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2016 Annual report Center of Expertise in Mycology A cooperation between Canisius Wilhelmina Hospital and Radboudumc (EMRC)

2016 Annual report Center of Expertise in Mycology Radboudumc/CWZ ‘The EMRC is an expert center appointed by the Netherlands Federation of University Medical Centers and by Stichting Top-Klinische Ziekenhuizen (STZ).’ 1. EMRC The Center of Expertise in Mycology Radboudumc/CWZ (EMRC) is an expert center appointed by the Netherlands Federation of University Medical Centers and by the Stichting Top-Klinische Ziekenhuizen (STZ) to offer highly specialized care for patients with complex fungal diseases. The EMRC incorporates experts from various medical specialities, including infectious diseases, pharmacology, respiratory medicine and medical microbiology, and is a joint center with the Expert Center Clinical Mycology team at Canisius Wilhelmina Hospital (CWZ). The EMRC can be consulted to help manage patients with fungal disease and patients can be referred to the expert center for specialized care. EMRC research focuses on fungal pathogens, antifungal drug pharma­ cology and fungal immunology, and ranges from molecular biology to public health epidemiology. The expert center organizes mycology courses for technicians and medical professionals and hosts an ESCMID observership facility for interested professionals from all over the world.


2016 Annual report Center of Expertise in Mycology

2. MDOM Once every two weeks a multidisciplinary meeting (MDOM: Multi Disciplinair Overleg Mycologie) is held to discuss the management of patients with fungal diseases. The meeting involves experts in mycology from various specialties including medical microbiology, infectious diseases, respiratory medicine and pharmacology. Patient cases admitted to the Radboud University Medical Center and Canisius Wilhelmina Hospital are discussed, but also patients with fungal diseases from other hospitals are discussed through video conferencing.

3. Mycology reference laboratory The EMRC offers reference tests for diagnosis of fungal diseases including various biomarkers, identification, in vitro susceptibility testing and molecular typing; plasma concentrations of antifungal agents in a wide variety of matrices and immunological tests to map the immune status of the patient that suffers from fungal disease. These tests stratify patients into categories that help to provide tailored treatment. The center of expertise performs Aspergillus resistance surveillance in collaboration with the national centers for infectious disease prevention and control (Cib) and several Dutch hospitals. In addition this center coordinates the international quality control scheme for analytical testing of antifungal drugs.

4. News desk • A national newspaper NRC has published an article on the study performed by the Dutch-Belgian Mycosis Study Group (DB-MSG) initiated and coordinated by the EMRC on influenza associated aspergillosis [Am J Resp Crit Care Med 2017; [Epub April 7th]. Young people without an apparent immunodeficiency dying in the recent flu-season of invasive aspergillosis is alarming. The EMRC has carefully brought this news to the national and international community and has taken responsibility to coordinate this with the RIVM to take further action. This has also been communicated in an article in ‘Medisch Contact’ to increase awareness of this emerging problem. EMRC also disseminated in this way the possibility to consult the EMRC for difficult mycological problems in the Netherlands via MDOM. • EMRC was consulted to help treat a bottlenose dolphin who suffered from invasive pulmonary aspergillosis due to an azole-resistant A. fumigatus. In collaboration with the veterinarian the dolphin


2016 Annual report Center of Expertise in Mycology

was successfully treated with high dose posaconazole [Med Mycol Case Rep 2017;16:16-19]. • Dutch radio and television covered a story on new sampling strategies using dried blood spot analyses to allow remote sampling of antifungal drugs. We investigated a novel sampling method to draw blood for the purpose of concentration measurement to individualize drug dosing. This method has various advantages over the current ‘golden standard’: the vena puncture. Patients can perform the sampling themselves by means of a simple finger prick which can be performed at home after which it is send to the laboratory by regular mail. Patients can decide for the best possible sampling moment, that less interferes with daily activities such as school, work or leisure activities. In the setting of research it allows for full pharmacokinetic profiling of patients in the outpatient setting. • An international expert meeting on the management of fungal keratitis, organized by EMRC, was held in November 2016, and supported by the Royal Netherlands Academy of Arts and Sciences (KNAW). Experts from 11 countries and from various fields including ophthalmology, microbiology, infectious diseases and pharmacology discussed various challenges in the epidemiology, diagnosis and management of fungal keratitis working towards care pathways and a research agenda.

