentration of posaconazole (pharmacogenetics).