Paul Verweij and Paulien Bunskoek with the successfully treated dolphin


2016 Annual report Center of Expertise in Mycology

5. Dutch-Belgian Mycosis Study Group (DB-MSG) and Netherlands Centre for One Health (NCOH) Severe infections caused by fungal pathogens continue to be a challenge: influenza-associated aspergillosis with high mortality in young people, fungal keratitis due to Fusarium with risk of permanent visual loss, and the newly recognized Candida auris sepsis with high mortality are just a few examples from 2016. Moreover, antimicrobial resistance is not only emerging in bacteria but also in fungi. Three relevant clinical examples are azole-resistance in Aspergillus fumigatus, multidrug resistance in Fusarium which causes fungal keratitis and the emergence of Candida auris. A network has been initiated by the EMRC to coordinate knowledge into improved prediction, detection, prevention, and control strategies. The Dutch-Belgian Mycosis Study Group (DB-MSG) is a network that includes all academic hospitals in the Netherlands and four hospitals in Belgium. This collaboration offers the possibility to recruit a sufficient number of patients to perform high quality clinical trials, to initiate funding possibilities for mycology research which is virtually lacking, and to serve as a think tank and watchdog for medical mycology. Similar to antibacterial agents, antifungal compounds are used for various applications including crop protection, material preservation and treatment of fungal disease in animals and humans. Fungal resistance is an increasing concern in A. fumigatus and a problem that requires an integrated approach from a one-health perspective. The EMRC will coordinate fundamental, translational, clinical and applied One Health research in antifungal drug resistance within NCOH-AMR in collaboration with partners from other themes within NCOH such as Wageningen University and Research (NCOH-SHF).

6. Educational activities • The EMRC aims to develop educational activities for medical professionals to increase the awareness of fungal disease. Following the observation of severe cases of invasive aspergillosis in association with influenza, a national expert meeting was held by the public health institute (RIVM) to discuss measures for following influenza seasons. These measures were communicated by the EMRC through round table meetings with relevant medical professions including intensive care physicians.


2016 Annual report Center of Expertise in Mycology

• In 2016 a successful international course was held on basic clinical mycology, which attracted participants from various European countries. Other ongoing activities include specialized mycology courses for technicians and the annual clinical mycology course for residents in medical microbiology. • The EMRC helps to support clinicians in the management of drug-drug interactions with antifungal drugs through the provision of a tool and app ( This tool helps in the decision making process to select the most optimal drug of choice and prevent unwanted side effects or suboptimal exposure. The app and tool are free of charge and updated weekly.

7. Publications Clinical mycology • Verweij PE, et al. Azole resistance in Aspergillus fumigatus: can we retain the clinical use of mold-active antifungal azoles? Clin Infect Dis 2016;62:362-8. • Chowdhary A, et al. Filamentous fungi in respiratory infections. What lies beyond aspergillosis and mucormycosis? PLoS Pathog. 2016;12:e1005491. • Kolwijck E, et al. Voriconazole-susceptible and voriconazole-resistant Aspergillus fumigatus coinfection. Am J Resp Crit Care Med 2016;193:927-9. • Al-Hatmi AM, et al. Fusarium: molecular diversity and intrinsic drug resistance. PLoS Pathog. 2016;12:e1005464. • Verweij PE, et al. In-host adaptation and acquired triazole resistance in Aspergillus fumigatus: a dilemma for clinical management. Lancet Infect Dis. 2016;16:e251-e260. Fungal Immunology • van de Veerdonk FL, et al. CBLB ubiquitin ligase: a major regulator of antifungal immunity. Nat Med. 2016;22:834-5. • Becker KL, et al. Th2 and Th9 responses in patients with chronic mucocutaneous candidiasis and hyper-IgE syndrome. Clin Exp Allergy. 2016;46:1564-1574. • Gresnigt MS, et al. Reducing hypoxia and inflammation during invasive pulmonary aspergillosis by targeting the Interleukin-1 receptor. Sci Rep. 2016;6:26490. • Toubiana J, et al. International STAT1 Gain-of-Function Study Group. Heterozygous STAT1 gain-of-function mutations underlie an unexpectedly broad clinical phenotype. Blood. 2016;127:3154-64. • Wang X, et al. When the fight against fungi goes wrong. PLoS Pathog. 2016; 12:e1005400. Pharmacology • Roger C, et al. Caspofungin population pharmacokinetics in critically ill patients undergoing continuous veno-venous haemofiltration or haemodiafiltration. Clin Pharmacokinet. 2016 [Dec 29 ahead of print]. • Agrawal S, et al. The role of the multidisciplinary team in antifungal stewardship. J Antimicrob Chemother. 2016;71(suppl 2):ii37-ii42. • Lempers VJ, et al. Does weight impact anidulafungin pharmacokinetics? Clin Pharmacokinet. 2016;55:1289-94. • Martial LC, et al. Dose reduction of caspofungin in intensive care unit patients with child pugh B will result in suboptimal exposure. Clin Pharmacokinet. 2016;55:723-33. • Lempers VJ, et al. Antifungal therapy: drug-drug interactions at your fingertips. J Antimicrob Chemother. 2016;71:285-9.


2016 Annual report Center of Expertise in Mycology

Bio Paul Verweij.

The main research interest of Paul Verweij is the management of invasive fungal diseases. The emergence of azole resistance in Aspergillus is another topic of interest which addresses the origin and epidemiology of resistance, and clinical management. Third topic is efficacy of antifungal agents in relation to pharmacodynamic and pharmacokinetic parameters using experimental models of fungal infection.

Bio Frank van de Veerdonk.

Van de Veerdonk’s research over the last five years has focussed on the primary immunodeficiencies (PIDs) chronic mucocutaneous candidiasis (CMC), hyper IgE Syndrome (HIES) and chronic granulomatous disease (CGD). These PIDs are all associated with fungal infections, and studying the antifungal host defence in these diseases has elucidated several new insights in immunology.

Bio Jacques Meis.

Jacques Meis investigates clinically important emerging resistant or newly emerging fungal pathogens. Examples of emerging fungi he has worked on in the past 5 years comprise Fusarium, filamentous basidiomycetes, Talaromyces spp., Cryptococcus spp., Candida auris and azole resistance in Aspergillus including cryptic species. In addition he has a special interest in the diagnosis and therapy of imported endemic mycoses into the Netherlands.

Bio Roger Brüggemann.

In recent years Roger Brüggemann has been responsible for translational pharmacological research on anti-infectives, with a specific focus on antifungal drugs and recently antibacterial drugs. Roger’s research involves understanding pharmacokinetic (PK) and pharmacodynamic (PD) behaviour and associated influencing factors with the goal to design better diagnostics and therapies for invasive aspergillosis, candidemia, and other infections.


2016 Annual report Center of Expertise in Mycology

8. Interesting links • Interviews of PhD student Lisa Martial regarding the dried blood spot assay. - - - (vanaf 04:35) • Interviews of Frank van de Veerdonk concerning influenza associated asper­gil­losis. NRC: Combinatie van schimmel en griep werd IC-patiënten fataal”. - een-griepseizoen-met-dodelijke-schimmelinfecties.htm • Interview of Frank van de Veerdonk and Paul Verweij concerning influenza-associated aspergillosis. Medisch Contact: “Een griepseizoen met dodelijke schimmelinfecties”. -

Contact Center of Expertise in Mycology Radboudumc/CWZ E T +31 (0)24 361 9041 W schimmelinfecties-radboudumc-cwz

Canisius Wilhelmina Ziekenhuis

Radboud universitair medisch centrum

2016 annual report center of expertise in mycology radboudumc cwz  

EMRC is a multidisciplinary expert center that aims to improve the care for patients with complex fungal diseases, perform and facilitate fu...